No retraction, correction or concern found when last checked on Oct 17, 2026.

Molecular and cellular mechanisms of pulmonary fibrosis

Nevins W Todd, Irina G Luzina, Sergei P Atamas

Fibrogenesis & Tissue Repair · 2012 · Review

Abstract

Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Pulmonary fibrosis is a chronic lung disease characterized pathologically by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture, and additionally characterized by recognizable clinical, physiologic, and radiographic findings. Though some descriptions of fibrous diseases of the lungs can be found as early as the 5th century BC by Hippocrates, more modern descriptions of pulmonary fibrosis occurred in the early part of the 20th century with reports by Hamman and Rich of four patients with rapidly progressive diffuse interstitial fibrosis of the lungs. Although the prognosis of patients with diffuse pulmonary fibrosis is poor, it was subsequently realized that many patients did not have the extremely rapid deteriorating course that was described by Hamman and Rich. With further pathologic analysis, several distinct types of pulmonary fibrosis were described, and the terms diffuse fibrosing alveolitis, diffuse interstitial fibrosis, and idiopathic pulmonary fibrosis (IPF) were introduced to describe a more insidious, yet still debilitating form of chronic pulmonary fibrosis. Currently, IPF is considered the most common and severe form of pulmonary fibrosis, with a disheartening median survival of approximately three years, with no proven effective therapy, and with lung transplantation remaining the only viable intervention in end-stage disease.

2The pathologic findings in pulmonary fibrosis (excessive accumulation of ECM and remodeling of the lung architecture) are a consequence of disturbances in two physiologically balanced processes: proliferation and apoptosis of fibroblasts, and accumulation and breakdown of ECM. When the normal balance between ECM deposition and turnover is shifted toward deposition or away from breakdown, excessive ECM accumulates. When the balance between fibroblast proliferation and apoptosis is shifted toward accelerated proliferation or slowed apoptosis, fibroblasts - the primary ECM producers - accumulate. Several possible origins of ECM-producing mesenchymal cells have been described, and have included accumulation of resident lung fibroblasts, homing and fibroblastic differentiation of bone marrow-derived cells such as circulating fibrocytes or monocytes, or epithelial-mesenchymal transition (EMT). Independent of the source of fibroblast expansion in the lungs (resident or systemic), it seems agreed upon that the ultimate effector cell in pulmonary fibrosis is the myofibroblast, a differentiated fibroblast which has contractile properties similar to smooth muscle cells, and which is characterized by the presence of alpha-smooth muscle actin (α-SMA).

3In addition to altered mesenchymal cells, abnormalities of the alveolar epithelium in patients with pulmonary fibrosis have been noted from the earliest descriptions of the disease process. Loss of normal type I alveolar epithelium and replacement by hyperplastic type II cells or bronchiolar cuboidal cells is a consistent finding in patients with IPF. In addition to these observations, more recent mechanistic studies have focused on the interplay, or cross-talk, between damaged epithelial cells and lung mesenchymal cells. This epithelial-mesenchymal interplay lends support to a key theme in pulmonary fibrosis, in which altered lung mesenchymal cells coupled with alveolar epithelial cell injury result in the accumulation of ECM and remodeling of the lung architecture.

4An extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years, and Figure 1 shows the accelerating pace of research in this field over the past two decades. Although the precise mechanisms that drive the development of fibrosis in most patients remain incompletely understood, three broad areas (as seen in Figure 2) have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: (1) inflammation and immune mechanisms: the role of acute and chronic inflammation driven by cytokines, cells or cell surface molecules; (2) oxidative stress and oxidative signaling: the role of reactive oxygen species; and (3) a procoagulant milieu in the lung: the role of the coagulation proteinases and their tissue receptors. Each of these processes will be considered separately to facilitate clarity, but we hope the reader will appreciate the significant interplay that may occur amongst these pathways in patients with pulmonary fibrosis.

Inflammation and immune mechanisms

5From the earliest descriptions of patients with pulmonary fibrosis, cellular inflammation in the lung parenchyma has been a consistent pathologic finding. Histologic analysis has shown varied accumulations of lymphocytes, macrophages, plasma cells, eosinophils and neutrophils, and the presence of lymphoid follicles with germinal centers has been observed in many patients in the lung interstitium. The initial terms ‘diffuse fibrosing alveolitis’ and ‘cryptogenic fibrosing alveolitis’ were used as a reflection of the inflammatory component of the pathologic process in pulmonary fibrosis, and most patients with usual interstitial pneumonia (UIP), the pathologic hallmark of IPF, will manifest a mild to moderate degree of chronic cellular inflammation in the lung.

6Over the past 15 to 20 years, however, the role of inflammation has been questioned, and the hypothesis has been put forward that active cellular lung inflammation is not a major feature or requirement for the development of IPF. Recent pathologic descriptions of patients with UIP have emphasized the epithelial, mesenchymal, and ECM abnormalities while de-emphasizing the cellular inflammatory features. This paradigm has thus shifted emphasis in IPF towards a process of epithelial cell injury coupled with exaggerated wound healing, and inflammation has been relegated to a mechanistically less important and bystander role in the fibrotic process. Probably the major supporting argument for inflammation playing a non-causal role stems from the observation that anti-inflammatory therapies, particularly corticosteroids, have been uniformly ineffective in improving pulmonary function or survival in patients with IPF.

7However, even though the role of inflammation in IPF has been recently de-emphasized, the original findings of cellular inflammation in the lung have been supplemented with an extensive accumulation of scientific studies which have implicated numerous inflammation-related cytokines and cell surface molecules in profibrotic mechanisms. It is also important to note that resistance to corticosteroids does not necessarily indicate or equate with a lack of inflammatory involvement, as there are several well-established diseases in which inflammation is clearly accepted to be the predominant underlying mechanism, but in which traditional anti-inflammatory therapy has been poorly effective. Stemming from the observations on inflammatory cells, cytokines, chemokines, and cell surface molecules, the inflammation hypothesis has dominated the field of pulmonary fibrosis for nearly four decades, and IPF continues to be viewed by many authorities as a chronic inflammatory disease of the lung parenchyma.

8It is difficult if not impossible to comprehensively review the evidence in support of the role of inflammation in pulmonary fibrosis. Such evidence is abundant from mechanistic studies in cell culture, experimental research in animals, and observations in human patients. Below, we provide an overview of such evidence and lines of thought, in hopes to provide a springboard for continued independent studies in the field.

Role of cytokines

9Over the past 40 years of research into mechanisms of pulmonary fibrosis, an immense amount of literature has described alterations in cytokine expression and function in animals and patients with pulmonary fibrosis. Most of the findings have described a propensity for a variety of cytokines to promote and enhance the fibrotic process, whereas in some instances, up-regulation of a particular cytokine is associated with inhibition of fibrosis. In Table 1, we have listed the cytokines which we currently interpret as most relevant to mechanisms of pulmonary fibrosis, and have summarized the most pertinent in vitro, animal model, and human trial data for each cytokine. The potential sources of these cytokines in the lung are numerous, and include resident or systemic epithelial, mesenchymal, or inflammatory cells (T lymphocytes, B lymphocytes, macrophages, neutrophils, eosinophils, and platelets).

10There are additional cytokines (for example, TGF-α, IFN-α, fibroblastic growth factor, IL-6) not included in Table 1 which have been studied in pulmonary fibrosis, but in our judgement, their regulatory role in fibrosis has been less clearly defined, and the high level of complexity of their regulation does not allow for clear designation as profibrotic or antifibrotic. Additionally, many small molecules (for example, serotonin, endothelin, leptin, lysophosphatidic acid, histamine, angiotensin) have also been studied in pulmonary fibrosis, but likewise their roles in fibrosis are less clearly defined at present.

T lymphocytes

11A consistent finding in most fibrotic diseases of the lungs is the presence of T lymphocytes, one of the major inflammatory cell types. Mechanistic studies regarding the role of T cells in pulmonary fibrosis have been performed in animals which lacked T lymphocytes or had selective attraction of T lymphocytes to the lungs. Most of these studies used bleomycin as a model of lung injury, in which fibrosis is preceded by pulmonary inflammation.

12In athymic mice lacking T cells, administration of bleomycin resulted in less fibroblast proliferation and less ECM accumulation compared to wild-type mice. Mice whose T lymphocytes lacked CD28, a central co-stimulatory cell surface molecule necessary for full T cell activation, showed markedly attenuated fibrosis following exposure to bleomycin, and transferring CD28-positive T lymphocytes into these CD28-deficient animals restored the fibrotic response to bleomycin. In mice systemically depleted of T lymphocytes, exposure to bleomycin resulted in less collagen accumulation and increased survival compared with controls. In our mouse model in which selective attraction of T lymphocytes to the lung was achieved by over-expressing human CCL18 (PARC), a prolonged infiltration of T cells occurred, moderate collagen accumulation developed, and systemic depletion of T cells prevented the collagen accumulation despite the continuous expression of CCL18, suggesting that T cells were indeed the driving force of fibrosis. It should be noted that although human CCL18 appears to be fully functional in mice in cell culture and in vivo, the chemokine CCL18 has not been definitely identified in mice.

13There may be a complex interplay among subtypes of T lymphocytes in pulmonary fibrosis, particularly between T effector and T regulatory cells. T regulatory lymphocytes (T regs) are profibrotic and immunosuppressive, and exert their profibrotic actions primarily via transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). In an animal model of silica-induced pulmonary fibrosis, T regs were recruited to the lungs, caused fibroblast proliferation, had increased expression of TGF-β1 and PDGF, and caused pulmonary fibrosis upon transfer into silica-unexposed animals. In silica-exposed animals depleted of T regs, pulmonary fibrosis occurred, but increased numbers of CD4+ T effectors were present. These T effectors caused fibroblast proliferation, caused pulmonary fibrosis upon transfer into T reg deficient (but not T reg competent) animals, and neutralizing antibody against these T effectors eliminated collagen accumulation. These results suggest a complex interplay between lymphocyte subsets, with T regulatory cells themselves acting profibrotically, and the role of CD4+ T effector cells depending on the presence or absence of T regulatory cell competence.

14Observational studies in humans link T cell infiltration to fibrosis. In patients with IPF, the presence of T cells within lung tissue and BAL of patients has been consistently observed. These T cells are activated and antigen experienced, and characterization has shown that both CD4+ and CD8+ cells are present, with the suggestion that CD8+ T cells represent the majority. Increased numbers of CD8+ T cells in lung tissue from IPF patients was associated with worse pulmonary outcomes, and in BAL fluid, higher CD4/CD8 ratios correlated with an improved clinical response to anti-inflammatory therapy. In patients with IPF, well-organized lymph-node-like structures with features of ‘lymphoid neogenesis’ are present, which are composed of T cells expressing CD40L, B cells, and mature dendritic cells. These T and B cells are activated, but not proliferating, and most are CD45RO + indicative of a memory phenotype. These findings support the concept that organized lymphoid tissue can persist in the lung and contribute to chronic inflammation even in the absence of cellular proliferation.

15In other forms of interstitial pneumonia, accumulation of T cells has been shown in BAL from patients with scleroderma, rheumatoid arthritis, and polymyositis/dermatomyositis. In general, it appears that although both CD4+ and CD8+ T cells are associated with pulmonary fibrosis, CD8+ T cells appear to be associated with a worse prognosis. In patients with sarcoidosis, beryliosis, rheumatoid arthritis, and hypersensitivity pneumonitis, CD4+ T cells were predominant in the lungs, consistent with the better prognosis of these diseases compared with IPF.

16Thus, there are numerous observations in animal models and in patients which describe an association of pulmonary fibrosis with T lymphocytic infiltration. The preponderance of evidence suggests that such association is reflective of T cell profibrotic action, but depending on cell phenotype and the nature of the pulmonary milieu, T cells may promote or diminish the pulmonary fibrotic process. Two broad mechanisms by which T cells may influence the fibrotic process include production of Th-1 or Th-2 cytokines (as seen in Table 1) and cell surface molecule interactions with epithelial or mesenchymal cells, which will be described subsequently below.

Macrophages

17Macrophages constitute the majority of cells recovered from BAL of normal individuals, and have essential roles in phagocytosis, innate and adaptive immunity, and surfactant homeostasis. A pathogenic role for macrophages in pulmonary fibrosis has been postulated for many years, and described mechanisms have included overexpression of reactive oxygen species, proteinase-activated receptors, Fas ligand, and profibrotic cytokines.

18One feature regarding a potential role of macrophages in pulmonary fibrosis relates to the concept of alternative activation. Classical activation of macrophages is induced by interferon-γ, and is characterized by macrophage expression of IL-1β, IL-6, TNF-α, and nitric oxide. Alternative activation of macrophages is induced most notably by the Th-2 cytokines IL-4 and IL-13, and is characterized by macrophage expression of mannose receptor-1 (CD206), arginase-1, the lectin-binding protein Ym1, the resistin-like protein Fizz1, and the chemokine CCL18.

19Several animal models of pulmonary fibrosis have demonstrated that alveolar macrophages (AM) display a phenotype consistent with alternative activation. In the silica-induced model, mRNA expression of Ym1 in the lung increased significantly in wild-type mice consistent with alternative activation, but did not increase in silica-exposed IL-4R null mice, indicating that a Th-2 milieu was necessary for alternative activation and fibrosis. In the herpes virus-induced and transgenic TGF-β models of fibrosis, AM accumulated in the lungs and expressed the alternative activation markers Ym1/2, Fizz1 and arginase-1.

20Likewise, in patients with pulmonary fibrosis, the preponderance of data suggests that AM display an alternatively activated phenotype. In patients with IPF compared to healthy controls, AM showed increased expression of CD206, and spontaneously generated higher levels of the proinflammatory cytokines CCL17, CCL18, and CCL22. Co-culture of cell supernatants from alternatively activated AM of IPF patients with normal lung fibroblasts generated higher amounts of collagen production than supernatants from AM of healthy controls. In patients with IPF, expression of arginase-1 was increased compared with healthy controls, as demonstrated by immunostaining of AM, immunostaining of lung tissue in areas of interstitial fibrosis, and by higher levels of arginase-1 protein in lung tissue lysates.

21The above constellation of findings indicate that alternative activation of macrophages may play a mechanistic role in pulmonary fibrosis. Blocking alternative macrophage activation may prove therapeutic, and development of such new approaches to therapies for pulmonary fibrosis is under way. For example, serum amyloid P inhibited bleomycin and TGF-β induced pulmonary fibrosis at least partially through attenuation of alternative macrophage accumulation.

B lymphocytes

22Though most literature regarding potential lymphocyte involvement in mechanisms of fibrosis has referenced T cells, a role for B cells has been suggested for many years. As mentioned previously, patients with IPF often have well-organized lymph-node-like structures in the lung composed of activated T and B cells. Production of antibody is a major function of B cells, and production of autoantibodies has been demonstrated against alveolar epithelial cell antigens such as vimentin and cytokeratins in patients with IPF. Most recently, autoantibodies against periplakin, a component of desmosomes within epithelium, were identified in patients with IPF, and were associated with worse physiologic parameters.

23A mechanistic role for B cells in pulmonary fibrosis is also supported by animal and patient data regarding CD19, a crucial cell-surface signaling molecule which is expressed on B cells and regulates B cell function. In patients with systemic sclerosis (SSc), an autoimmune disease in which pulmonary fibrosis is a major cause of morbidity and mortality, systemic B cells overexpress CD19 compared to healthy controls, and polymorphisms in CD19 are associated with an increased susceptibility to SSc. In an animal model of SSc, mice deficient in CD19 showed attenuated pulmonary and dermal fibrosis in response to subcutaneous bleomycin compared with wild-type controls. In the intratracheal bleomycin model, overexpression of CD19 correlated with increased histologic lung fibrosis, increased lung hydroxyproline content, and reduced survival compared to wild-type controls, and mice deficient in CD19 had reduced fibrosis and improved survival compared to controls. The number of B cells in BAL correlated with CD19 expression, and CD19 expression was necessary for B cell accumulation. Since it has been demonstrated that the presence of CD19 alters B cell phenotype, the above results suggest that CD19 may have a mechanistic role in fibrosis by skewing B cells towards profibrotic cytokine expression.

24Conversely, the presence of B cells in fibrosis may be protective. In the silica-induced model, overexpression of the anti-inflammatory cytokine IL-9 was accompanied by an expansion of B cells within the lungs and with reduced lung fibrosis. The presence of B cells was necessary for the protective effect of IL-9, demonstrated by lack of reduction in fibrosis in B cell-deficient mice, and by a restoration of the reduction in fibrosis by B cell reconstitution. The concept of conflicting roles for B cells in fibrosis is similar to that postulated for T cells, in which depending on cell phenotype and the nature of the pulmonary milieu, lymphocytes may promote or diminish the pulmonary fibrotic process.

Fibrocytes

25Bone-marrow-derived cells that produce collagen and express markers of leukocytes (CD45) and stem cells (CD34) normally circulate at low frequencies, below 1% of circulating cells. These cells were termed fibrocytes in a seminal study. In response to local and systemic injuries, including pulmonary insults, fibrocytes are released from bone marrow in higher numbers, and home to sites of injury, where they differentiate into myofibroblasts and contribute to ECM deposition. Additionally, circulating monocytes may home to sites of injury and differentiate into mesenchymal cells. Recruitment of bone-marrow-derived mesenchymal progenitors is driven by several cytokines that are produced by injured tissues, including CXCL12, CCL2, CCL3, and IL-10. These observations indicate that anti-fibrotic therapies should be limited not only to the organ affected by the disease, but have systemic mechanisms of action as well.

CD40-CD40L

26CD40 ligand (CD40L or CD154) and CD40, members of the TNF family of cytokines and receptors, respectively, are cell surface molecules first identified as co-stimulatory molecules involved in the process of immune cell activation, with activated CD4+ T cells expressing CD40L, and activated antigen presenting cells expressing CD40. It was subsequently demonstrated that CD40 may also be expressed on several non-hematopoietic cell types, including human lung fibroblasts, which raised the possibility that CD40/CD40L interactions may affect fibroblast function. Subsequent work showed that engagement of CD40 on fibroblasts by CD40L or by agonistic antibody caused cell proliferation, mobilization of NF-κB, production of IL-6 and IL-8, and expression of ICAM-1 and VCAM-1. Combined stimulation with IL-4, a potent stimulant for fibroblast proliferation, and ligation of CD40 had synergistic effects on enhancing fibroblast proliferation. In animals, disruption of the engagement of CD40 by antibody against CD40L protected against radiation-induced, oxygen-induced, and autoimmune models of pulmonary injury and fibrosis.

27In patients with IPF, areas of lymphocyte aggregates are often present which contain large numbers of activated T cells expressing CD40L. Additional sources of CD40L include platelets, which are present in areas of lung injury due to the increased procoagulant milieu, and dendritic cells, which are present in lymphocyte aggregates in patients with IPF. Interestingly, CD40L expression was also found in primary human fibroblasts, and found to be expressed and elevated in fibroblasts from patients with IPF compared to normal controls.

28The constellation of findings suggests that the CD40/CD40L system may be an important pathway by which several cell types rich in CD40L may promote and perpetuate fibrosis through engagement of CD40 on fibroblasts. The finding that lung fibroblasts also express CD40L suggests that fibroblasts themselves may be able to perpetuate fibrosis in an autocrine and paracrine fashion via the CD40/CD40L pathway.

Fas-FasL

29Fas (Fas antigen, Fas receptor, or CD95) is a member of the TNF family of cell surface receptors, is expressed in numerous cell types, and induces cellular apoptosis once engaged by FasL. FasL (Fas ligand or CD178) is a transmembrane protein belonging to the TNF family, is predominantly expressed on activated T lymphocytes and natural killer cells, and induces apoptosis in Fas-bearing cells. The role of the Fas-FasL pathway in pulmonary fibrosis has been examined in both epithelial and mesenchymal cells.

30Bronchiolar and alveolar epithelial cell apoptosis has been a consistent finding in the bleomycin model, along with up-regulation of Fas mRNA and Fas pathway genes in epithelial cells, and up-regulation of FasL in lung tissue and infiltrating lymphocytes. In mice, inhalation of agonistic anti-Fas antibody alone caused apoptosis of bronchiolar and alveolar epithelial cells, increased inflammation in BAL and lung tissue, increased collagen content, and increased lung tissue TGF-β mRNA similar to that observed with bleomycin. Inhalation or injection of soluble Fas (aimed at binding and neutralizing inherent FasL) along with bleomycin reduced epithelial cell apoptosis, tissue inflammatory cell infiltration, and collagen accumulation. Mice deficient in Fas (lpr) or FasL (gld) had substantially reduced tissue inflammatory cells, epithelial cell apoptosis, and collagen accumulation compared to controls in response to bleomycin challenge. Conversely, selective inactivation of Fas in T lymphocytes (via Cre-mediated recombination) led to up-regulation of T cell FasL, massive infiltration of inflammatory cells in the lungs, and development of pulmonary fibrosis. Treatment with neutralizing anti-FasL antibody completely prevented the accumulation of lymphocytes in the lung.

31In mesenchymal cells, the preponderance of mechanistic data suggests inherent resistance to Fas-mediated apoptosis. In primary lung fibroblasts, ligation of cell surface Fas by agonistic antibody was unable to induce apoptosis, and resulted in increased levels of the anti-apoptotic proteins X-linked inhibitor of apoptosis (ILP) and FLICE-like inhibitor protein (FLIPL). Similarly, fibroblasts from patients with pulmonary fibrosis demonstrated resistance to apoptosis when exposed to recombinant FasL, and demonstrated prominent signals for ILP and FLIPL in lung tissue. Despite inherent resistance to Fas-mediated apoptosis, several studies have shown that TNF-α and IFN-γ, particularly in combination, increase Fas expression in fibroblasts and increase susceptibility to apoptosis. Attenuation of Fas expression in fibroblasts by small interfering RNA (siRNA) inhibited the ability of TNF-α and IFN-γ to increase susceptibility to apoptosis, whereas transduction of fibroblasts with Fas-expressing adenovirus-enhanced apoptosis when engaged with agonistic antibody. The ability of TNF-α and IFN-γ to sensitize fibroblasts to apoptosis suggests that altered pro-inflammatory cytokine milieus may contribute to the development of pulmonary fibrosis.

32It appears that enhanced apoptosis in epithelial cells coupled with resistance to apoptosis in mesenchymal cells affects the cross-talk between these two cell types. This altered cross-talk is often mediated by TGF-β. In the bleomycin model, myofibroblasts demonstrated overexpression of FasL and induced epithelial cell apoptosis in vitro. In epithelial cells, TGF-β induced apoptosis in vitro, and low concentrations of TGF-β, which were unable to induce epithelial cell apoptosis alone, increased apoptosis in epithelial cells stimulated with agonistic anti-Fas antibody or soluble FasL. In vivo administration of TGF-β along with agonistic anti-Fas antibody increased epithelial cell apoptosis to a degree greater than with either agent alone, and the induction of epithelial cell apoptosis by soluble FasL was inhibited by antibodies against TGF-β.

33Observational studies in patients with IPF have demonstrated up-regulation of Fas and Fas-signaling molecules in epithelial cells compared to normal controls. Mesenchymal cells within fibroblastic foci demonstrated minimal or absent expression of Fas, and fibroblasts from patients with pulmonary fibrosis had lower expression of surface bound Fas, but higher levels of soluble Fas in the supernatant. In regards to FasL, there was increased expression of soluble FasL in BAL and serum in patients with active IPF and connective tissue disease-interstitial pneumonia. In lung tissue from patients with IPF, increased FasL protein was demonstrated in infiltrating granulocytes and T cells, and strong expression of FasL was seen in myofibroblasts. In non-smoking patients with IPF, BAL showed increased percentages of alveolar macrophages and CD8+ cells expressing FasL along with increased levels of soluble FasL, and these findings were inversely correlated with vital capacity. The summative observations in cell culture, animal models, and patients support a mechanistic role for disturbances in Fas and FasL in the development of pulmonary fibrosis.

Integrins

34Integrins are heterodimeric, transmembrane cell surface molecules which primarily mediate cell-cell and cell-ECM adhesion, but also play major roles in cell migration, growth, and survival. Currently, eighteen α-subunits and eight β-subunits have been identified which associate to form 24 known integrins. Mechanistic roles for integrins in the pathogenesis of pulmonary fibrosis have been described in epithelial, inflammatory, and mesenchymal cells.

35The integrin αvβ6, which is expressed principally in epithelial cells, is one of the αv-integrins which has the ability to activate latent TGF-β by binding to the tripeptide RGD sequence on TGF-β latency-associated peptide (LAP). In a landmark study, αvβ6 activated latent TGF-β by binding to the RGD sequence, and in the bleomycin model, mice lacking β6 developed increased pulmonary inflammation, but were protected from pulmonary fibrosis. In the animal model of radiation-induced fibrosis, β6 was up-regulated following injury, and lack of β6 or mutation of integrin binding site on TGF-β LAP significantly reduced pulmonary fibrosis. In the radiation-induced or bleomycin model, antibody against αvβ6 reduced histologic evidence of fibrosis, hydroxyproline content, and phosphorylation of nuclear Smad 2/3. In patients with IPF, αvβ6 was overexpressed within alveolar epithelial cells compared with normal controls, and in patients with systemic sclerosis, was overexpressed to a greater extent in patients with a UIP vs. NSIP pathologic pattern.

36The integrin αvβ8 is also expressed in epithelial cells and fibroblasts. In fibroblasts, αvβ8 contributes to TGF-β activation, fibrosis, and regulation of immune processes including dendritic cell function. In airway epithelial cells, the β8 subunit was highly expressed, active TGF-β was produced, and airway proliferation was minimal. Antibody against β8 or TGF-β reduced active TGF-β production and resulted in enhanced airway proliferation, indicating that β8 activation of latent TGF-β was regulating epithelial cell proliferation. In an epithelial wounding model, administration of TGF-β delayed wound closure, and antibody against αvβ8 reduced activation of latent TGF-β and enhanced epithelial wound closure. Both of these studies suggest that activation of latent TGF-β by αvβ8 may contribute to the broad mechanism of impaired epithelial cell regeneration coupled with mesenchymal cell proliferation in patients with pulmonary fibrosis.

37The integrin α3β1 is an epithelial cell integrin and laminin receptor. Specific loss of α3 expression in lung epithelial cells of mice exposed to bleomycin resulted in typical findings of acute inflammation and lung injury, but had reduced accumulation of myofibroblasts and type I collagen. Specific loss of α3 expression resulted in an inability to form β-catenin/Smad2 complexes, a process implicated in the development of epithelial-mesenchymal transition (EMT), suggesting that the α3β1 integrin may play a central role in EMT.

38Several integrins have been examined in inflammatory cells in pulmonary fibrosis. First, in our animal model of CCL18 overexpression, T lymphocytes accumulated in the lungs, expressed αvβ3 and αvβ5 integrins, and administration of neutralizing antibody against αv or genetic deficiency of β3 significantly reduced pulmonary T cell infiltration and collagen accumulation. Transformed T cells that overexpressed αvβ3 and αvβ5 stimulated collagen accumulation in co-cultured fibroblasts, which was mediated by TGF-β, and pulmonary T cells from patients with systemic sclerosis expressed αvβ3 and αvβ5 integrins. Second, many T cells express αEβ7, which is up-regulated by TGF-β, and binds to E-cadherin on epithelial cells. In the bleomycin model, the majority of CD8+ and γδ T cells in BAL expressed αEβ7, and in patients with IPF, a significantly higher percentage of CD4+ and CD8+ T cells in BAL expressed αEβ7 when compared to peripheral blood. Third, lymphocytes and eosinophils may express α4 integrin, which binds to vascular cell adhesion molecule-1 (VCAM-1) on endothelium. In the bleomycin model, treatment with neutralizing antibody against α4 resulted in reduced cellular inflammation, lipid peroxidation, hydroxyproline content, histologic fibrosis, and α-SMA compared with controls. Though the precise role of T cells in the pathogenesis of pulmonary fibrosis remains incompletely understood, T cell expression of several integrins which bind epithelium or ECM skew the pulmonary milieu towards a pro- or anti-phenotype depending on the T cell phenotype.

39Integrins expressed on fibroblasts have been shown to activate latent TGF-β and promote fibrosis. The α2β1 integrin is a major type I collagen receptor. In normal fibroblasts, exposure to polymerized collagen inhibited proliferation, whereas fibroblasts from patients with IPF demonstrated abnormal proliferation due to activation of the PI3K-Akt-S6K1 pathway and low activity of the tumor suppressor phosphatase and tensin homologue (PTEN). Protein expression of PTEN was preserved, but there was defective regulation of PTEN function by the α2β1-polymerized collagen interaction. Consistent with these in-vitro experiments, mice haploinsufficient for PTEN showed an exaggerated fibroproliferative response and increased collagen deposition in a cutaneous and bleomycin injury model, and immunohistochemistry in patients with IPF showed activation of Akt in fibroblastic foci.

40Myofibroblast contraction has been shown to activate TGF-β by inducing conformational changes in LAP mediated by integrin binding. Contraction of myofibroblasts along with mechanically-resistant ECM activated latent TGF-β via αvβ5 binding, and blocking antibodies against αvβ5 prevented this TGF-β activation. Thy-1, a cell surface glycoprotein which inhibits a fibrogenic phenotype in fibroblasts and is associated with decreased fibrosis in the bleomycin model, may have a role in cell contraction-mediated TGF-β activation. Several studies have shown that Thy-1 can bind to integrins, and specifically, Thy-1 bound αvβ5 in a cell-free system and on the surface of lung fibroblasts. Upon exposure to cell contraction agonists, fibroblasts either lacking Thy-1 or in which Thy-1/αvβ5 binding was prevented were able to activate latent TGF-β and promote myofibroblast differentiation, whereas these effects were absent in fibroblasts expressing Thy-1. Thesis data suggested that Thy-1 is able to bind αvβ5 on the cell surface, and prevent myofibroblast contraction-induced integrin-dependent activation of latent TGF-β.

41In patients with localized or diffuse scleroderma, fibroblasts demonstrated increased expression of αvβ5, and exposure to exogenous latent TGF-β increased collagen production. Overexpression of αvβ5 on normal fibroblasts recruited latent TGF-β on the cell surface, increased collagen promoter activity, and resulted in differentiation to a myofibroblastic phenotype, with each of these reduced or reversed with antibody against αvβ5. Thesis data in aggregate from patients with scleroderma showed that up-regulation of αvβ5 expression in fibroblasts increased ECM production and promoted myofibroblastic differentiation through enhanced autocrine TGF-β signaling.

Absence of cellular infiltration does not equate with lack of inflammation

42As mentioned previously, recent pathologic descriptions of patients with IPF have emphasized the epithelial, mesenchymal, and ECM abnormalities, while de-emphasizing the possible contributions of inflammation to mechanisms of the disease. Most patients with IPF will manifest a mild to moderate degree of chronic cellular inflammation in the lung pathologically, but it is true that some patients with end-stage lung disease and advanced UIP on biopsy will have minimal evidence of chronic inflammatory cells in the lung parenchyma. Although infiltration with inflammatory cells is an overall common feature of inflammation, the degree of cellular infiltration may vary significantly depending on the particular tissue which is involved. In disease of tendons (tendinopathies), the presence of inflammatory cells is rather limited, due most likely to tissue architecture constraints, but an active inflammatory process is present based on levels of cytokines, growth factors, prostaglandins, and neuropeptides. In the spatially confined brain, often considered an “immune-privileged” organ, cellular infiltration following injuries or autoimmune processes is minor, but the brain is fully capable of an active inflammatory response, with cytokines playing key roles. Molecular rather than cellular inflammation appears to drive the response to injury in tendons and brain, and the lack of inflammatory cells does not equate with lack of inflammation.

Resistance to corticosteroids does not equate with lack of inflammation

43An additional concept that should not be equated with lack of inflammation is resistance to corticosteroids. There are several well-established diseases in which inflammation is clearly accepted to be the predominant underlying mechanism, but traditional anti-inflammatory therapy has been poorly or completely ineffective in groups or subgroups of patients. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lungs, with high levels of pro-inflammatory cells and cytokines, but most studies have shown that inhaled or systemic corticosteroids do not significantly reduce cellular or molecular markers of inflammation, and do not improve long-term lung function or survival in patients. Asthma is also a prototypical inflammatory lung disease of the airways, and although most patients with asthma respond well to corticosteroids, a subset of patients have steroid-resistant asthma, manifested clinically by a poor response to treatment, and mechanistically by continued expression of pro-inflammatory and profibrotic cytokines in alveolar macrophages and T cells despite exposure to corticosteroids. In the autoimmune inflammatory diseases rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE), a subset of patients will respond poorly to corticosteroids, and mononuclear and T cells from these patients showed less inhibition of proliferation and less apoptosis when exposed to corticosteroids. Similarly, a proportion of patients with inflammatory bowel disease (IBD) will have a poor or absent response to corticosteroids, and peripheral blood T cells from these patients showed less inhibition of proliferation when exposed to corticosteroids.

44The normal mechanisms by which corticosteroids reduce inflammation have been reviewed in detail. Several mechanisms have been postulated by which patients with inflammatory diseases may manifest resistance to corticosteroid therapy, and these have included abnormalities in bone morphogenetic protein receptor, increased phosphorylation and subsequent reduced nuclear translocation of the activated glucocorticoid receptor (GR), reduced expression of the anti-inflammatory protein MKP-1 resulting from increased p38 mitogen-activated protein kinase activity, reduced binding affinity of GR for corticosteroids due to nitrosylation of GR by inducible nitric oxide synthase, or excessive activation of the transcription factor AP-1 which prevents GR interaction with DNA glucocorticoid response elements. One other particularly noteworthy cause of corticosteroid-resistant inflammation in chronic lung disease results from decreased histone deacetylase activity. Corticosteroids normally reduce inflammation by decreasing transcription of activated inflammatory genes, which occurs at least in part by recruitment of histone deacetylase-2 (HDAC2). In epithelial cells, inhibition of histone deacetylase activity promoted corticosteroid resistance, and this resistance was reversed by HDAC2 overexpression. Reduced levels of histone deacetylase-2 (HDAC2) have been observed in patients with COPD and refractory asthma, and one mechanism of reduced deacetylase activity is inactivation of HDAC2 by oxidative stress, which has been demonstrated in epithelial cells, animal models, and patients with COPD.

45Based on all the available mechanistic, animal model, and observational data regarding inflammation and immune mechanisms, it may be a reasonable conclusion that IPF is a chronic inflammatory disease of the lung, but cellular infiltration is minor compared to the substantial changes in pulmonary cytokines, and the absence of clinical improvement in treated patients may be a manifestation of resistance to conventional anti-inflammatory therapies. The fact that oxidative stress has been found capable of promoting steroid-resistant inflammation is certainly a thought provoking concept, given the large amount of data demonstrating high levels of oxidative stress in patients with pulmonary fibrosis, which will be discussed below.

Oxidative stress and oxidative signaling

46Molecular oxygen is central to aerobic metabolism, is critically required for vertebrates, and must be constantly supplied to ensure survival. However, oxygen is a strong oxidant, and has damaging effects on cells and biologic macromolecules due to formation of reactive oxygen species (ROS). Oxidative stress occurs when there is an imbalance between the generation of ROS and the capacity to detoxify these intermediates, which occurs when generation of ROS is excessive, antioxidant defenses are reduced, or both disturbances occur together. Additionally, extensive evidence suggests that ROS may be also involved with post-translational processing of proteins and intracellular signaling mechanisms in health and disease, including activation or deactivation of signaling factors, regulation of gene expression, and cell differentiation. Over many years, there has been accumulating evidence that oxidative stress and/or oxidative signaling may play a major role in the pathogenesis of pulmonary fibrosis.

Overview of reactive oxygen species and antioxidant defenses

47Reactive oxygen species are formed by single electron reductions of molecular oxygen, leading to formation of superoxide anion (O2.–), hydrogen peroxide (H2O2), and the hydroxyl radical (.OH). Due to their powerful oxidizing capability, ROS can lead to generation of advanced oxidation molecular products and induce damage to cellular and subcellular structures within the lung, including DNA, proteins, cell membranes, and mitochondria. Reactive oxygen species production may result from several sources in the lung, including the mitochondrial electron transport chain, myeloperoxidase, xanthine oxidase, and NADPH oxidases.

48The enzyme system in the lung that has recently gained the most attention for its ability to produce ROS is the NADPH oxidase family of enzymes, also termed the NOX family of enzymes. The primary function of these enzymes was originally viewed as host defense in phagocytic cells against invading microbes, however, NADPH oxidases have now been found in virtually all tissues, and ROS generated by the NADPH oxidases have been shown to have numerous diverse roles in cellular function. Seven isoforms of the NADPH oxidases have been described in mammals, and the isoform NOX4 is the major NADPH oxidase up regulated by TGF-β1.

49The detrimental effect of ROS is expected to be uniquely most profound in the lung due to its constant exposure to the high oxygen tension of the ambient atmosphere. Consequently, the lung has evolved significant defense mechanisms against cellular damage from reactive oxygen species, which most notably include the family of superoxide dismutases (SOD), the peroxidase catalase, and reduced glutathione. Superoxide dismutase has three isoforms and catalyzes the breakdown of superoxide anion to hydrogen peroxide, and catalase accelerates the breakdown of hydrogen peroxide to water. Reduced glutathione (GSH) is a tripeptide containing the amino acid cysteine, and with its sulfhydryl group, acts as one of the major antioxidants present in the lung.

Observations in humans

50Most of the observational data suggest that an oxidant/antioxidant imbalance exists in cells and lung tissue of patients with pulmonary fibrosis. Alveolar inflammatory cells (macrophages, lymphocytes, neutrophils, and eosinophils) and fibroblasts from patients with IPF spontaneously generated higher amounts of ROS than normal controls. The amount of myeloperoxidase in the alveolar epithelial lining fluid from patients with IPF was also significantly higher than controls, and within the IPF group, those patients with higher levels of myeloperoxidase had a more rapidly deteriorating clinical course than those with lower levels. Whereas alveolar epithelial lining fluid of normal controls contained high levels of GSH, patients with IPF had substantially decreased levels of GSH in epithelial lining fluid, BAL fluid, and BAL cells, and had a decreased ratio of reduced to oxidized glutathione (GSH/GSSG). In patients with IPF, immunoreactivity of gamma-glutamylcysteine synthetase, the rate limiting enzyme in reduced glutathione synthesis, was high in areas of regenerating bronchiolar epithelium, but low in fibrotic areas and fibroblastic foci. Extracellular superoxide dismutase (EC-SOD), the major enzyme responsible for inactivating superoxide anion in the extracellular matrix, was absent by immunohistochemistry in fibrotic areas and fibroblastic foci of patients with IPF. Histopathologic sections of lung tissue from patients with IPF showed high expression of the NADPH oxidase isoform NOX4 in fibroblastic foci and in hyperplastic type II cells. The constellation of these findings together suggests a significant oxidant/antioxidant imbalance in the lungs of patients with IPF.

Studies in animal models

51The role of antioxidant defenses or effects of antioxidant therapy have been examined animal models of lung injury and fibrosis. The oxidant/antioxidant balance in the lung may be shifted through administration of the antioxidant n-acetylcysteine (NAC), a synthetic precursor of reduced glutathione. Intraperitoneal, oral, or aerosolized NAC lead to reduced inflammation (BAL inflammatory cells and acute inflammatory cytokines) and reduced collagen deposition (hydroxyproline and histology) in the bleomycin model. Intraperitoneal administration of the antioxidant MnTBAP, a metalloporphyrin, attenuated lung fibrosis in the bleomycin model as assessed by hydroxyproline content, airway dysfunction, and histopathology. Mice who were germline-deficient for extracellular superoxide dismutase (EC-SOD) and received bleomycin demonstrated a significant increase in inflammation and fibrosis (hydroxyproline and histopathology) compared to wild type controls, whereas mice that were transgenic for EC-SOD had less acute lung injury and less fibrosis than wild-type controls. Mice that were genetically deficient of Nrf2, a transcription factor which contributes to GSH homeostasis, had increased inflammation, increased epithelial cell death, and increased indices of lung fibrosis (hydroxyproline content, collagen accumulation, histopathologic score) compared with wild-type controls in response to bleomycin challenge.

52Additional animal models have examined the role of the NADPH oxidase isoform NOX4. In wild-type mice, administration of bleomycin increased protein expression of NOX4 in a time dependent manner, and instillation of small interfering RNA (siRNA) against NOX4 or pharmacologic inhibition of NOX4 reduced histopathologic evidence of fibrosis, lung homogenate hydroxyproline content, and α-SMA production compared with controls. In NOX4-deficient mice, administration of bleomycin resulted in decreased amounts of Smad 2 phosphorylation, α-SMA, procollagen mRNA, total collagen content, and histologic fibrosis compared to controls. Although fibrosis was reduced as a result of NOX4 deficiency, the robust pulmonary inflammation in response to bleomycin was not altered, suggesting that inflammation by itself is not sufficient to drive bleomycin-induced fibrosis. Notably, this decreased fibrosis was associated with less alveolar epithelial cell death compared to controls. These results in combination suggest that oxidative stress may be contributing to both alveolar epithelial cell death and lung fibroblast proliferation in pulmonary fibrosis.

Mechanistic in vitro studies

53Many in vitro studies have examined a variety of oxidant and antioxidant mechanisms in lung cells that involve ROS, glutathione, and cysteine. Alveolar inflammatory cells and alveolar epithelial lining fluid from IPF patients are cytotoxic to primary pulmonary epithelial cells; this cytotoxic effect was reduced by the antioxidant enzyme catalase, and did not occur from exposure to cells and epithelial fluid from normal controls. Lung fibroblasts exposed to GSH had substantially suppressed cellular proliferation, whereas oxidized glutathione disulfide (GSSG) had no suppressive effect on proliferation. Exposure of lung fibroblasts to the oxidized thiol/disulfide couple cysteine/cystine (Cys/CySS) resulted in enhanced fibroblast proliferation, expression of fibronectin, expression of TGF-β1, and expression of Smad3; these effects did not occur with exposure to reduced Cys/CySS.

54Much of the recent mechanistic work regarding oxidative mechanisms in pulmonary fibrosis has centered around the two-way interplay between TGF-β1 and ROS mediated processes. ROS have been shown to activate latent TGF-β1, and TGF-β1 increases production of ROS in human lung fibroblasts. Exposure of epithelial cells and fibroblasts to TGF-β1 decreased levels of GSH, decreased levels of the antioxidant enzymes glutathione reductase and catalase, and increased cell cytoxicity mediated by hydrogen peroxide. Inhibiting the synthesis of intracellular GSH content in vitro increased TGF-β1 mediated collagen production. TGF-β1 markedly decreased expression of gamma-glutamylcysteine synthetase, whereas the acute inflammatory cytokine TNF-alpha caused a mild induction of this enzyme. Lung fibroblasts from patients with IPF that were exposed to TGF-β1 generated H2O2; these fibroblasts were cytotoxic to pulmonary epithelial cells in co-cultures, and this cytotoxic effect was inhibited by the addition of catalase, or by blockade of H2O2 generation. TGF-β1has been shown to promote epithelial-mesenchymal transition (EMT), one of the possible sources of increased resident mesenchymal cells in pulmonary fibrosis. The addition of glutathione, NAC, or ROS inhibitors prevented TGF-β1-augmented EMT in alveolar epithelial cells, suggesting that oxidative stress mediated by TGF-β1stimulation plays a role in epithelial-mesenchymal transdifferentiation. Additionally, the administration of NAC along with TGF-β1 blocked TGF-β1-augmented collagen gel contraction, expression of α-SMA, and release of fibronectin, vascular endothelial growth factor (VEGF), and collagen. The mechanisms by which NAC may affect TGF-β1 signaling appear diverse, as NAC decreased TGF-β1-induced reporter gene activity, decreased phosphorylation of Smad 2/3, reduced active TGF-β1 dimer to an inactive TGF-β1 monomer, and interfered with TGF-β1 receptor signaling. These findings suggest that NAC may directly interfere with TGF-β1 signaling and function, in addition to its well-established ability to function as a precursor to glutathione synthesis and as a non-specific scavenger of ROS.

55In addition to the well-established observations that TGF-β1 alters cellular oxidant/antioxidant balance, TGF-β1 also specifically induces the expression of the NADPH oxidase isoform NOX4 in numerous mesenchymal cell types. These have included pulmonary artery smooth muscle cells, cardiac fibroblasts, kidney fibroblasts, human fetal lung mesenchymal cells, and mesenchymal cells from patients with IPF. Furthermore, there has been accumulating evidence that TGF-β1-induced expression of NOX4 is closely tied to myofibroblastic differentiation, and that myofibroblast differentiation is dependent on the generation of ROS by NOX4.

56Exposure of fibroblasts to TGF-β1 increased expression of NOX4, superoxide anion, α-SMA, and ECM-related proteins (connective tissue growth factor, fibronectin and collagen). Attenuation of NOX4 expression by siRNA significantly reduced production of superoxide anion, phosphorylation of Smad 2/3, expression of α-SMA, and production of the ECM-related proteins. A similar effect was achieved by inhibiting ROS production with ROS species inhibitors. These findings suggested that TGF-β1 stimulation of NOX4 and generation of ROS were essential for Smad 2/3 phosphorylation and for the full manifestation of the myofibroblast phenotype.

57Similarly, in human lung mesenchymal cells, TGF-β1 induced NOX4 expression, induced extracellular release of hydrogen peroxide (H2O2), upregulated production of α-SMA, and caused collagen gel contraction. Pharmacological inhibition of TGF-β1 receptor signaling or attenuation of Smad-3 expression by specific siRNA inhibited the induction of NOX4 and the release of H2O2. The TGF-β1-stimulated upregulation of α-SMA and collagen gel contraction was inhibited by catalase and by siRNA-mediated inhibition of NOX4. These findings indicated that H2O2 production from the upregulation of NOX4 was required for TGF-β1 to induce differentiation to a myofibroblast phenotype.

Antioxidant therapy in patients with IPF

58Administration of n-acetylcysteine (NAC) to patients with IPF increased intracellular GSH content and GSH levels in BAL fluid, and the spontaneous oxidative activity of BAL cells decreased following NAC treatment. One multicenter study has been performed looking at antioxidant therapy in patients with IPF. In this study, patients were randomly assigned to receive either prednisone and azathioprine, or the combination of prednisone, azathioprine and NAC. Patients who received NAC had a better preservation of the vital capacity and the diffusing capacity for carbon monoxide at one year, although there was no demonstrated improvement in survival. Despite the extensive amount of data regarding alterations in the oxidant/antioxidant balance in lungs with pulmonary fibrosis, administration of antioxidant therapy to patients has not yet been shown to provide clear-cut clinical benefit.

Procoagulant milieu in the lung

59Essential in the process of wound healing in response to tissue injury are procoagulant signaling mechanisms. Activation of the coagulation cascade by tissue injury contributes to both cessation of bleeding as well as tissue repair. Over the past 15 years, there has been an accumulation of evidence in humans and animal models that imbalances in procoagulant or antifibrinolytic activity are present in the lungs of patients with pulmonary fibrosis. Most of the descriptions of these imbalances have centered on abnormalities of tissue factor, factor Xa, thrombin, or proteinase-activated receptors.

Overview of coagulation

60Coagulation is most often initiated at sites of tissue injury, at which time tissue factor (TF), a transmembrane glycoprotein widely expressed on vascular interstitial cells, becomes exposed to plasma serine proteinases. As TF binds to activated factor VIIa in plasma, the extrinsic coagulation pathway begins and continues with the activation of factor X to factor Xa, conversion of prothrombin to thrombin, and conversion of fibrinogen to fibrin, the main component of a mature thrombus. Additional activation of the intrinsic coagulation pathway by thrombin results in the desired effect of sustained hemostasis at sites of tissue injury. The coagulation process is normally opposed by fibrinolysis, the process of cleaving fibrin into degradation products, which is initiated when plasminogen is converted to plasmin by plasminogen activators. The activity of plasminogen activators is balanced by the presence of plasminogen activator inhibitors, and additional naturally occurring anticoagulants include tissue factor pathway inhibitor, which inactivates the TF/VIIa complex, and activated protein C, which inactivates factor V and PAI-1.

61In addition to promoting hemostasis, thrombin and several of the activated coagulation proteinases bind to members of a family of proteinase-activated receptors (PARs). PARs are transmembrane G-protein coupled receptors that have a unique mechanism of activation in which a portion of the receptor (the tethered ligand) is cleaved by proteolysis and then functions as the ligand for the receptor. Binding of ligand to the major thrombin receptor PAR-1 has been shown to cause multiple downstream effects related broadly to wound healing and repair, and specifically to inflammation, epithelial and mesenchymal cell function, and TGF-β.

Epidemiologic clues

62Epidemiologic observations in humans have suggested a relationship between disorders of the coagulation system and the development of pulmonary fibrosis. In a large cohort of patients in Denmark, patients who were homozygous for a mutation in factor V (factor V Leiden) had abnormalities of several respiratory indices when compared to non-carriers, which included an increase in severe dyspnea, lower forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), and increased rate of annual decline in the FEV1 and FVC. In another large cohort of patients from Denmark, the relationship between a history of deep venous thrombosis or pulmonary embolism was correlated with the presence of interstitial lung disease or idiopathic interstitial pneumonia. The incidence rates of idiopathic interstitial pneumonia and interstitial lung disease were higher in patients with a history of venous thromboembolism or pulmonary embolism than control patients.

Tissue factor (TF)

63Elevated levels of TF in BAL fluid have been found in patients with IPF compared with normal controls, and in patients with an acute exacerbation of IPF, BAL levels of TF were markedly elevated. Immunohistochemical analyses revealed large amounts of TF in cuboidal epithelial cells in patients with IPF, and in type II pneumocytes of patients with IPF, systemic sclerosis, and cryptogenic organizing pneumonia. Increased TF mRNA and protein were seen in fibroblasts from IPF patients compared with normal lung fibroblasts, and expression of TF assessed by qRT-PCR was up-regulated in fibroblastic foci of these IPF patients. Procoagulant activity was increased in patients with IPF and other forms of diffuse parenchymal lung disease, and this increase in procoagulant activity was TF-dependent. Interestingly, this TF-dependent increase in procoagulant activity correlated with a reduction in lung compliance, which is well-known to occur in patients with IPF.

Factor VII and Factor X

64Increases in factor VII antigen in BAL fluid and mRNA in alveolar type II epithelial cells were detected in the lungs of patients with IPF compared with normal lung tissue. Similarly, increased expression of factor X mRNA was seen in alveolar septa in the lungs of patients with IPF, whereas there was no significant expression of factor X in normal healthy lung tissue.

Anti-fibrinolytic activity

65Contributing to the balance between procoagulant and anticoagulant mechanisms in the lung are the fibrinolytic plasminogen activators (urokinase-type and tissue-type) and the anti-fibrinolytic plasminogen activator inhibitors (plasminogen activator inhibitor 1 [PAI-1] and plasminogen activator inhibitor 2 [PAI-2]). BAL levels of PAI-1 and PAI-2 were elevated in patients with IPF vs control patients, accompanied by no difference in urokinase-type plasminogen activator levels, suggesting an imbalance shifted towards anti-fibrinolytic (or procoagulant) activity in the lungs of patients with IPF.

PAR-1 and PAR-2

66The major thrombin receptor PAR-1 was highly expressed in macrophages and fibroblasts within fibroproliferative foci in patients with IPF, whereas there was only weak staining by immunohistochemistry for PAR-1 in resident alveolar macrophages from normal lung tissue. Similarly, in patients with systemic sclerosis, PAR-1 expression by immunohistochemistry was elevated in areas of inflammation and fibroproliferation, but showed only minimal expression in normal control patients. Recently, PAR-1 expression was shown to be up-regulated on activated epithelium within the fibrotic areas of IPF patients, and additionally, was co-expressed in these epithelial cells with chemokine CCL2, also known as monocyte chemotactic protein-1 (MCP-1).

67In addition to PAR-1, increased expression of mRNA and protein of PAR-2, which is activated by tissue factor, factor VIIa, and factor Xa, but not by thrombin, was found in lung homogenates and fibroblasts of patients with IPF compared with controls. Increased expression of PAR-2 by immunohistochemistry was also seen in type II alveolar epithelial cells and in fibroblastic foci, and tissue factor (TF) co-localized with PAR-2 in these fibroblastic foci.

Studies in animal models

68Consistent with an overall procoagulant milieu, administration of bleomycin has been shown to increase expression of procoagulant activity and thrombin in BAL, increase PAR-1 expression in lung tissue, alveolar epithelium, and bronchial epithelium, increase factor X gene expression and factor X mRNA levels, and decrease levels of activated protein C. Administration of molecules which favor an anticoagulant milieu has also been performed in the bleomycin model. Aerosolization of heparin or urokinase-type plasminogen activator following bleomycin challenge resulted in reduced soluble collagen and hydroxyproline accumulation, reduced histologic and CT features of fibrosis, and improved lung compliance. Intratracheal administration of activated protein C along with bleomycin resulted in less fibrosis, less hydroxyproline content, and a higher ratio of plasminogen activator to thrombin activity than controls. Administration of a direct thrombin inhibitor along with bleomycin resulted in reduced lung collagen accumulation and connective tissue growth factor (CTGF) mRNA compared with controls. Administration of a direct factor Xa inhibitor along with bleomycin resulted in reduced total lung collagen accumulation compared with bleomycin treatment alone. Adenovirus-mediated gene delivery of tissue factor pathway inhibitor along with bleomycin challenge decreased procoagulant and thrombin activity in BAL, reduced the expression of connective tissue growth factor (CTGF) and TGF-β1 mRNA in BAL, reduced hydroxyproline accumulation in the lungs, and reduced histologic evidence of fibrosis.

69The effects of gene deletion or insertion using transgene technology have also been studied in the bleomycin model. Administration of bleomycin to mice deficient in PAR-1 resulted in reductions in inflammatory cell recruitment, BAL protein, total lung collagen accumulation, and pulmonary levels of MCP-1 and TGF-β1 compared with controls. Administration of bleomycin to mice transgenic for overexpression of PAI-1 resulted in increased lung hydroxyproline content, whereas lung hydroxyproline content and lung histology in PAI-1 deficient mice were not significantly different than that of mice treated with saline alone.

Mechanistic in vitro studies

70Activation of fibroblasts by one or more of the coagulation proteinases via proteinase-activated receptors (PARs) has been studied extensively in vitro over the last fifteen years in relation to the ability to promote fibroblast proliferation and extracellular matrix production. Thrombin is a known mitogen for human lung fibroblasts and inhibits fibroblast apoptosis. Thrombin stimulated mitogen-activated protein (MAP) kinase activation and DNA synthesis in normal mouse fibroblasts, and these responses were absent in fibroblasts from thrombin receptor knockout mice. In addition to its mitogenic effect, thrombin increased production of procollagen in human lung fibroblasts in a dose-dependent manner. This increase in procollagen was mimicked by agonist peptides for PAR-1 and abolished by inhibitors of thrombin’s proteolytic activity, suggesting that thrombin was exerting its effects via PAR-1. Furthermore, thrombin caused collagen gel contraction and stimulated the production of α-SMA in normal human lung fibroblasts in a dose- and time-dependent manner, indicating fibroblast differentiation to a myofibroblast phenotype. Both of these effects were mediated via PAR-1 and subsequent protein kinase C-mediated intracellular signaling, and both occurred independently of TGF-β1. In human fetal and adult lung fibroblasts, thrombin increased production and synthesis of connective tissue disease growth factor (CTGF), a potent fibroblast mitogen. This increased production of CTGF occurred via PAR-1 and was independent of TGF-β1.

71Similar to thrombin, factor Xa increased fibroblast proliferation in human and mouse lung fibroblasts, and stimulated procollagen-alpha 1 (I) promoter activity and procollagen production in human and mouse lung fibroblasts. These effects on collagen were mediated via PAR-1, since factor Xa had no effect on procollagen production in PAR-1 deficient mouse lung fibroblasts. Similar to thrombin, factor Xa increased production and synthesis of CTGF mRNA in human lung fibroblasts.

72Although the above studies indicate that the profibrotic effects of thrombin and factor Xa are mediated predominantly via PAR-1, a similar role for PAR-2 in pulmonary fibrosis has recently been suggested. Exposure of human lung fibroblasts to TGF-β1 increased expression of PAR-2 mRNA and protein. One of the known ligands for PAR-2 is factor VIIa, and factor VIIa exhibited mitogenic effects on human lung fibroblasts. This mitogenic effect was mediated via PAR-2 and TF, since it was inhibited by siRNAs against PAR-2 or TF, and was greatly enhanced by the simultaneous overexpression of both receptors.

73The proliferative and profibrotic effects of the coagulation proteinases on fibroblasts may not only be direct, but may also occur through indirect mechanisms. One described indirect mechanism is activation of PAR-1 on epithelial cells leading to integrin-mediated activation of latent TGF-β1. Another indirect mechanism relates to the described role of epithelial apoptosis in pulmonary fibrosis. Activation of PAR-1 with thrombin or a PAR-1 agonist led to apoptosis of pulmonary epithelial cells, which was reduced by treatment with a PAR-1 inhibitor and in cells with reduced PAR-1 expression via gene silencing. Based on the multiple effects of PAR-1 activation, it is interesting to note that thrombin induced apoptosis in epithelial cells, but inhibited apoptosis in lung fibroblasts. These findings are consistent with one of the major proposed mechanisms for IPF in which pulmonary fibrosis is driven by a combination of apoptosis of epithelial cells and numerical expansion of fibroblasts and myofibroblasts.

Anticoagulation therapy in patients with IPF

74Two trials have been published examining the effects of anticoagulation therapy in patients with IPF. In a study of 20 patients with IPF, the safety and tolerability of inhaled heparin were examined, and demonstrated safety of inhaled heparin and an overall stability in pulmonary function parameters and quality of life scores. In a randomized study of 56 patients, those who received anticoagulation therapy along with prednisolone had an improved overall survival compared with patients treated with prednisolone alone, but this study did have limitations which reduced the ability to make generalized conclusions. Despite the extensive amount of data indicating the profibrotic activity of the coagulation proteinases and the procoagulant milieu in the fibrotic lung, administration of anticoagulation therapy to patients has not been shown to provide clear-cut clinical benefit, and is not currently recommended.

Conclusions

75Pulmonary fibrosis is a chronic condition of the lungs with characteristic clinical, radiographic, physiologic, and pathologic findings. At the present time, no proven effective therapies exist for pulmonary fibrosis. In some patients, lung injury and subsequent fibrosis occur in which the deposition of excess ECM seems to cease, the impairment in lung function is mild, and the lack of effective therapies does not adversely impact patients. In other patients such as those with IPF, the deposition of excess ECM appears to be progressive, impairment in lung function is severe, and the lack of effective therapies in these patients results in the morbidity and mortality from this disease.

76One limitation to advancing our knowledge in this field is that none of the currently accepted animal models of pulmonary fibrosis (bleomycin, radiation, silica, transgenic, viral vectors) accurately mimic human IPF. Despite this limitation, an extensive amount of mechanistic work has been performed using these models, with a resultant immense amount of insight gained into epithelial and mesenchymal cell biology of pulmonary fibrosis. In this review, we have attempted to provide an overview of three broad areas which have been explored, and which may be responsible for the observed epithelial, mesenchymal, and ECM abnormalities: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. In each of these processes, there is a preponderance of mechanistic, animal model, and human data indicating that disturbances in these mechanisms exist, but at present, pharmacologic targeting of these disturbances in patients has not resulted in improved outcomes. Continued efforts aimed at determining the precise relationship between these disturbances and the development of fibrosis will hopefully lead to effective therapies for patients in the future.

Abbreviations

77α-SMA, Alpha-smooth muscle actin; ECM, Extracellular matrix; EC-SOD, Extracellular superoxide dismutase; EMT, Epithelial mesenchymal transition; GSH, Reduced glutathione; H2O2, Hydrogen peroxide; IPF, Idiopathic pulmonary fibrosis; NAC, n-acetylcysteine; NOX, NADPH oxidase; O2.–, Superoxide anion; ROS, Reactive oxygen species; siRNA, Small interfering RNA; TGF-β, Transforming growth factor-beta; UIP, Usual interstitial pneumonia.

Competing interests

78The authors declare they have no competing interests.

Authors’ contributions

79This manuscript has been seen and approved by all co-authors, and all authors contributed sufficiently to warrant their inclusion on the author list and to take responsibility for the content of this report.

References 331

1.
Takishima T Shimura S Takishima TDefinition and Classification of Pulmonary FibrosisBasic and clinical aspects of pulmonary fibrosis1994 CRC Press, Boca Raton, FL293303
Not in our library
2.
Orr CR Jacobs WF Pulmonary FibrosisRadiology1926 7318325
Not in our library
3.
Hamman L Rich AR Fulminating diffuse interstitial fibrosis of the lungsTrans Am Clin Climatol Assoc1935 51154163
Not in our library
4.
Hamman L Rich A Acute diffuse interstitial fibrosis of the lungsBull Johns Hopkins Hosp1944 74177212
Not in our library
5.
Scadding JG Hinson KF Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs). Correlation of histology at biopsy with prognosisThorax1967 22291304
Not in our library10.1136/thx.22.4.291
6.
Crystal RG Fulmer JD Roberts WC Moss ML Line BR Reynolds HY Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspectsAnn Intern Med1976 85769788
Not in our library10.7326/0003-4819-85-6-769
7.
Raghu G Collard HR Egan JJ Martinez FJ Behr J Brown KK Colby TV Cordier JF Flaherty KR Lasky JA Lynch DA Ryu JH Swigris JJ Wells AU Ancochea J Bouros D Carvalho C Costabel U Ebina M Hansell DM Johkoh T Kim DS King TE Kondoh Y Myers J Müller NL Nicholson AG Richeldi L Selman M Dudden RF An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and managementAm J Respir Crit Care Med2011 183788824
Not in our library10.1164/rccm.2009-040gl
8.
Hashimoto N Jin H Liu T Chensue SW Phan SH Bone marrow-derived progenitor cells in pulmonary fibrosisJ Clin Invest2004 113243252
Not in our library10.1172/jci18847
9.
Bucala R Spiegel LA Chesney J Hogan M Cerami A Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repairMol Med1994 17181
Not in our library
10.
Kuwana M Okazaki Y Kodama H Izumi K Yasuoka H Ogawa Y Kawakami Y Ikeda Y Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiationJ Leukoc Biol2003 74833845
Not in our library10.1189/jlb.0403170
11.
Postlethwaite AE Shigemitsu H Kanangat S Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosisCurr Opin Rheumatol2004 16733738
Not in our library10.1097/01.bor.0000139310.77347.9c
12.
Willis BC Liebler JM Luby-Phelps K Nicholson AG Crandall ED du Bois RM Borok Z Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosisAm J Pathol2005 16613211332
Not in our library10.1016/s0002-9440(10)62351-6
13.
Coalson JJ The ultrastructure of human fibrosing alveolitisVirchows Arch A Pathol Anat Histol1982 395181199
Not in our library10.1007/bf00429611
14.
Kawanami O Ferrans VJ Crystal RG Structure of alveolar epithelial cells in patients with fibrotic lung disordersLab Invest1982 463953
Not in our library
15.
du Bois RM Wells AU Cryptogenic fibrosing alveolitis/idiopathic pulmonary fibrosisEur Respir J2001 32Suppl 143s55s
Not in our library
16.
Katzenstein AL Myers JL Idiopathic pulmonary fibrosis: clinical relevance of pathologic classificationAm J Respir Crit Care Med1998 15713011315
Not in our library10.1164/ajrccm.157.4.9707039
17.
Leslie KO Pathology of the idiopathic interstitial pneumoniasExp Lung Res2005 31Suppl 12340
Not in our library
18.
American Thoracic Society; European Respiratory SocietyAmerican Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001Am J Respir Crit Care Med2002 165277304
Not in our library10.1164/ajrccm.165.2.ats01
19.
Selman M King TE Pardo A Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapyAnn Intern Med2001 134136151
Not in our library10.7326/0003-4819-134-2-200101160-00015
20.
Horowitz JC Thannickal VJ Epithelial-mesenchymal interactions in pulmonary fibrosisSemin Respir Crit Care Med2006 27600612
Not in our library10.1055/s-2006-957332
21.
Richeldi L Davies HR Ferrara G Franco F Corticosteroids for idiopathic pulmonary fibrosisCochrane Database Syst Rev2003 3CD002880
Not in our library10.1002/14651858.cd002880
22.
Davies HR Richeldi L Walters EH Immunomodulatory agents for idiopathic pulmonary fibrosisCochrane Database Syst Rev2003 3CD003134
Not in our library10.1002/14651858.cd003134
23.
Barnes PJ Adcock IM Glucocorticoid resistance in inflammatory diseasesLancet2009 37319051917
Not in our library10.1016/s0140-6736(09)60326-3
24.
Homer RJ Elias JA Lee CG Herzog E Modern concepts on the role of inflammation in pulmonary fibrosisArch Pathol Lab Med2011 135780788
Not in our library10.5858/2010-0296-ra.1
25.
Wynn TA Integrating mechanisms of pulmonary fibrosisJ Exp Med2011 20813391350
Not in our library10.1084/jem.20110551
26.
Crystal RG Bitterman PB Mossman B Schwarz MI Sheppard D Almasy L Chapman HA Friedman SL King TE Leinwand LA Liotta L Martin GR Schwartz DA Schultz GS Wagner CR Musson RA Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working groupAm J Respir Crit Care Med2002 166236246
Not in our library10.1164/rccm.2201069
27.
Tanaka T Yoshimi M Maeyama T Hagimoto N Kuwano K Hara N Resistance to Fas-mediated apoptosis in human lung fibroblastEur Respir J2002 20359368
Not in our library10.1183/09031936.02.00252602
28.
Hagimoto N Kuwano K Inoshima I Yoshimi M Nakamura N Fujita M Maeyama T Hara N TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cellsJ Immunol2002 16864706478
Not in our library10.4049/jimmunol.168.12.6470
29.
Cucoranu I Clempus R Dikalova A Phelan PJ Ariyan S Dikalov S Sorescu D NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblastsCirc Res2005 97900907
Not in our library10.1161/01.res.0000187457.24338.3d
30.
Gharaee-Kermani M Hu B Phan SH Gyetko MR Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblastCurr Med Chem2009 1614001417
Not in our library10.2174/092986709787846497
31.
Cutroneo KR White SL Phan SH Ehrlich HP Therapies for bleomycin induced lung fibrosis through regulation of TGF-beta1 induced collagen gene expressionJ Cell Physiol2007 211585589
Not in our library10.1002/jcp.20972
32.
Border WA Noble NA Transforming growth factor beta in tissue fibrosisN Engl J Med1994 33112861292
Not in our library10.1056/nejm199411103311907
33.
Sime PJ Xing Z Graham FL Csaky KG Gauldie J Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lungJ Clin Invest1997 100768776
Not in our library10.1172/jci119590
34.
Sheppard D Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosisProc Am Thorac Soc2006 3413417
Not in our library10.1513/pats.200601-008aw
35.
Gauldie J Bonniaud P Sime P Ask K Kolb M TGF-beta, Smad3 and the process of progressive fibrosisBiochem Soc Trans2007 35661664
Not in our library10.1042/bst0350661
36.
Biernacka A Dobaczewski M Frangogiannis NG TGF-beta signaling in fibrosisGrowth Factors2011 29196202
Not in our library10.3109/08977194.2011.595714
37.
Chambers RC Leoni P Blanc-Brude OP Wembridge DE Laurent GJ Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1J Biol Chem2000 2753558435591
Not in our library10.1074/jbc.m003188200
38.
Atamas SP Complex cytokine regulation of tissue fibrosisLife Sci2002 72631643
Not in our library10.1016/s0024-3205(02)02299-3
39.
Atamas SP White B Cytokine regulation of pulmonary fibrosis in sclerodermaCytokine Growth Factor Rev2003 14537550
Not in our library10.1016/s1359-6101(03)00060-1
40.
Ihn H Pathogenesis of fibrosis: role of TGF-beta and CTGFCurr Opin Rheumatol2002 14681685
Not in our library10.1097/00002281-200211000-00009
41.
Lasky JA Ortiz LA Tonthat B Hoyle GW Corti M Athas G Lungarella G Brody A Friedman M Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosisAm J Physiol1998 275L365L371
Not in our library10.1152/ajplung.1998.275.2.l365
42.
Duncan MR Frazier KS Abramson S Williams S Klapper H Huang X Grotendorst GR Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMPFASEB J1999 1317741786
Not in our library
43.
Bonniaud P Margetts PJ Kolb M Haberberger T Kelly M Robertson J Gauldie J Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosisAm J Respir Crit Care Med2003 168770778
Not in our library10.1164/rccm.200210-1254oc
44.
Kottmann RM Hogan CM Phipps RP Sime PJ Determinants of initiation and progression of idiopathic pulmonary fibrosisRespirology2009 14917933
Not in our library10.1111/j.1440-1843.2009.01624.x
45.
Lo Re S Lecocq M Uwambayinema F Yakoub Y Delos M Demoulin JB Lucas S Sparwasser T Renauld JC Lison D Huaux F Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosisAm J Respir Crit Care Med2011 18412701281
Not in our library10.1164/rccm.201103-0516oc
46.
Trojanowska M Role of PDGF in fibrotic diseases and systemic sclerosisRheumatology (Oxford)2008 47Suppl 5v2v4
Not in our library10.1093/rheumatology/ken265
47.
Bonner JC Regulation of PDGF and its receptors in fibrotic diseasesCytokine Growth Factor Rev2004 15255273
Not in our library10.1016/j.cytogfr.2004.03.006
48.
Abdollahi A Li M Ping G Plathow C Domhan S Kiessling F Lee LB McMahon G Gröne HJ Lipson KE Huber PE Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosisJ Exp Med2005 201925935
Not in our library10.1084/jem.20041393
49.
Daniels CE Lasky JA Limper AH Mieras K Gabor E Schroeder DR Imatinib-IPF Study InvestigatorsImatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial resultsAm J Respir Crit Care Med2010 181604610
Not in our library10.1164/rccm.200906-0964oc
50.
Aono Y Nishioka Y Inayama M Ugai M Kishi J Uehara H Izumi K Sone S Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in miceAm J Respir Crit Care Med2005 17112791285
Not in our library10.1164/rccm.200404-531oc
51.
Mio T Nagai S Kitaichi M Kawatani A Izumi T Proliferative characteristics of fibroblast lines derived from open lung biopsy specimens of patients with IPF (UIP)Chest1992 102832837
Not in our library10.1378/chest.102.3.832
52.
Hetzel M Bachem M Anders D Trischler G Faehling M Different effects of growth factors on proliferation and matrix production of normal and fibrotic human lung fibroblastsLung2005 183225237
Not in our library10.1007/s00408-004-2534-z
53.
Bonner JC Osornio-Vargas AR Badgett A Brody AR Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophagesAm J Respir Cell Mol Biol1991 5539547
Not in our library10.1165/ajrcmb/5.6.539
54.
Osornio-Vargas AR Goodell AL Hernández-Rodríguez NA Brody AR Coin PG Badgett A Bonner JC Platelet-derived growth factor (PDGF)-AA, -AB, and -BB induce differential chemotaxis of early-passage rat lung fibroblasts in vitroAm J Respir Cell Mol Biol1995 123340
Not in our library10.1165/ajrcmb.12.1.7811469
55.
Goldstein RH Poliks CF Pilch PF Smith BD Fine A Stimulation of collagen formation by insulin and insulin-like growth factor I in cultures of human lung fibroblastsEndocrinology1989 124964970
Not in our library10.1210/endo-124-2-964
56.
Gillery P Leperre A Maquart FX Borel JP Insulin-like growth factor-I (IGF-I) stimulates protein synthesis and collagen gene expression in monolayer and lattice cultures of fibroblastsJ Cell Physiol1992 152389396
Not in our library10.1002/jcp.1041520221
57.
Hsu E Feghali-Bostwick CA Insulin-like growth factor-II is increased in systemic sclerosis-associated pulmonary fibrosis and contributes to the fibrotic process via Jun N-terminal kinase- and phosphatidylinositol-3 kinase-dependent pathwaysAm J Pathol2008 17215801590
Not in our library10.2353/ajpath.2008.071021
58.
Frankel SK Moats-Staats BM Cool CD Wynes MW Stiles AD Riches DW Human insulin-like growth factor-IA expression in transgenic mice promotes adenomatous hyperplasia but not pulmonary fibrosisAm J Physiol2005 288L805L812
Not in our library10.1152/ajplung.00420.2004
59.
Maeda A Hiyama K Yamakido H Ishioka S Yamakido M Increased expression of platelet-derived growth factor A and insulin-like growth factor-I in BAL cells during the development of bleomycin-induced pulmonary fibrosis in miceChest1996 109780786
Not in our library10.1378/chest.109.3.780
60.
Gordon S Martinez FO Alternative activation of macrophages: mechanism and functionsImmunity2010 32593604
Not in our library10.1016/j.immuni.2010.05.007
61.
Atamas SP Luzina IG Dai H Wilt SG White B Synergy between CD40 ligation and IL-4 on fibroblast proliferation involves IL-4 receptor signalingJ Immunol2002 16811391145
Not in our library10.4049/jimmunol.168.3.1139
62.
Jakubzick C Kunkel SL Puri RK Hogaboam CM Therapeutic targeting of IL-4- and IL-13-responsive cells in pulmonary fibrosisImmunol Res2004 30339349
Not in our library10.1385/ir:30:3:339
63.
Fuschiotti P Role of IL-13 in systemic sclerosisCytokine2011 56544549
Not in our library10.1016/j.cyto.2011.08.030
64.
Joshi BH Hogaboam C Dover P Husain SR Puri RK Role of interleukin-13 in cancer, pulmonary fibrosis, and other T(H)2-type diseasesVitam Horm2006 74479504
Not in our library10.1016/s0083-6729(06)74019-5
65.
Gharaee-Kermani M Nozaki Y Hatano K Phan SH Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosisCytokine2001 15138147
Not in our library10.1006/cyto.2001.0903
66.
Monroe JG Haldar S Prystowsky MB Lammie P Lymphokine regulation of inflammatory processes: interleukin-4 stimulates fibroblast proliferationClin Immunol Immunopathol1988 49292298
Not in our library10.1016/0090-1229(88)90119-5
67.
Postlethwaite AE Holness MA Katai H Raghow R Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4J Clin Invest1992 9014791485
Not in our library10.1172/jci116015
68.
Wilson MS Wynn TA Pulmonary fibrosis: pathogenesis, etiology and regulationMucosal Immunol2009 2103121
Not in our library10.1038/mi.2008.85
69.
Wynes MW Edelman BL Kostyk AG Edwards MG Coldren C Groshong SD Cosgrove GP Redente EF Bamberg A Brown KK Reisdorph N Keith RC Frankel SK Riches DW Increased cell surface Fas expression is necessary and sufficient to sensitize lung fibroblasts to Fas ligation-induced apoptosis: implications for fibroblast accumulation in idiopathic pulmonary fibrosisJ Immunol2011 187527537
Not in our library10.4049/jimmunol.1100447
70.
King TE Albera C Bradford WZ Costabel U Hormel P Lancaster L Noble PW Sahn SA Szwarcberg J Thomeer M Valeyre D du Bois RM INSPIRE Study GroupEffect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trialLancet2009 374222228
Not in our library10.1016/s0140-6736(09)60551-1
71.
Raghu G Brown KK Bradford WZ Starko K Noble PW Schwartz DA King TE Idiopathic Pulmonary Fibrosis Study GroupA placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosisN Engl J Med2004 350125133
Not in our library10.1056/nejmoa030511
72.
Kim JH Kim HY Kim S Chung JH Park WS Chung DH Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-gammaAm J Pathol2005 16712311241
Not in our library10.1016/s0002-9440(10)61211-4
73.
Gurujeyalakshmi G Giri SN Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expressionExp Lung Res1995 21791808
Not in our library10.3109/01902149509050842
74.
Duncan MR Berman B Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferationJ Exp Med1985 162516527
Not in our library10.1084/jem.162.2.516
75.
Yuan W Yufit T Li L Mori Y Chen SJ Varga J Negative modulation of alpha1(I) procollagen gene expression in human skin fibroblasts: transcriptional inhibition by interferon-gammaJ Cell Physiol1999 17997108
Not in our library10.1002/(sici)1097-4652(199904)179:1<97::aid-jcp12>3.0.co;2-e
76.
Gillery P Serpier H Polette M Bellon G Clavel C Wegrowski Y Birembaut P Kalis B Cariou R Maquart FX Gamma-interferon inhibits extracellular matrix synthesis and remodeling in collagen lattice cultures of normal and scleroderma skin fibroblastsEur J Cell Biol1992 57244253
Not in our library
77.
Wynn TA Fibrotic disease and the T(H)1/T(H)2 paradigmNat Rev Immunol2004 4583594
Not in our library10.1038/nri1412
78.
Hoshino T Okamoto M Sakazaki Y Kato S Young HA Aizawa H Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and miceAm J Respir Cell Mol Biol2009 41661670
Not in our library10.1165/rcmb.2008-0182oc
79.
Kolb M Margetts PJ Anthony DC Pitossi F Gauldie J Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosisJ Clin Invest2001 10715291536
Not in our library10.1172/jci12568
80.
Diaz A Munoz E Johnston R Korn JH Jimenez SA Regulation of human lung fibroblast alpha 1(I) procollagen gene expression by tumor necrosis factor alpha, interleukin-1 beta, and prostaglandin E2J Biol Chem1993 2681036410371
Not in our library
81.
Bhatnagar R Penfornis H Mauviel A Loyau G Saklatvala J Pujol JP Interleukin-1 inhibits the synthesis of collagen by fibroblastsBiochem Int1986 13709720
Not in our library
82.
Mauviel A Heino J Kähäri VM Hartmann DJ Loyau G Pujol JP Vuorio E Comparative effects of interleukin-1 and tumor necrosis factor-alpha on collagen production and corresponding procollagen mRNA levels in human dermal fibroblastsJ Invest Dermatol1991 96243249
Not in our library10.1111/1523-1747.ep12462185
83.
Postlethwaite AE Lachman LB Kang AH Induction of fibroblast proliferation by interleukin-1 derived from human monocytic leukemia cellsArthritis Rheum1984 279951001
Not in our library10.1002/art.1780270905
84.
Ortiz LA Lasky J Hamilton RF Holian A Hoyle GW Banks W Peschon JJ Brody AR Lungarella G Friedman M Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in miceExp Lung Res1998 24721743
Not in our library10.3109/01902149809099592
85.
Sime PJ Marr RA Gauldie D Xing Z Hewlett BR Graham FL Gauldie J Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblastsAm J Pathol1998 153825832
Not in our library10.1016/s0002-9440(10)65624-6
86.
Chou DH Lee W McCulloch CA TNF-alpha inactivation of collagen receptors: implications for fibroblast function and fibrosisJ Immunol1996 15643544362
Not in our library
87.
Postlethwaite AE Seyer JM Stimulation of fibroblast chemotaxis by human recombinant tumor necrosis factor alpha (TNF-alpha) and a synthetic TNF-alpha 31–68 peptideJ Exp Med1990 17217491756
Not in our library10.1084/jem.172.6.1749
88.
Raghu G Brown KK Costabel U Cottin V du Bois RM Lasky JA Thomeer M Utz JP Khandker RK McDermott L Fatenejad S Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trialAm J Respir Crit Care Med2008 178948955
Not in our library10.1164/rccm.200709-1446oc
89.
Wilson MS Madala SK Ramalingam TR Gochuico BR Rosas IO Cheever AW Wynn TA Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependentJ Exp Med2010 207535552
Not in our library10.1084/jem.20092121
90.
Simonian PL Roark CL Wehrmann F Lanham AK Diaz del Valle F Born WK O’Brien RL Fontenot AP Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosisJ Immunol2009 182657665
Not in our library
91.
Mozaffarian A Brewer AW Trueblood ES Luzina IG Todd NW Atamas SP Arnett HA Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosisJ Immunol2008 18172437253
Not in our library10.4049/jimmunol.181.10.7243
92.
Langdon C Kerr C Tong L Richards CD Oncostatin M regulates eotaxin expression in fibroblasts and eosinophilic inflammation in C57BL/6 miceJ Immunol2003 170548555
Not in our library10.4049/jimmunol.170.1.548
93.
Richards CD Kerr C Tong L Langdon C Modulation of extracellular matrix using adenovirus vectorsBiochem Soc Trans2002 30107111
Not in our library
94.
Ihn H Tamaki K Oncostatin M stimulates the growth of dermal fibroblasts via a mitogen-activated protein kinase-dependent pathwayJ Immunol2000 16521492155
Not in our library10.4049/jimmunol.165.4.2149
95.
Ihn H LeRoy EC Trojanowska M Oncostatin M stimulates transcription of the human alpha2(I) collagen gene via the Sp1/Sp3-binding siteJ Biol Chem1997 2722466624672
Not in our library10.1074/jbc.272.39.24666
96.
Scaffidi AK Mutsaers SE Moodley YP McAnulty RJ Laurent GJ Thompson PJ Knight DA Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblastsBr J Pharmacol2002 136793801
Not in our library10.1038/sj.bjp.0704769
97.
Pechkovsky DV Prasse A Kollert F Engel KM Dentler J Luttmann W Friedrich K Müller-Quernheim J Zissel G Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transductionClin Immunol2010 13789101
Not in our library10.1016/j.clim.2010.06.017
98.
Sun L Louie MC Vannella KM Wilke CA LeVine AM Moore BB Shanley TP New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axisAm J Physiol Lung Cell Mol Physiol2011 300L341L353
Not in our library10.1152/ajplung.00122.2010
99.
Arai T Abe K Matsuoka H Yoshida M Mori M Goya S Kida H Nishino K Osaki T Tachibana I Kaneda Y Hayashi S Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivoAm J Physiol Lung Cell Mol Physiol2000 278L914L922
Not in our library10.1152/ajplung.2000.278.5.l914
100.
García-Prieto E González-López A Cabrera S Astudillo A Gutiérrez-Fernández A Fanjul-Fernandez M Batalla-Solís E Puente XS Fueyo A López-Otín C Albaiceta GM Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10PLoS One2010 5e13242
Not in our library10.1371/journal.pone.0013242
101.
Moore BB Kolodsick JE Thannickal VJ Cooke K Moore TA Hogaboam C Wilke CA Toews GB CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injuryAm J Pathol2005 166675684
Not in our library10.1016/s0002-9440(10)62289-4
102.
Zhang K Gharaee-Kermani M Jones ML Warren JS Phan SH Lung monocyte chemoattractant protein-1 gene expression in bleomycin-induced pulmonary fibrosisJ Immunol1994 15347334741
Not in our library
103.
Johnston CJ Williams JP Okunieff P Finkelstein JN Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor familiesRadiat Res2002 157256265
Not in our library10.1667/0033-7587(2002)157[0256:ripfeo]2.0.co;2
104.
Gharaee-Kermani M Denholm EM Phan SH Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptorsJ Biol Chem1996 2711777917784
Not in our library10.1074/jbc.271.30.17779
105.
Liu X Das AM Seideman J Griswold D Afuh CN Kobayashi T Abe S Fang Q Hashimoto M Kim H Wang X Shen L Kawasaki S Rennard SI The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6Am J Respir Cell Mol Biol2007 37121128
Not in our library10.1165/rcmb.2005-0253oc
106.
Gharaee-Kermani M McCullumsmith RE Charo IF Kunkel SL Phan SH CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosisCytokine2003 24266276
Not in our library10.1016/j.cyto.2003.08.003
107.
Rose CE Sung SS Fu SM Significant involvement of CCL2 (MCP-1) in inflammatory disorders of the lungMicrocirculation2003 10273288
Not in our library10.1038/sj.mn.7800193
108.
Inoshima I Kuwano K Hamada N Hagimoto N Yoshimi M Maeyama T Takeshita A Kitamoto S Egashira K Hara N Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in miceAm J Physiol Lung Cell Mol Physiol2004 286L1038L1044
Not in our library10.1152/ajplung.00167.2003
109.
Pochetuhen K Luzina IG Lockatell V Todd NW Atamas SP Complex regulation of pulmonary inflammation and fibrosis by CCL18Am J Pathol2007 171428437
Not in our library10.2353/ajpath.2007.061167
110.
Atamas SP Luzina IG Choi J Tsymbalyuk N Carbonetti NH Singh IS Trojanowska M Jimenez SA White B Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblastsAm J Respir Cell Mol Biol2003 29743749
Not in our library10.1165/rcmb.2003-0078oc
111.
Luzina IG Tsymbalyuk N Choi J Hasday JD Atamas SP CCL18-stimulated upregulation of collagen production in lung fibroblasts requires Sp1 signaling and basal Smad3 activityJ Cell Physiol2006 206221228
Not in our library10.1002/jcp.20452
112.
Luzina IG Highsmith K Pochetuhen K Nacu N Rao JN Atamas SP PKC- alpha mediates CCL18-stimulated collagen production in pulmonary fibroblastsAm J Respir Cell Mol Biol2006 35298305
Not in our library10.1165/rcmb.2006-0033oc
113.
Luzina IG Papadimitriou JC Anderson R Pochetuhen K Atamas SP Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte-dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18Arthritis Rheum2006 5426432655
Not in our library10.1002/art.21950
114.
Prasse A Probst C Bargagli E Zissel G Toews GB Flaherty KR Olschewski M Rottoli P Müller-Quernheim J Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosisAm J Respir Crit Care Med2009 179717723
Not in our library10.1164/rccm.200808-1201oc
115.
Tiev KP Hua-Huy T Kettaneh A Gain M Duong-Quy S Tolédano C Cabane J Dinh-Xuan AT Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosisEur Respir J2011 3813551360
Not in our library10.1183/09031936.00004711
116.
Ishida Y Kimura A Kondo T Hayashi T Ueno M Takakura N Matsushima K Mukaida N Essential roles of the CC chemokine ligand 3-CC chemokine receptor 5 axis in bleomycin-induced pulmonary fibrosis through regulation of macrophage and fibrocyte infiltrationAm J Pathol2007 170843854
Not in our library10.2353/ajpath.2007.051213
117.
Yang X Walton W Cook DN Hua X Tilley S Haskell CA Horuk R Blackstock AW Kirby SL The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosisAm J Respir Cell Mol Biol2011 45127135
Not in our library10.1165/rcmb.2010-0265oc
118.
Smith RE Strieter RM Phan SH Lukacs NW Huffnagle GB Wilke CA Burdick MD Lincoln P Evanoff H Kunkel SL Production and function of murine macrophage inflammatory protein–1 alpha in bleomycin-induced lung injuryJ Immunol1994 15347044712
Not in our library
119.
Russo RC Alessandri AL Garcia CC Cordeiro BF Pinho V Cassali GD Proudfoot AE Teixeira MM Therapeutic effects of evasin-1, a chemokine binding protein, in bleomycin-induced pulmonary fibrosisAm J Respir Cell Mol Biol2011 457280
Not in our library10.1165/rcmb.2009-0406oc
120.
Lama VN Phan SH The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyondProc Am Thorac Soc2006 3373376
Not in our library10.1513/pats.200512-133tk
121.
Andersson-Sjöland A de Alba CG Nihlberg K Becerril C Ramírez R Pardo A Westergren-Thorsson G Selman M Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosisInt J Biochem Cell Biol2008 4021292140
Not in our library10.1016/j.biocel.2008.02.012
122.
Phillips RJ Burdick MD Hong K Lutz MA Murray LA Xue YY Belperio JA Keane MP Strieter RM Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosisJ Clin Invest2004 114438446
Not in our library10.1172/jci20997
123.
Schrier DJ Phan SH McGarry BM The effects of the nude (nu/nu) mutation on bleomycin-induced pulmonary fibrosisAm Rev Respir Dis1983 127614617
Not in our library10.1164/arrd.1983.127.5.614
124.
Okazaki T Nakao A Nakano H Takahashi F Takahashi K Shimozato O Takeda K Yagita H Okumura K Impairment of bleomycin-induced lung fibrosis in CD28-deficient miceJ Immunol2001 16719771981
Not in our library10.4049/jimmunol.167.4.1977
125.
Piguet PF Collart MA Grau GE Kapanci Y Vassalli P Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosisJ Exp Med1989 170655663
Not in our library10.1084/jem.170.3.655
126.
Sharma SK MacLean JA Pinto C Kradin RL The effect of an anti-CD3 monoclonal antibody on bleomycin-induced lymphokine production and lung injuryAm J Respir Crit Care Med1996 154193200
Not in our library10.1164/ajrccm.154.1.8680680
127.
Luzina IG Papadimitriou JC Anderson R Pochetuhen K Atamas SP Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte-dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18Arthritis Rheum2006 5426432655
Not in our library10.1002/art.21950
128.
Maggi E Cosmi L Liotta F Romagnani P Romagnani S Annunziato F Thymic regulatory T cellsAutoimmun Rev2005 4579586
Not in our library10.1016/j.autrev.2005.04.010
129.
Kradin RL Divertie MB Colvin RB Ramirez J Ryu J Carpenter HA Bhan AK Usual interstitial pneumonitis is a T-cell alveolitisClin Immunol Immunopathol1986 40224235
Not in our library10.1016/0090-1229(86)90025-5
130.
Daniil Z Kitsanta P Kapotsis G Mathioudaki M Kollintza A Karatza M Milic-Emili J Roussos C Papiris SA CD8+ T lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosisRespir Res2005 681
Not in our library10.1186/1465-9921-6-81
131.
Parra ER Kairalla RA Ribeiro de Carvalho CR Eher E Capelozzi VL Inflammatory cell phenotyping of the pulmonary interstitium in idiopathic interstitial pneumoniaRespiration2007 74159169
Not in our library10.1159/000097133
132.
Marchal-Somme J Uzunhan Y Marchand-Adam S Valeyre D Soumelis V Crestani B Soler P Cutting edge: nonproliferating mature immune cells form a novel type of organized lymphoid structure in idiopathic pulmonary fibrosisJ Immunol2006 17657355739
Not in our library10.4049/jimmunol.176.10.5735
133.
Fireman E Vardinon N Burke M Spizer S Levin S Endler A Stav D Topilsky M Mann A Schwarz Y Kivity S Greif J Predictive value of response to treatment of T-lymphocyte subpopulations in idiopathic pulmonary fibrosisEur Respir J1998 11706711
Not in our library
134.
Pignatti P Brunetti G Moretto D Yacoub MR Fiori M Balbi B Balestrino A Cervio G Nava S Moscato G Role of the chemokine receptors CXCR3 and CCR4 in human pulmonary fibrosisAm J Respir Crit Care Med2006 173310317
Not in our library10.1164/rccm.200502-244oc
135.
Wells AU Lorimer S Majumdar S Harrison NK Corrin B Black CM Jeffery PK du Bois RM Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitiumEur Respir J1995 8266271
Not in our library10.1183/09031936.95.08020266
136.
CD28 Down-Regulation on Circulating CD4 T-Cells Is Associated with Poor Prognoses of Patients with Idiopathic Pulmonary Fibrosis · 2010
No notice
137.
Shimizu Y Kuwabara H Ono A Higuchi S Hisada T Dobashi K Utsugi M Mita Y Mori M Intracellular Th1/Th2 balance of pulmonary CD4(+) T cells in patients with active interstitial pneumonia evaluated by serum KL-6Immunopharmacol Immunotoxicol2006 28295304
Not in our library10.1080/08923970600809389
138.
Atamas SP Yurovsky VV Wise R Wigley FM Goter Robinson CJ Henry P Alms WJ White B Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosisArthritis Rheum1999 4211681178
Not in our library10.1002/1529-0131(199906)42:6<1168::aid-anr13>3.0.co;2-l
139.
Luzina IG Atamas SP Wise R Wigley FM Choi J Xiao HQ White B Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patientsArthritis Rheum2003 4822622274
Not in our library10.1002/art.11080
140.
Popp W Ritschka L Scherak O Braun O Kolarz G Rauscher H Zwick H Bronchoalveolar lavage in rheumatoid arthritis and secondary Sjogren's syndromeLung1990 168221231
Not in our library10.1007/bf02719696
141.
Sauty A Rochat T Schoch OD Hamacher J Kurt AM Dayer JM Nicod LP Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodiesEur Respir J1997 1029072912
Not in our library10.1183/09031936.97.10122907
142.
Kourakata H Takada T Suzuki E Enomoto K Saito I Taguchi Y Tsukada H Nakano M Arakawa M Flowcytometric analysis of bronchoalveolar lavage fluid cells in polymyositis/dermatomyositis with interstitial pneumoniaRespirology1999 4223228
Not in our library10.1046/j.1440-1843.1999.00179.x
143.
Capelli A Di Stefano A Lusuardi M Gnemmi I Donner CF Increased macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosisAm J Respir Crit Care Med2002 165236241
Not in our library10.1164/ajrccm.165.2.2106084
144.
Bill JR Mack DG Falta MT Maier LA Sullivan AK Joslin FG Martin AK Freed BM Kotzin BL Fontenot AP Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II beta-chainJ Immunol2005 17570297037
Not in our library10.4049/jimmunol.175.10.7029
145.
Murayama J Yoshizawa Y Ohtsuka M Hasegawa S Lung fibrosis in hypersensitivity pneumonitis. Association with CD4+ but not CD8+ cell dominant alveolitis and insidious onsetChest1993 1043843
Not in our library10.1378/chest.104.1.38
146.
Reynolds HY Lung inflammation and fibrosis: an alveolar macrophage-centered perspective from the 1970s to 1980sAm J Respir Crit Care Med2005 17198102
Not in our library10.1164/rccm.200406-788pp
147.
Cantin AM North SL Fells GA Hubbard RC Crystal RG Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosisJ Clin Invest1987 7916651673
Not in our library10.1172/jci113005
148.
Reactive Oxygen Species Are Required for Maintenance and Differentiation of Primary Lung Fibroblasts in Idiopathic Pulmonary Fibrosis · 2010
No notice
149.
Kiemle-Kallee J Kreipe H Radzun HJ Parwaresch MR Auerswald U Magnussen H Barth J Alveolar macrophages in idiopathic pulmonary fibrosis display a more monocyte-like immunophenotype and an increased release of free oxygen radicalsEur Respir J1991 4400406
Not in our library
150.
Schaberg T Rau M Stephan H Lode H Increased number of alveolar macrophages expressing surface molecules of the CD11/CD18 family in sarcoidosis and idiopathic pulmonary fibrosis is related to the production of superoxide anions by these cellsAm Rev Respir Dis1993 14715071513
Not in our library10.1164/ajrccm/147.6_pt_1.1507
151.
Ye Q Dalavanga Y Poulakis N Sixt SU Guzman J Costabel U Decreased expression of haem oxygenase-1 by alveolar macrophages in idiopathic pulmonary fibrosisEur Respir J2008 3110301036
Not in our library10.1183/09031936.00125407
152.
Scotton CJ Krupiczojc MA Königshoff M Mercer PF Lee YC Kaminski N Morser J Post JM Maher TM Nicholson AG Moffatt JD Laurent GJ Derian CK Eickelberg O Chambers RC Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injuryJ Clin Invest2009 11925502563
Not in our library10.1172/jci33288
153.
Howell DC Johns RH Lasky JA Shan B Scotton CJ Laurent GJ Chambers RC Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosisAm J Pathol2005 16613531365
Not in our library10.1016/s0002-9440(10)62354-1
154.
Tani K Ogushi F Takahashi H Kawano T Endo T Sone S Thrombin stimulates platelet-derived growth factor release by alveolar macrophages in rats–significance in bleomycin-induced pulmonary fibrosisJ Med Invest1997 445965
Not in our library
155.
Kopiński P Balicka-Ślusarczyk B Dyczek A Szpechciński A Przybylski G Jarzemska A Wandtke T Jankowski M Iwaniec T Chorostowska-Wynimko J Enhanced expression of Fas Ligand (FasL) in the lower airways of patients with fibrotic interstitial lung diseases (ILDs)Folia Histochem Cytobiol2011 49636645
Not in our library10.5603/fhc.2011.0087
156.
Martinet Y Rom WN Grotendorst GR Martin GR Crystal RG Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosisN Engl J Med1987 317202209
Not in our library10.1056/nejm198707233170404
157.
Nagaoka I Trapnell BC Crystal RG Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosisJ Clin Invest1990 8520232027
Not in our library10.1172/jci114669
158.
Zhang Y Lee TC Guillemin B Yu MC Rom WN Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposureJ Immunol1993 15041884196
Not in our library
159.
Furuie H Yamasaki H Suga M Ando M Altered accessory cell function of alveolar macrophages: a possible mechanism for induction of Th2 secretory profile in idiopathic pulmonary fibrosisEur Respir J1997 10787794
Not in our library
160.
Büttner C Skupin A Reimann T Rieber EP Unteregger G Geyer P Frank KH Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4Am J Respir Cell Mol Biol1997 17315325
Not in our library10.1165/ajrcmb.17.3.2279
161.
Prasse A Pechkovsky DV Toews GB Jungraithmayr W Kollert F Goldmann T Vollmer E Müller-Quernheim J Zissel G A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18Am J Respir Crit Care Med2006 173781792
Not in our library10.1164/rccm.200509-1518oc
162.
Migliaccio CT Buford MC Jessop F Holian A The IL-4Ralpha pathway in macrophages and its potential role in silica-induced pulmonary fibrosisJ Leukoc Biol2008 83630639
Not in our library10.1189/jlb.0807533
163.
Mora AL Torres-González E Rojas M Corredor C Ritzenthaler J Xu J Roman J Brigham K Stecenko A Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosisAm J Respir Cell Mol Biol2006 35466473
Not in our library10.1165/rcmb.2006-0121oc
164.
Murray LA Chen Q Kramer MS Hesson DP Argentieri RL Peng X Gulati M Homer RJ Russell T van Rooijen N Elias JA Hogaboam CM Herzog EL TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid PInt J Biochem Cell Biol2011 43154162
Not in our library10.1016/j.biocel.2010.10.013
165.
Serum Amyloid P Therapeutically Attenuates Murine Bleomycin-Induced Pulmonary Fibrosis via Its Effects on Macrophages · 2010
No notice
166.
Wallace WA Roberts SN Caldwell H Thornton E Greening AP Lamb D Howie SE Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitisThorax1994 49218224
Not in our library10.1136/thx.49.3.218
167.
Wallace WA Schofield JA Lamb D Howie SE Localisation of a pulmonary autoantigen in cryptogenic fibrosing alveolitisThorax1994 4911391145
Not in our library10.1136/thx.49.11.1139
168.
Yang Y Fujita J Bandoh S Ohtsuki Y Yamadori I Yoshinouchi T Ishida T Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumoniaClin Exp Immunol2002 128169174
Not in our library10.1046/j.1365-2249.2002.01811.x
169.
Dobashi N Fujita J Ohtsuki Y Yamadori I Yoshinouchi T Kamei T Tokuda M Hojo S Okada H Takahara J Detection of anticytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disordersThorax1998 53969974
Not in our library10.1136/thx.53.11.969
170.
Fujita J Dobashi N Ohtsuki Y Yamadori I Yoshinouchi T Kamei T Tokuda M Hojo S Okada H Takahara J Elevation of anticytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disordersLung1999 177311319
Not in our library10.1007/pl00007649
171.
Feghali-Bostwick CA Tsai CG Valentine VG Kantrow S Stoner MW Pilewski JM Gadgil A George MP Gibson KF Choi AM Kaminski N Zhang Y Duncan SR Cellular and humoral autoreactivity in idiopathic pulmonary fibrosisJ Immunol2007 17925922599
Not in our library10.4049/jimmunol.179.4.2592
172.
Taillé C Grootenboer-Mignot S Boursier C Michel L Debray MP Fagart J Barrientos L Mailleux A Cigna N Tubach F Marchal-Sommé J Soler P Chollet-Martin S Crestani B Identification of periplakin as a new target for autoreactivity in idiopathic pulmonary fibrosisAm J Respir Crit Care Med2011 183759766
Not in our library10.1164/rccm.201001-0076oc
173.
Sato S Hasegawa M Fujimoto M Tedder TF Takehara K Quantitative genetic variation in CD19 expression correlates with autoimmunityJ Immunol2000 16566356643
Not in our library10.4049/jimmunol.165.11.6635
174.
Tsuchiya N Kuroki K Fujimoto M Murakami Y Tedder TF Tokunaga K Takehara K Sato S Association of a functional CD19 polymorphism with susceptibility to systemic sclerosisArthritis Rheum2004 5040024007
Not in our library10.1002/art.20674
175.
Yoshizaki A Iwata Y Komura K Ogawa F Hara T Muroi E Takenaka M Shimizu K Hasegawa M Fujimoto M Tedder TF Sato S CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced sclerodermaAm J Pathol2008 17216501663
Not in our library10.2353/ajpath.2008.071049
176.
Komura K Yanaba K Horikawa M Ogawa F Fujimoto M Tedder TF Sato S CD19 regulates the development of bleomycin-induced pulmonary fibrosis in a mouse modelArthritis Rheum2008 5835743584
Not in our library10.1002/art.23995
177.
Arras M Huaux F Vink A Delos M Coutelier JP Many MC Barbarin V Renauld JC Lison D Interleukin-9 reduces lung fibrosis and type 2 immune polarization induced by silica particles in a murine modelAm J Respir Cell Mol Biol2001 24368375
Not in our library10.1165/ajrcmb.24.4.4249
178.
Arras M Louahed J Simoen V Barbarin V Misson P van den Brûle S Delos M Knoops L Renauld JC Lison D Huaux F B lymphocytes are critical for lung fibrosis control and prostaglandin E2 regulation in IL-9 transgenic miceAm J Respir Cell Mol Biol2006 34573580
Not in our library10.1165/rcmb.2004-0383oc
179.
Hess S Rensing-Ehl A Schwabe R Bufler P Engelmann H CD40 function in nonhematopoietic cells. Nuclear factor kappa B mobilization and induction of IL-6 productionJ Immunol1995 15545884595
Not in our library
180.
Fries KM Sempowski GD Gaspari AA Blieden T Looney RJ Phipps RP CD40 expression by human fibroblastsClin Immunol Immunopathol1995 774251
Not in our library10.1016/0090-1229(95)90135-3
181.
Yellin MJ Winikoff S Fortune SM Baum D Crow MK Lederman S Chess L Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferationJ Leukocyte Biol1995 58209
Not in our library10.1002/jlb.58.2.209
182.
Sempowski GD Chess PR Phipps RP CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule on normal human lung fibroblastsJ Immunol1997 15846704677
Not in our library
183.
Zhang-Hoover J Sutton A Stein-Streilein J CD40/CD40 ligand interactions are critical for elicitation of autoimmune-mediated fibrosis in the lungJ Immunol2001 16635563563
Not in our library10.4049/jimmunol.166.5.3556
184.
Adawi A Zhang Y Baggs R Rubin P Williams J Finkelstein J Phipps RP Blockade of CD40-CD40 ligand interactions protects against radiation-induced pulmonary inflammation and fibrosisClin Immunol Immunopathol1998 89222230
Not in our library10.1006/clin.1998.4606
185.
Adawi A Zhang Y Baggs R Finkelstein J Phipps RP Disruption of the CD40-CD40 ligand system prevents an oxygen-induced respiratory distress syndromeAm J Pathol1998 152651657
Not in our library
186.
Henn V Slupsky JR Gräfe M Anagnostopoulos I Förster R Müller-Berghaus G Kroczek RA CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cellsNature1998 391591594
Not in our library10.1038/35393
187.
Pinchuk LM Klaus SJ Magaletti DM Pinchuk GV Norsen JP Clark EA Functional CD40 ligand expressed by human blood dendritic cells is up-regulated by CD40 ligationJ Immunol1996 15743634370
Not in our library
188.
Kaufman J Sime PJ Phipps RP Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by IFN-gamma and IL-13, and implications for fibrosisJ Immunol2004 17218621871
Not in our library10.4049/jimmunol.172.3.1862
189.
Kaufman J Graf BA Leung EC Pollock SJ Koumas L Reddy SY Blieden TM Smith TJ Phipps RP Fibroblasts as sentinel cells: role of the CDcd40-CDcd40 ligand system in fibroblast activation and lung inflammation and fibrosisChest2001 1201 Suppl53S55S
Not in our library10.1378/chest.120.1_suppl.s53
190.
Hagimoto N Kuwano K Nomoto Y Kunitake R Hara N Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin-induced pulmonary fibrosis in miceAm J Respir Cell Mol Biol1997 1691101
Not in our library10.1165/ajrcmb.16.1.8998084
191.
Golan-Gerstl R Wallach-Dayan SB Amir G Breuer R Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosisAm J Respir Cell Mol Biol2007 36270275
Not in our library10.1165/rcmb.2006-0133oc
192.
Hagimoto N Kuwano K Miyazaki H Kunitake R Fujita M Kawasaki M Kaneko Y Hara N Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigenAm J Respir Cell Mol Biol1997 17272278
Not in our library10.1165/ajrcmb.17.3.2893
193.
Matute-Bello G Winn RK Jonas M Chi EY Martin TR Liles WC Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammationAm J Pathol2001 158153161
Not in our library10.1016/s0002-9440(10)63953-3
194.
Kuwano K Hagimoto N Kawasaki M Yatomi T Nakamura N Nagata S Suda T Kunitake R Maeyama T Miyazaki H Hara N Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosisJ Clin Invest1999 1041319
Not in our library10.1172/jci5628
195.
Hao Z Hampel B Yagita H Rajewsky K T cell-specific ablation of Fas leads to Fas ligand-mediated lymphocyte depletion and inflammatory pulmonary fibrosisJ Exp Med2004 19913551365
Not in our library10.1084/jem.20032196
196.
Bühling F Wille A Röcken C Wiesner O Baier A Meinecke I Welte T Pap T Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosisRespir Res2005 637
Not in our library10.1186/1465-9921-6-37
197.
Frankel SK Cosgrove GP Cha SI Cool CD Wynes MW Edelman BL Brown KK Riches DW TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosisAm J Respir Cell Mol Biol2006 34293304
Not in our library10.1165/rcmb.2005-0155oc
198.
Kuwano K Miyazaki H Hagimoto N Kawasaki M Fujita M Kunitake R Kaneko Y Hara N The involvement of Fas-Fas ligand pathway in fibrosing lung diseasesAm J Respir Cell Mol Biol1999 205360
Not in our library10.1165/ajrcmb.20.1.2941
199.
Maeyama T Kuwano K Kawasaki M Kunitake R Hagimoto N Matsuba T Yoshimi M Inoshima I Yoshida K Hara N Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosisEur Respir J2001 17180189
Not in our library10.1183/09031936.01.17201800
200.
Kuwano K Kawasaki M Maeyama T Hagimoto N Nakamura N Shirakawa K Hara N Soluble form of fas and fas ligand in BAL fluid from patients with pulmonary fibrosis and bronchiolitis obliterans organizing pneumoniaChest2000 118451458
Not in our library10.1378/chest.118.2.451
201.
Kuwano K Maeyama T Inoshima I Ninomiya K Hagimoto N Yoshimi M Fujita M Nakamura N Shirakawa K Hara N Increased circulating levels of soluble Fas ligand are correlated with disease activity in patients with fibrosing lung diseasesRespirology2002 71521
Not in our library10.1046/j.1440-1843.2002.00369.x
202.
Hyytiäinen M Penttinen C Keski-Oja J Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activationCrit Rev Clin Lab Sci2004 41233264
Not in our library10.1080/10408360490460933
203.
Goodwin A Jenkins G Role of integrin-mediated TGFbeta activation in the pathogenesis of pulmonary fibrosisBiochem Soc Trans2009 37849854
Not in our library10.1042/bst0370849
204.
Weber GF Bjerke MA DeSimone DW Integrins and cadherins join forces to form adhesive networksJ Cell Sci2011 12411831193
Not in our library10.1242/jcs.064618
205.
Ye F Kim C Ginsberg MH Reconstruction of integrin activationBlood2012 1192633
Not in our library10.1182/blood-2011-04-292128
206.
Munger JS Huang X Kawakatsu H Griffiths MJ Dalton SL Wu J Pittet JF Kaminski N Garat C Matthay MA Rifkin DB Sheppard D The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosisCell1999 96319328
Not in our library10.1016/s0092-8674(00)80545-0
207.
Puthawala K Hadjiangelis N Jacoby SC Bayongan E Zhao Z Yang Z Devitt ML Horan GS Weinreb PH Lukashev ME Violette SM Grant KS Colarossi C Formenti SC Munger JS Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosisAm J Respir Crit Care Med2008 1778290
Not in our library10.1164/rccm.200706-806oc
208.
Horan GS Wood S Ona V Li DJ Lukashev ME Weinreb PH Simon KJ Hahm K Allaire NE Rinaldi NJ Goyal J Feghali-Bostwick CA Matteson EL O'Hara C Lafyatis R Davis GS Huang X Sheppard D Violette SM Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammationAm J Respir Crit Care Med2008 1775665
Not in our library10.1164/rccm.200706-805oc
209.
Kitamura H Cambier S Somanath S Barker T Minagawa S Markovics J Goodsell A Publicover J Reichardt L Jablons D Wolters P Hill A Marks JD Lou J Pittet JF Gauldie J Baron JL Nishimura SL Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-βJ Clin Invest2011 12128632875
Not in our library10.1172/jci45589
210.
Fjellbirkeland L Cambier S Broaddus VC Hill A Brunetta P Dolganov G Jablons D Nishimura SL Integrin alphavbeta8-mediated activation of transforming growth factor-beta inhibits human airway epithelial proliferation in intact bronchial tissueAm J Pathol2003 163533542
Not in our library10.1016/s0002-9440(10)63681-4
211.
Neurohr C Nishimura SL Sheppard D Activation of transforming growth factor-beta by the integrin alphavbeta8 delays epithelial wound closureAm J Respir Cell Mol Biol2006 35252259
Not in our library10.1165/rcmb.2006-0013oc
212.
Kim KK Wei Y Szekeres C Kugler MC Wolters PJ Hill ML Frank JA Brumwell AN Wheeler SE Kreidberg JA Chapman HA Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosisJ Clin Invest2009 119213224
Not in our library10.1172/jci36940
213.
Borok Z Role for alpha3 integrin in EMT and pulmonary fibrosisJ Clin Invest2009 119710
Not in our library10.1172/jci38084
214.
Luzina IG Todd NW Nacu N Lockatell V Choi J Hummers LK Atamas SP Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytesArthritis Rheum2009 6015301539
Not in our library10.1002/art.24435
215.
Kilshaw PJ Alpha E beta 7Mol Pathol1999 52203207
Not in our library10.1136/mp.52.4.203
216.
Braun RK Sterner-Kock A Kilshaw PJ Ferrick DA Giri SN Integrin alpha E beta 7 expression on BAL CD4+, CD8+, and gamma delta T-cells in bleomycin-induced lung fibrosis in mouseEur Respir J1996 9673679
Not in our library10.1183/09031936.96.09040673
217.
Rihs S Walker C Virchow JC Boer C Kroegel C Giri SN Braun RK Differential expression of alpha E beta 7 integrins on bronchoalveolar lavage T lymphocyte subsets: regulation by alpha 4 beta 1-integrin crosslinking and TGF-betaAm J Respir Cell Mol Biol1996 15600610
Not in our library10.1165/ajrcmb.15.5.8918367
218.
Vajkoczy P Laschinger M Engelhardt B Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvesselsJ Clin Invest2001 108557565
Not in our library10.1172/jci12440
219.
Wang Q Wang Y Hyde DM Gotwals PJ Lobb RR Ryan ST Giri SN Effect of antibody against integrin alpha4 on bleomycin-induced pulmonary fibrosis in miceBiochem Pharmacol2000 6019491958
Not in our library10.1016/s0006-2952(00)00491-3
220.
Jokinen J Dadu E Nykvist P Käpylä J White DJ Ivaska J Vehviläinen P Reunanen H Larjava H Häkkinen L Heino J Integrin-mediated cell adhesion to type I collagen fibrilsJ Biol Chem2004 2793195631963
Not in our library10.1074/jbc.m401409200
221.
Xia H Diebold D Nho R Perlman D Kleidon J Kahm J Avdulov S Peterson M Nerva J Bitterman P Henke C Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosisJ Exp Med2008 20516591672
Not in our library10.1084/jem.20080001
222.
Wipff PJ Rifkin DB Meister JJ Hinz B Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrixJ Cell Biol2007 17913111323
Not in our library10.1083/jcb.200704042
223.
Zhou Y Hagood JS Murphy-Ullrich JE Thy-1 expression regulates the ability of rat lung fibroblasts to activate transforming growth factor-beta in response to fibrogenic stimuliAm J Pathol2004 165659669
Not in our library10.1016/s0002-9440(10)63330-5
224.
Hagood JS Prabhakaran P Kumbla P Salazar L MacEwen MW Barker TH Ortiz LA Schoeb T Siegal GP Alexander CB Pardo A Selman M Loss of fibroblast Thy-1 expression correlates with lung fibrogenesisAm J Pathol2005 167365379
Not in our library10.1016/s0002-9440(10)62982-3
225.
Zhou Y Hagood JS Lu B Merryman WD Murphy-Ullrich JE Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiationJ Biol Chem2010 2852238222393
Not in our library10.1074/jbc.m110.126227
226.
Asano Y Ihn H Jinnin M Mimura Y Tamaki K Involvement of alphavbeta5 integrin in the establishment of autocrine TGF-beta signaling in dermal fibroblasts derived from localized sclerodermaJ Invest Dermatol2006 12617611769
Not in our library10.1038/sj.jid.5700331
227.
Asano Y Ihn H Yamane K Kubo M Tamaki K Increased expression levels of integrin alphavbeta5 on scleroderma fibroblastsAm J Pathol2004 16412751292
Not in our library10.1016/s0002-9440(10)63215-4
228.
Asano Y Ihn H Yamane K Jinnin M Tamaki K Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblastsAm J Pathol2006 168499510
Not in our library10.2353/ajpath.2006.041306
229.
Fredberg U Stengaard-Pedersen K Chronic tendinopathy tissue pathology, pain mechanisms, and etiology with a special focus on inflammationScand J Med Sci Sports2008 18315
Not in our library10.1111/j.1600-0838.2007.00746.x
230.
Schulze-Tanzil G Al-Sadi O Wiegand E Ertel W Busch C Kohl B Pufe T The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: new insightsScand J Med Sci Sports2011 21337351
Not in our library10.1111/j.1600-0838.2010.01265.x
231.
Arvin B Neville LF Barone FC Feuerstein GZ The role of inflammation and cytokines in brain injuryNeurosci Biobehav Rev1996 20445452
Not in our library10.1016/0149-7634(95)00026-7
232.
Ghirnikar RS Lee YL Eng LF Inflammation in traumatic brain injury: role of cytokines and chemokinesNeurochem Res1998 23329340
Not in our library10.1023/a:1022453332560
233.
Helmy A De Simoni MG Guilfoyle MR Carpenter KL Hutchinson PJ Cytokines and innate inflammation in the pathogenesis of human traumatic brain injuryProg Neurobiol2011 95352372
Not in our library10.1016/j.pneurobio.2011.09.003
234.
Keatings VM Jatakanon A Worsdell YM Barnes PJ Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPDAm J Respir Crit Care Med1997 155542548
Not in our library10.1164/ajrccm.155.2.9032192
235.
Barnes PJ Glucocorticosteroids: current and future directionsBr J Pharmacol2011 1632943
Not in our library10.1111/j.1476-5381.2010.01199.x
236.
Suissa S Barnes PJ Inhaled corticosteroids in COPD: the case againstEur Respir J2009 341316
Not in our library10.1183/09031936.00190908
237.
Calverley PM Anderson JA Celli B Ferguson GT Jenkins C Jones PW Yates JC Vestbo J TORCH investigatorsSalmeterol and fluticasone propionate and survival in chronic obstructive pulmonary diseaseN Engl J Med2007 356775789
Not in our library10.1056/nejmoa063070
238.
Yang IA Fong KM Sim EH Black PN Lasserson TJ Inhaled corticosteroids for stable chronic obstructive pulmonary diseaseCochrane Database Syst Rev2007 2CD002991
Not in our library10.1002/14651858.cd002991.pub2
239.
Culpitt SV Maziak W Loukidis S Nightingale JA Matthews JL Barnes PJ Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med1999 16016351639
Not in our library10.1164/ajrccm.160.5.9811058
240.
Loppow D Schleiss MB Kanniess F Taube C Jörres RA Magnussen H In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammationRespir Med2001 95115121
Not in our library10.1053/rmed.2000.0960
241.
Hattotuwa KL Gizycki MJ Ansari TW Jeffery PK Barnes NC The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy studyAm J Respir Crit Care Med2002 16515921596
Not in our library10.1164/rccm.2105025
242.
Leung DY Martin RJ Szefler SJ Sher ER Ying S Kay AB Hamid Q Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthmaJ Exp Med1995 1813340
Not in our library10.1084/jem.181.1.33
243.
Kay AB Diaz P Carmicheal J Grant IW Corticosteroid-resistant chronic asthma and monocyte complement receptorsClin Exp Immunol1981 44576580
Not in our library
244.
Poznansky MC Gordon AC Douglas JG Krajewski AS Wyllie AH Grant IW Resistance to methylprednisolone in cultures of blood mononuclear cells from glucocorticoid-resistant asthmatic patientsClin Sci (Lond)1984 67639645
Not in our library10.1042/cs0670639
245.
Corrigan CJ Brown PH Barnes NC Tsai JJ Frew AJ Kay AB Glucocorticoid resistance in chronic asthma. Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin AAm Rev Respir Dis1991 14410261032
Not in our library10.1164/ajrccm/144.5.page
246.
Hew M Bhavsar P Torrego A Meah S Khorasani N Barnes PJ Adcock I Chung KF Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthmaAm J Respir Crit Care Med2006 174134141
Not in our library10.1164/rccm.200512-1930oc
247.
Bhavsar P Hew M Khorasani N Torrego A Barnes PJ Adcock I Chung KF Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthmaThorax2008 63784790
Not in our library10.1136/thx.2007.090027
248.
Sliwinska-Stanczyk P Pazdur J Ziolkowska M Jaworski J Kaminska-Tchorzewska E Lacki JK The effect of methylprednisolone on proliferation of PBMCs obtained from steroid-sensitive and steroid-resistant rheumatoid arthritis patientsScand J Rheumatol2007 36167171
Not in our library10.1080/03009740601154111
249.
Seki M Ushiyama C Seta N Abe K Fukazawa T Asakawa J Takasaki Y Hashimoto H Apoptosis of lymphocytes induced by glucocorticoids and relationship to therapeutic efficacy in patients with systemic lupus erythematosusArthritis Rheum1998 41823830
Not in our library10.1002/1529-0131(199805)41:5<823::aid-art8>3.0.co;2-#
250.
Farrell RJ Kelleher D Glucocorticoid resistance in inflammatory bowel diseaseJ Endocrinol2003 178339346
Not in our library10.1677/joe.0.1780339
251.
Hearing SD Norman M Probert CS Haslam N Dayan CM Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytesGut1999 45382388
Not in our library10.1136/gut.45.3.382
252.
Donn R Berry A Stevens A Farrow S Betts J Stevens R Clayton C Wang J Warnock L Worthington J Scott L Graham S Ray D Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRIIFASEB J2007 21402414
Not in our library10.1096/fj.06-7236com
253.
Irusen E Matthews JG Takahashi A Barnes PJ Chung KF Adcock IM p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthmaJ Allergy Clin Immunol2002 109649657
Not in our library10.1067/mai.2002.122465
254.
Bhavsar P Hew M Khorasani N Torrego A Barnes PJ Adcock I Chung KF Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthmaThorax2008 63784790
Not in our library10.1136/thx.2007.090027
255.
Galigniana MD Piwien-Pilipuk G Assreuy J Inhibition of glucocorticoid receptor binding by nitric oxideMol Pharmacol1999 55317323
Not in our library10.1124/mol.55.2.317
256.
Loke TK Mallett KH Ratoff J O'Connor BJ Ying S Meng Q Soh C Lee TH Corrigan CJ Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patientsJ Allergy Clin Immunol2006 118368375
Not in our library10.1016/j.jaci.2006.04.055
257.
Ito K Yamamura S Essilfie-Quaye S Cosio B Ito M Barnes PJ Adcock IM Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppressionJ Exp Med2006 203713
Not in our library10.1084/jem.20050466
258.
Ito K Ito M Elliott WM Cosio B Caramori G Kon OM Barczyk A Hayashi S Adcock IM Hogg JC Barnes PJ Decreased histone deacetylase activity in chronic obstructive pulmonary diseaseN Engl J Med2005 35219671976
Not in our library10.1056/nejmoa041892
259.
Hew M Bhavsar P Torrego A Meah S Khorasani N Barnes PJ Adcock I Chung KF Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthmaAm J Respir Crit Care Med2006 174134141
Not in our library10.1164/rccm.200512-1930oc
260.
Ito K Hanazawa T Tomita K Barnes PJ Adcock IM Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitrationBiochem Biophys Res Commun2004 315240245
Not in our library10.1016/j.bbrc.2004.01.046
261.
Marwick JA Caramori G Casolari P Mazzoni F Kirkham PA Adcock IM Chung KF Papi A A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary diseaseJ Allergy Clin Immunol2010 12511461153
Not in our library10.1016/j.jaci.2010.02.003
262.
Marwick JA Caramori G Stevenson CS Casolari P Jazrawi E Barnes PJ Ito K Adcock IM Kirkham PA Papi A Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in miceAm J Respir Crit Care Med2009 179542548
Not in our library10.1164/rccm.200810-1570oc
263.
Kinnula VL Crapo JD Superoxide dismutases in the lung and human lung diseasesAm J Respir Crit Care Med2003 16716001619
Not in our library10.1164/rccm.200212-1479so
264.
Crapo JD Oxidative stress as an initiator of cytokine release and cell damageEur Respir J Suppl2003 44suppl4s6s
Not in our library10.1183/09031936.03.00000203a
265.
Griffith B Pendyala S Hecker L Lee PJ Natarajan V Thannickal VJ NOX enzymes and pulmonary diseaseAntioxid Redox Signal2009 1125052516
Not in our library10.1089/ars.2009.2599
266.
Kinnula VL Fattman CL Tan RJ Oury TD Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapyAm J Respir Crit Care Med2005 172417422
Not in our library10.1164/rccm.200501-017pp
267.
Bartz RR Piantadosi CA Clinical review: oxygen as a signaling moleculeCrit Care2010 14234
Not in our library10.1186/cc9185
268.
Bedard K Krause K The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiologyPhysiol Rev2007 87245313
Not in our library10.1152/physrev.00044.2005
269.
Griendling KK NADPH oxidases: new regulators of old functionsAntioxid Redox Signal2006 814431445
Not in our library10.1089/ars.2006.8.1443
270.
Hecker L Vittal R Jones T Jagirdar R Luckhardt TR Horowitz JC Pennathur S Martinez FJ Thannickal VJ NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injuryNat Med2009 1510771081
Not in our library10.1038/nm.2005
271.
Rahman I MacNee W Oxidative stress and regulation of glutathione in lung inflammationEur Respir J2000 16534554
Not in our library10.1034/j.1399-3003.2000.016003534.x
272.
Cantin AM North SL Hubbard RC Crystal RG Normal alveolar epithelial lining fluid contains high levels of glutathioneJ Appl Physiol1987 63152157
Not in our library10.1152/jappl.1987.63.1.152
273.
Cantin AM Hubbard RC Crystal RG Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosisAm Rev Respir Dis1989 139370372
Not in our library10.1164/ajrccm/139.2.370
274.
Behr J Degenkolb B Krombach F Vogelmeier C Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteineEur Respir J2002 19906911
Not in our library10.1183/09031936.02.00204902
275.
Behr J Degenkolb B Maier K Braun B Beinert T Krombach F Vogelmeier C Fruhmann G Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitisEur Respir J1995 812861292
Not in our library10.1183/09031936.95.08081286
276.
Meyer A Buhl R Magnussen H The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosisEur Respir J1994 7431436
Not in our library10.1183/09031936.94.07030431
277.
Tiitto LH Peltoniemi MJ Kaarteenaho-Wiik RL Soini YM Pääkkö PK Sormunen RT Kinnula VL Cell-specific regulation of gamma-glutamylcysteine synthetase in human interstitial lung diseasesHum Pathol2004 35832839
Not in our library10.1016/j.humpath.2004.03.010
278.
Kinnula VL Hodgson UA Lakari EK Tan RJ Sormunen RT Soini YM Kakko SJ Laitinen TH Oury TD Pääkkö PK Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumoniaHistopathology2006 496674
Not in our library10.1111/j.1365-2559.2006.02470.x
279.
Pache JC Carnesecchi S Deffert C Donati Y Herrmann FR Barazzone-Argiroffo C Krause KH NOX4 is expressed in thickened pulmonary arteries in idiopathic pulmonary fibrosisNat Med2011 173132
Not in our library10.1038/nm0111-31
280.
Carnesecchi S Deffert C Donati Y Basset O Hinz B Preynat-Seauve O Guichard C Arbiser JL Banfi B Pache JC Barazzone-Argiroffo C Krause KH A Key Role for NOX4 in Epithelial Cell Death During Development of Lung FibrosisAntioxid Redox Signal2011 15607619
Not in our library10.1089/ars.2010.3829
281.
Serrano-Mollar A Closa D Prats N Blesa S Martinez-Losa M Cortijo J Estrela JM Morcillo EJ Bulbena O In vivo antioxidant treatment protects against bleomycin-induced lung damage in ratsBr J Pharmacol2003 13810371048
Not in our library10.1038/sj.bjp.0705138
282.
Mata M Ruíz A Cerdá M Martinez-Losa M Cortijo J Santangelo F Serrano-Mollar A Llombart-Bosch A Morcillo EJ Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in ratsEur Respir J2003 22900905
Not in our library10.1183/09031936.03.00018003
283.
Hagiwara SI Ishii Y Kitamura S Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in miceAm J Respir Crit Care Med2000 162225231
Not in our library10.1164/ajrccm.162.1.9903129
284.
Oury TD Thakker K Menache M Chang LY Crapo JD Day BJ Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrinAm J Respir Cell Mol Biol2001 25164169
Not in our library10.1165/ajrcmb.25.2.4235
285.
Fattman CL Chang LY Termin TA Petersen L Enghild JJ Oury TD Enhanced bleomycin-induced pulmonary damage in mice lacking extracellular superoxide dismutaseFree Radic Biol Med2003 35763771
Not in our library10.1016/s0891-5849(03)00402-7
286.
Bowler RP Nicks M Warnick K Crapo JD Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosisAm J Physiol Lung Cell Mol Physiol2002 282L719L726
Not in our library10.1152/ajplung.00058.2001
287.
Cho HY Reddy SP Yamamoto M Kleeberger SR The transcription factor NRF2 protects against pulmonary fibrosisFASEB J2004 1812581260
Not in our library10.1096/fj.03-1127fje
288.
Cantin AM Larivée P Bégin RO Extracellular glutathione suppresses human lung fibroblast proliferationAm J Respir Cell Mol Biol1990 37985
Not in our library10.1165/ajrcmb/3.1.79
289.
Ramirez A Ramadan B Ritzenthaler JD Rivera HN Jones DP Roman J Extracellular cysteine/cystine redox potential controls lung fibroblast proliferation and matrix expression through upregulation of transforming growth factor-betaAm J Physiol Lung Cell Mol Physiol2007 293L972L981
Not in our library10.1152/ajplung.00010.2007
290.
Barcellos-Hoff MH Dix TA Redox-mediated activation of latent transforming growth factor-beta 1Mol Endocrinol1996 1010771083
Not in our library10.1210/mend.10.9.8885242
291.
Thannickal VJ Fanburg BL Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1J Biol Chem1995 2703033430338
Not in our library10.1074/jbc.270.51.30334
292.
Arsalane K Dubois CM Muanza T Bégin R Boudreau F Asselin C Cantin AM Transforming growth factor-beta1 is a potent inhibitor of glutathione synthesis in the lung epithelial cell line A549: transcriptional effect on the GSH rate-limiting enzyme gamma-glutamylcysteine synthetaseAm J Respir Cell Mol Biol1997 17599607
Not in our library10.1165/ajrcmb.17.5.2833
293.
Liu RM Liu Y Forman HJ Olman M Tarpey MM Glutathione regulates transforming growth factor-beta-stimulated collagen production in fibroblastsAm J Physiol Lung Cell Mol Physiol2004 286L121L128
Not in our library10.1152/ajplung.00231.2003
294.
Felton VM Borok Z Willis BC N-acetylcysteine inhibits alveolar epithelial-mesenchymal transitionAm J Physiol Lung Cell Mol Physiol2009 297L805L812
Not in our library10.1152/ajplung.00009.2009
295.
Waghray M Cui Z Horowitz JC Subramanian IM Martinez FJ Toews GB Thannickal VJ Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblastsFASEB J2005 19854856
Not in our library10.1096/fj.04-2882fje
296.
Sugiura H Ichikawa T Liu X Kobayashi T Wang XQ Kawasaki S Togo S Kamio K Mao L Ann Y Ichinose M Rennard SI N-acetyl-L-cysteine inhibits TGF-beta1-induced profibrotic responses in fibroblastsPulm Pharmacol Ther2009 22487491
Not in our library10.1016/j.pupt.2009.04.002
297.
Meurer SK Lahme B Tihaa L Weiskirchen R Gressner AM N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drugBiochem Pharmacol2005 7010261034
Not in our library10.1016/j.bcp.2005.07.001
298.
Lichtenberger FJ Montague C Hunter M Frambach G Marsh CB NAC and DTT promote TGF-beta1 monomer formation: demonstration of competitive bindingJ Inflamm (Lond)2006 37
Not in our library10.1186/1476-9255-3-7
299.
Sturrock A Cahill B Norman K Huecksteadt TP Hill K Sanders K Karwande SV Stringham JC Bull DA Gleich M Kennedy TP Hoidal JR Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cellsAm J Physiol Lung Cell Mol Physiol2006 290L661L673
Not in our library10.1152/ajplung.00269.2005
300.
Ismail S Sturrock A Wu P Cahill B Norman K Huecksteadt T Sanders K Kennedy T Hoidal J NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-{beta}1 and insulin-like growth factor binding protein-3Am J Physiol Lung Cell Mol Physiol2009 296L489L499
Not in our library10.1152/ajplung.90488.2008
301.
Bondi CD Manickam N Lee DY Block K Gorin Y Abboud HE Barnes JL NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblastsJ Am Soc Nephrol2010 2193102
Not in our library10.1681/asn.2009020146
302.
Demedts M Behr J Buhl R Costabel U Dekhuijzen R Jansen HM MacNee W Thomeer M Wallaert B Laurent F Nicholson AG Verbeken EK Verschakelen J Flower CD Capron F Petruzzelli S De Vuyst P van den Bosch JM Rodriguez-Becerra E Corvasce G Lankhorst I Sardina M Montanari M IFIGENIA Study GroupHigh-dose acetylcysteine in idiopathic pulmonary fibrosisN Engl J Med2005 35322292242
Not in our library10.1056/nejmoa042976
303.
Mackman N The many faces of tissue factorJ Thromb Haemost2009 7S136S139
Not in our library10.1111/j.1538-7836.2009.03368.x
304.
Breitenstein A Camici GG Tanner FC Tissue factor: beyond coagulation in the cardiovascular systemClin Sci (Lond)2009 118159172
Not in our library10.1042/cs20080622
305.
Chambers RC Procoagulant signaling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?Br J Pharmacol2008 153S367S378
Not in our library10.1038/sj.bjp.0707603
306.
Yasui H Gabazza EC Tamaki S Kobayashi T Hataji O Yuda H Shimizu S Suzuki K Adachi Y Taguchi O Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouseAm J Respir Crit Care Med2001 16316601668
Not in our library10.1164/ajrccm.163.7.9911068
307.
Juul K Tybjaerg-Hansen A Mortensen J Lange P Vestbo J Nordestgaard BG Factor V Leiden homozygosity, dyspnea, and reduced pulmonary functionArch Intern Med2005 16520322036
Not in our library10.1001/archinte.165.17.2032
308.
Sode BF Dahl M Nielsen SF Nordestgaard BG Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide studyAm J Respir Crit Care Med2010 18110851092
Not in our library10.1164/rccm.200912-1951oc
309.
Kotani I Sato A Hayakawa H Urano T Takada Y Takada A Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosisThromb Res1995 77493504
Not in our library10.1016/0049-3848(95)00025-9
310.
Imokawa S Sato A Hayakawa H Kotani M Urano T Takada A Tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosisAm J Respir Crit Care Med1997 156631636
Not in our library10.1164/ajrccm.156.2.9608094
311.
Wygrecka M Kwapiszewska G Jablonska E Gerlach S Henneke I Zakrzewicz D Guenther A Preissner KT Markart P Role of Protease-activated Receptor-2 in Idiopathic Pulmonary FibrosisAm J Respir Crit Care Med2011 18317031714
Not in our library10.1164/rccm.201009-1479oc
312.
Günther A Mosavi P Ruppert C Heinemann S Temmesfeld B Velcovsky HG Morr H Grimminger F Walmrath D Seeger W Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung diseaseThromb Haemost2000 83853860
Not in our library
313.
Bogatkevich GS Gustilo E Oates JC Feghali-Bostwick C Harley RA Silver RM Ludwicka-Bradley A Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblastsAm J Physiol Lung Cell Mol Physiol2005 288L190L201
Not in our library10.1152/ajplung.00448.2003
314.
Mercer PF Johns RH Scotton CJ Krupiczojc MA Königshoff M Howell DC McAnulty RJ Das A Thorley AJ Tetley TD Eickelberg O Chambers RC Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosisAm J Respir Crit Care Med2009 179414425
Not in our library10.1164/rccm.200712-1827oc
315.
Kijiyama N Ueno H Sugimoto I Sasaguri Y Yatera K Kido M Gabazza EC Suzuki K Hashimoto E Takeya H Intratracheal gene transfer of tissue factor pathway inhibitor attenuates pulmonary fibrosisBiochem Biophys Res Commun2006 33911131119
Not in our library10.1016/j.bbrc.2005.11.127
316.
Howell DC Goldsack NR Marshall RP McAnulty RJ Starke R Purdy G Laurent GJ Chambers RC Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosisAm J Pathol2001 15913831395
Not in our library10.1016/s0002-9440(10)62525-4
317.
Günther A Lübke N Ermert M Schermuly RT Weissmann N Breithecker A Markart P Ruppert C Quanz K Ermert L Grimminger F Seeger W Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbitsAm J Respir Crit Care Med2003 16813581365
Not in our library10.1164/rccm.2201082
318.
Eitzman DT McCoy RD Zheng X Fay WP Shen T Ginsburg D Simon RH Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 geneJ Clin Invest1996 97232237
Not in our library10.1172/jci118396
319.
Trejo J Connolly AJ Coughlin SR The cloned thrombin receptor is necessary and sufficient for activation of mitogen-activated protein kinase and mitogenesis in mouse lung fibroblasts. Loss of responses in fibroblasts from receptor knockout miceJ Biol Chem1996 2712153621541
Not in our library10.1074/jbc.271.35.21536
320.
Bogatkevich GS Tourkina E Silver RM Ludwicka-Bradley A Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathwayJ Biol Chem2001 2764518445192
Not in our library10.1074/jbc.m106441200
321.
Blanc-Brude OP Chambers RC Leoni P Dik WA Laurent GJ Factor Xa is a fibroblast mitogen via binding to effector-cell protease receptor-1 and autocrine release of PDGFAm J Physiol Cell Physiol2001 281C681C689
Not in our library10.1152/ajpcell.2001.281.2.c681
322.
Ohba T McDonald JK Silver RM Strange C LeRoy EC Ludwicka A Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptorAm J Respir Cell Mol Biol1994 10405412
Not in our library10.1165/ajrcmb.10.4.7510986
323.
Hernández-Rodríguez NA Cambrey AD Harrison NK Chambers RC Gray AJ Southcott AM duBois RM Black CM Scully MF McAnulty RJ Role of thrombin in pulmonary fibrosisLancet1995 34610711073
Not in our library10.1016/s0140-6736(95)91744-6
324.
Chambers RC Dabbagh K McAnulty RJ Gray AJ Blanc-Brude OP Laurent GJ Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1Biochem J1998 333121127
Not in our library10.1042/bj3330121
325.
Blanc-Brude OP Archer F Leoni P Derian C Bolsover S Laurent GJ Chambers RC Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activationExp Cell Res2005 3041627
Not in our library10.1016/j.yexcr.2004.10.021
326.
Jenkins RG Su X Su G Scotton CJ Camerer E Laurent GJ Davis GE Chambers RC Matthay MA Sheppard D Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injuryJ Clin Invest2006 11616061614
Not in our library10.1172/jci27183
327.
Suzuki T Moraes TJ Vachon E Ginzberg HH Huang TT Matthay MA Hollenberg MD Marshall J McCulloch CA Abreu MT Chow CW Downey GP Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cellsAm J Respir Cell Mol Biol2005 33231247
Not in our library10.1165/rcmb.2005-0109oc
328.
Markart P Nass R Ruppert C Hundack L Wygrecka M Korfei M Boedeker RH Staehler G Kroll H Scheuch G Seeger W Guenther A Safety and tolerability of inhaled heparin in idiopathic pulmonary fibrosisJ Aerosol Med Pulm Drug Deliv2010 23161172
Not in our library10.1089/jamp.2009.0780
329.
Kubo H Nakayama K Yanai M Suzuki T Yamaya M Watanabe M Sasaki H Anticoagulant therapy for idiopathic pulmonary fibrosisChest2005 12814751482
Not in our library10.1378/chest.128.3.1475
330.
Moore BB Hogaboam CM Murine models of pulmonary fibrosisAm J Physiol Lung Cell Mol Physiol2008 294L152L160
Not in our library10.1152/ajplung.00313.2007
331.
Chua F Gauldie J Laurent GJ Pulmonary fibrosis: searching for model answersAm J Respir Cell Mol Biol2005 33913
Not in our library10.1165/rcmb.2005-0062tr

Cited by papers we hold 11

Heavy metals: toxicity and human health effects · 2024
No notice
Nintedanib Ameliorates Bleomycin-Induced Pulmonary Fibrosis, Inflammation, Apoptosis, and Oxidative Stress by Modulating PI3K/Akt/mTOR Pathway in Mice · 2023
No notice
Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond · 2022
Not checked
Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF) · 2022
No notice
Downregulation of the PD-1/PD-Ls pathway in peripheral cells correlates with asbestosis severity · 2021
Not checked
Therapeutic Effects of the Bcl-2 Inhibitor on Bleomycin-induced Pulmonary Fibrosis in Mice · 2021
Not checked
GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1. · 2020
Not checked
Transforming growth factor (TGF)-β1-induced miR-133a inhibits myofibroblast differentiation and pulmonary fibrosis · 2019
No notice
Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis · 2019
No notice
Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis · 2018
No notice
Nosospecific features of redox processes in acute respiratory viral infections and chronic inflammatory diseases of the respiratory system · 2017
Not checked

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.