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The pathogenesis of COPD and IPF: Distinct horns of the same devil?

Marco Chilosi, Venerino Poletti, Andrea Rossi

Respiratory Research · 2012 · Review

doi:10.1186/1465-9921-13-3

Abstract

New paradigms have been recently proposed in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), evidencing surprising similarities between these deadly diseases, despite their obvious clinical, radiological and pathologic differences. There is growing evidence supporting a "double hit" pathogenic model where in both COPD and IPF the cumulative action of an accelerated senescence of pulmonary parenchyma (determined by either telomere dysfunction and/or a variety of genetic predisposing factors), and the noxious activity of cigarette smoke-induced oxidative damage are able to severely compromise the regenerative potential of two pulmonary precursor cell compartments (alveolar epithelial precursors in IPF, mesenchymal precursor cells in COPD/emphysema). The consequent divergent derangement of signalling pathways involved in lung tissue renewal (mainly Wnt and Notch), can eventually lead to the distinct abnormal tissue remodelling and functional impairment that characterise the alveolar parenchyma in these diseases (irreversible fibrosis and bronchiolar honeycombing in IPF, emphysema and airway chronic inflammation in COPD).

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Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two severe multifactorial pulmonary disorders characterised by quite distinct clinical and pathological features. COPD is characterised by a poorly reversible and progressive airflow limitation that is determined by the concurrence of airways inflammation and emphysema (from now on both included in the acronym COPD), whereas in IPF a restrictive pattern of lung volume abnormality is associated with impaired diffusion capacity. At imaging and pathological examinations COPD and IPF exhibit different appearances, as far as the involved pulmonary regions (upper lobes versus lower lobes), and the occurring parenchymal modifications are concerned (alveolar emphysematous dilation and bronchiolar inflammation in COPD, versus interstitial fibrosis and honeycombing in IPF). Finally, the incidence and prevalence of the two diseases are quite different, since IPF is considered a rare condition (although incidence and prevalence are both rising due to improved diagnostic tools), whereas the COPD prevalence is very high, although variable in different risk populations.

Nevertheless, a number of similarities can be recognised between the two disorders. Firstly, both COPD and IPF are chronic and progressive diseases of elderly people (with male predominance), that severely affect the lung function, and both are related to long term inhalation of external noxious agents (mainly tobacco smoking). Secondly, in both diseases a progressive loss of alveolar parenchyma takes place leading to severe impairment of respiratory function. Variants of pulmonary fibrosis associated with emphysema have been described, and these cases have been grouped in a newly defined syndrome of combined pulmonary fibrosis and emphysema (CPFE). In CPFE, lung volumes are commonly within normal limits due to the opposing effects of hyperinflation and fibrosis. The CPFE syndrome is more frequent in male smokers, and pulmonary hypertension can complicate all these disorders. Finally, both IPF and COPD are associated with an increased risk of cancer development, and several lines of evidence suggest that this increase is independent from the effect of cigarette smoking.

Despite the great deal of research, effective treatments are lacking for both COPD and IPF. This can be a consequence, at least in part, of the limited understanding of their pathogenesis, despite the overwhelming plethora of studies and theories proposed so far. Interestingly, for both diseases a gradual shift from "inflammatory-based" pathogenic theories to more complex approaches occurred in recent years. In this evolving scenario, a variety of concurrent underlying pathogenic mechanisms have been proposed for these diseases, including oxidative stress, protease/anti-protease imbalance, abnormal healing after damage, deranged remodelling, enhanced apoptosis, and others.

Accelerated senescence in the pathogenesis of IPF and COPD

The most striking new information linking the pathogenesis of IPF and COPD relates to their proposed inclusion within the category of diseases with alveolar senescence and lung "premature aging". The senescence hypothesis for both COPD and IPF pathogenesis is supported by a variety of studies demonstrating telomere length abnormalities, as well as the in situ expression of senescence-related cell-cycle regulators (p21WAF1 and p16INK4a ). The role of cell senescence is particularly evident in familial IPF, where nearly 10% of cases harbour mutations of one of the two key components involved in telomere lengthening: the reverse transcriptase component TERT and the RNA template component TERC. In addition, about 20% of patients suffering for dyskeratosis congenita, a well characterized genetic disease caused by telomerase mutations, develop pulmonary fibrosis.

Although abnormalities directly affecting telomerase genes have not been demonstrated in COPD, telomere decreased length has been demonstrated in either lung cells or peripheral leukocytes in COPD patients, compared with control subjects. The excess of telomere attrition further supports the concept of COPD as a systemic disorder of premature aging, as also suggested by the occurrence of relevant comorbidities, such as weight loss, osteoporosis, cardiovascular diseases, and depression, where premature senescence and telomere length abnormalities have been also documented. Further experimental evidence has been recently provided that telomere length is a susceptibility factor in emphysema.

Epithelial progenitor cell dysfunction in IPF

The pathogenic role of genetic abnormalities in IPF is much more evident than in COPD, and familial IPF has been recently included within the category of genetic diseases with "telomere dysfunction" together with acquired aplastic anaemia and dyskeratosis congenita. These diseases are characterised by clinical and pathologic heterogeneity despite the similarity of underlying genetic defects affecting the telomere elongating mechanisms (mainly TERT or TERC mutations). In these diseases specific phenotypes are likely related to the progenitor cell type(s) involved as "weak spots" in disease development (e.g. haemopoietic precursors in aplastic anaemia). A correct telomere maintaining program in precursor cells is crucial to avoid degenerative disorders and anticipated aging, and short telomeres cause precursor cell failure in experimental systems. In addition, it has been clearly established that the development of diseases with "telomere dysfunction" needs the contribution of both a genetic predisposing abnormality as well as an environmental factor in order to develop the entire disease phenotype. Thus, the exposure to benzene or other toxic substances, is key for the development of aplastic anaemia, as it can be considered tobacco smoke (or exposure to other toxic substances) in IPF. A significant role might be also exerted by gender, as it could be also expected in cases of pulmonary fibrosis complicating X-linked dyskeratosis congenita. Accordingly, most described cases of pulmonary fibrosis complicating dyskeratosis congenita are former-smoker and male.

Familial IPF cases have been linked not only to mutations of telomerase genes, but also to mutations in surfactant proteins coding genes (surfactant protein-C and A2). Chronic epithelial injury in these cases is likely related to protein abnormalities that can either impair the crucial functions of the surfactant, or induce endoplasmic reticulum stress and apoptosis. Type-II pneumocytes, that are the main producers of surfactant proteins and are the epithelial precursors of alveolar parenchyma, are the specific target of cellular death produced by surfactant protein abnormalities.

Thus different mechanisms can be responsible of the progressive loss of pneumocyte precursors in IPF, including accelerated senescence, surfactant abnormalities and endoplasmic reticulum stress, all potentially causing precursor cell exhaustion and abnormal alveolar re-epithelialisation. The concurrent action of environmental factors such as the exposure to toxic substances, and especially tobacco smoking and/or pollution appear as necessary for developing the disease in both familial and sporadic IPF, although IPF can occur also in non smokers(Figure 1).

Mesenchymal precursor cell insufficiency in COPD/emphysema

In COPD a large amount of data suggest that parenchymal remodelling and progressive dilation of alveolar spaces is related to decreased and/or deregulated production of extracellular matrix proteins, in particular elastin, with the eventual impaired capability to sustain connective and epithelial tissue repair. Connective tissue insufficiency can be either caused by genetic defects as observed in alpha-1 anti-trypsin deficiency (a well established genetically determined form of COPD/emphysema where elastin decrease can be directly related to the observed alveolar dilation, loss of elastic recoil and airflow obstruction), or it may be ascribed to ill defined causes inducing mesenchymal precursor cell senescence and progressive decrease of matrix protein production, as suggested in this review. Accordingly, senescence related markers in COPD are mainly demonstrable in mesenchymal cells (fibroblasts and endothelial cells), and a variety of abnormalities have been described affecting pulmonary mesenchymal cells, including fibroblasts and endothelial cells in both human and experimental COPD(Figure 1).

IPF and COPD: two distinct horns of the same devil?

All this taken into account, it is possible to hypothesise that in the pathogenesis of both COPD and IPF the main driving abnormality is the precocious senescence of pulmonary parenchyma.

But how can be reconciled this proposed similarity between the basic pathogenic mechanisms underlying COPD and IPF with the obvious diversity of their clinical and pathological presentations? A possible explanation can be searched in the diversity of the genetic alterations, including genetic/epigenetic inheritance or predisposing gene polymorphisms, compromising the renewal capacity of different target cells. As proposed above, if in IPF the major target is likely the alveolar epithelial precursor cell (type II pneumocyte), in COPD the Achille's heel may be represented by mesenchymal precursor cells within the alveolar parenchyma.

Human and experimental studies provide strong evidence that molecular networks regulating parenchymal lung tissue renewal are perturbed in both COPD and IPF, although in different ways. Among these networks, particular relevance has been focused on the interplay between Notch and Wnt, two signalling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation.

Wnt and Notch pathway perturbation in IPF

In IPF the senescent phenotype seems to mainly affect the epithelial precursors of alveolar tissue (type-II pneumocytes), thus preventing a correct epithelial renewal at anatomical sites where mechanical stress and alveolar damage are expected to be maximal (lower/peripheral lung zones). Pneumocyte loss is followed, in this pathogenic scheme of IPF, by attempted tissue regeneration and exaggerated release of molecular signals (Wnt and Notch) triggering fibroblast proliferation and migration. Several human and experimental studies have confirmed that the Wnt-pathway is abnormally activated in IPF, and this notion is included in recent pathogenic models for IPF. The relevance of abnormal Wnt-signalling activation in IPF is confirmed by the up-modulation of various Wnt-pathway molecular targets observed in IPF (MMP7, cyclin-D1 and others), as well as by the demonstration that experimental fibrosis can be attenuated by the Wnt/β-catenin pathway blockade. Accordingly, perturbation of the Wnt-pathway is directly related to abnormal myofibroblast activation and epithelial-mesenchymal transition, and mesenchymal precursor cells can further amplify the fibrotic process by triggering the Wnt-pathway. Myofibroblasts are key elements in IPF and their differentiation can be also triggered by loss of telomerase activity. Concurrently, Notch-signalling is crucial for myofibroblast differentiation and alveologenesis, and can also contribute to the differentiation of airway basal precursor cells.

But how can senescent pneumocytes abnormally trigger these pathways in IPF? Signals provided by the milieu of damaged alveolar cells can trigger a variety of reparative mechanisms, including the recruitment and stimulation of endogenous and exogenous progenitors, and it is possible to expect a severe derangement of this process in senescent alveoli. In several systems it has been demonstrated that cell senescence can trigger a "senescence-associated secretory phenotype", that is able to stimulate the production of proliferative and profibrotic mediators, including growth factors, cytokines, chemokines, and metalloproteinases, acting on neighbouring epithelial and mesenchymal cells thus perturbing their physiological crosstalk as previously proposed. In line with this assumption, both Wnt- and Notch pathways have been shown to be activated by cell senescence, and epithelial mesenchymal transition and mobilization of beta-catenin are among the features characterising the senescence-related hyper-secretive phenotype. In senescent alveoli mesenchymal and epithelial precursors could be the target of this deranged cascade of stimulatory signals, with eventual myofibroblast activation and bronchiolar remodelling. Senescent myofibroblasts in turn could be also stimulated to acquire a secretive phenotype, and this effect is likely to occur at short distance from damaged areas, thus contributing to produce the patchy distortion of pulmonary tissue characterising the "usual interstitial pneumonia" (UIP) pattern. Recently, we demonstrated that fibroblast foci are mainly located within micro-honeycombing lesions in IPF, at sites where basal cell airway precursors abnormally show over-expression of molecules involved in cell-motility (laminin-5 γ-2-chain and heath shock protein 27), and molecules that can be directly related to cellular senescence including p21waf1 and p53. Small airways and alveolar epithelia are characterised by quite different renewal strategies at the molecular level, and telomere dysfunction and cellular senescence could be expected to act differently in these two compartments. Bronchiolar progenitors, located in the basal layer, express high levels of ΔN-p63+, a potent anti-apoptotic mediator that can interfere with the p53/p21 pathway and may potentially contrast cell senescence in basal cells. Bronchiolar abnormal proliferation and honeycomb changes are common in IPF and can be considered as consequence of divergent behaviours in proximal and distal lung compartments. In our view, exaggerated autocrine and paracrine activation of the Wnt- and Notch-pathways can in part explain honeycomb cyst formation, since proliferation and differentiation of basal cell precursors in small airways depend on the correct expression of these signalling pathways. Further contribute to the aberrant bronchiolar proliferation and honeycomb cyst formation in IPF is likely provided by abnormalities affecting the production of airway mucins, as recently demonstrated. Interestingly, disordered mucin production with increased MUC5B forms is also observed in the airway of COPD patients.

Wnt and Notch signalling perturbation in COPD

Interestingly, the same signalling pathways involved in IPF (Wnt- and Notch), seem to have a relevant role also in COPD, but in the opposite way. In fact, both Wnt- and Notch- appear as significantly inhibited in COPD, rather than activated as observed in IPF, and this observation can explain why in emphysema enlarged alveoli are mainly covered by type-I differentiated pneumocytes and type II pneumocyte proliferation is minimal. In different systems in fact, the classical role of the Notch- and Wnt-signalling, acting in concert, is the maintenance of self-renewal potential of epithelial precursor cells and the regulation of cell differentiation, and the abnormal decrease of these pathways, as observed in emphysema, can be detrimental for the correct renewal of pulmonary parenchyma. Accordingly, activation of the Wnt/beta-catenin pathway can attenuate experimental emphysema, and accelerated precursor cell senescence and dysfunction are related to aberrant Notch and Wnt-signalling, particularly affecting the correct differentiation of mesenchymal precursors.

The observed inhibition of Wnt-signalling in COPD may be ascribed to a variety of concurrent causes, including the smoking-related up-regulation of extracellular Wnt antagonists (e.g. secreted frizzled-related proteins). Interestingly, the Wnt-pathway is sensitive to mechanical stimuli in different systems, and it is considered to represent a key factor in mechano-transcription processes. It is then possible to hypothesise that the decrease of elastic recoil occurring in emphysematous parenchyma may significantly contribute, in a vicious circle, to perpetuate the Wnt-signalling down-modulation. In IPF, on the other hand, Wnt activation could be amplified at sites where mechanical stress is higher (e.g. in the subpleural lower lung portions, typically affected in IPF), thus contributing to ongoing alveolar loss and fibrosis, as recently hypothesised.

All these data taken together, it is possible to hypothesise that in COPD the abnormal senescence of mesenchymal precursors can cause both an impaired production of extracellular matrix proteins (e.g. elastin), as well as a derangement of the interplay between signalling pathways that regulate alveologenesis (in particular Wnt and Notch). These abnormalities are likely sufficient to cause the progressive weakening of the scaffold interstitial structures sustaining the pulmonary parenchyma, with eventual alveolar dilatation and emphysema.

Precursor cell senescence and inflammation in COPD-emphysema

Interestingly, the here proposed pathogenic scheme, centred on alveolar senescence and mesenchymal precursor cell insufficiency, can in part reconcile some controversial issues regarding the significance and role of inflammation and autoimmunity in the development of airway disease occurring in COPD. Evidence has been in fact provided of a robust regulatory function of mesenchymal stem cells (MSC) on cells of both the innate and adaptive immune systems, and bone marrow derived MSC are able to inhibit the release of pro-inflammatory cytokines and also stimulate the functional activity of regulatory T-lymphocytes. The regulatory functions of MSC is similar in different tissues, including the lung [Ricciardi M, et al: unpublished data]. It is then possible to hypothesise that in COPD the regulatory functions of senescent MSC can be variably impaired, with eventual triggering of "autoimmune-like" chronic inflammation in small airways, similar to that observed in the variety of lung diseases presenting as constrictive bronchiolitis in different settings (lung allografts, exposure to toxic substances, autoimmunity, post-viral, etc.). According to this hypothesis is the recent demonstration of a direct role of mesenchymal cell senescence and telomere dysfunction in causing airway inflammation in COPD. In this scheme, the airway remodelling characterising COPD could be tentatively explained by the concurrence action of the inflammatory stimuli derived by the above described inhibition of MSC immune-modulatory role, and the proliferative response of airway epithelium to the chronic damaging effect of exogenous toxic substances (e.g. cigarette smoke).

Conclusions

In summary, in both COPD and IPF a common pathogenic scheme can be traced where an accelerated cellular senescence determined by the "two hits" paradigm (genetic predisposition to cell senescence with the concurrence of tobacco smoke), determines an impaired regeneration of the lung parenchyma after damage. The divergence in two horns in this model is provided by the affected precursor cells (mesenchymal in COPD and emphysema, epithelial in IPF), the relevance of genetic background, as well as by the basic signalling pathways involved in the development of either emphysema or fibrosis (Wnt-, Notch-, etc.)(Figure 2). Both mechanisms could be involved in the cases with combined pulmonary fibrosis and emphysema.

The complexity of this network is difficult to be completely deciphered in both IPF and COPD, since beyond precursor cell senescence, as here described, other genetic predisposing factors and molecular mechanisms are likely involved in both diseases, including micro-RNA regulation. Interestingly, perturbation of micro-RNAs can also affect TGF-beta, a potent profibrotic effector, that plays a relevant role in early lung development, has significant interconnections with the Wnt-pathway, and is involved in the pathogenesis of both IPF and COPD. Another player in this complex scenario is likely represented by caveolin-1, the member of a protein family involved in the formation of cellular caveolae, that plays divergent roles in the development of IPF and emphysema, respectively.

These evolving concepts open new options to better understand the pathogenesis of both IPF and COPD, as far as the involvement of both parenchymal and small airway components are concerned, and also new perspectives for alternative treatment options, including drugs specifically addressing some of the mechanisms described in this review. The high relevance of the type of cell precursor involved in the two diseases is emphasised, since future efforts should be focused on their pharmacological protection or specific replacement.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All Authors participated in the design of the review and helped to draft the manuscript. All authors read and approved the final manuscript.

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  54. 54.

    Lawson WE Grant SW Ambrosini V Womble KE Dawson EP Lane KB Markin C Renzoni E Lympany P Thomas AQ Roldan J Scott TA Blackwell TS Phillips JA Loyd JE du Bois RM Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPFThorax2004 59977980

    Not in our library10.1136/thx.2004.026336

  55. 55.

    Lawson WE Crossno PF Polosukhin VV Roldan J Cheng DS Lane KB Blackwell TR Xu C Markin C Ware LB Miller GG Loyd JE Blackwell TS Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infectionAm J Physiol Lung Cell Mol Physiol2008 294L1119L1126

    Not in our library10.1152/ajplung.00382.2007

  56. 56.

    Chilosi M Doglioni C Murer B Poletti V Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosisSarcoidosis Vasc Diffuse Lung Dis2010 27718

    Not in our library

  57. 57.

    Korfei M Ruppert C Mahavadi P Henneke I Markart P Koch M Lang G Fink L Bohle RM Seeger W Weaver TE Guenther A Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosisAm J Respir Crit Care Med2008 178838846

    Not in our library10.1164/rccm.200802-313oc

  58. 58.

    Lawson WE Cheng DS Degryse AL Tanjore H Polosukhin VV Xu XC Newcomb DC Jones BR Roldan J Lane KB Morrisey EE Beers MF Yull FE Blackwell TS Endoplasmic reticulum stress enhances fibrotic remodeling in the lungsProc Natl Acad Sci USA2011 1081056210567

    Not in our library10.1073/pnas.1107559108

  59. 59.

    Sisson TH Mendez M Choi K Subbotina N Courey A Cunningham A Dave A Engelhardt JF Liu X White ES Thannickal VJ Moore BB Christensen PJ Simon RH Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosisAm J Respir Crit Care Med2010 181254263

    Not in our library10.1164/rccm.200810-1615oc

  60. 60.

    Babizhayev MA Savelʼyeva EL Moskvina SN Yegorov YE Telomere Length is a Biomarker of Cumulative Oxidative Stress, Biologic Age, and an Independent Predictor of Survival and Therapeutic Treatment Requirement Associated With Smoking BehaviorAm J Ther2010

    Not in our library10.1097/mjt.0b013e3181cf8ebb

  61. 61.
    Lung fibroblasts from patients with emphysema show markers of senescence in vitro · 2006
    No notice
  62. 62.

    Kasahara Y Tuder RM Taraseviciene-Stewart L Le Cras TD Abman S Hirth PK Waltenberger J Voelkel NF Inhibition of VEGF receptors causes lung cell apoptosis and emphysemaJ Clin Invest2000 10613111319

    Not in our library10.1172/jci10259

  63. 63.

    Kasahara Y Tuder RM Cool CD Lynch DA Flores SC Voelkel NF Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysemaAm J Respir Crit Care Med2001 163737744

    Not in our library10.1164/ajrccm.163.3.2002117

  64. 64.

    Horowitz JC Martinez FJ Thannickal VJ Mesenchymal cell fate and phenotypes in the pathogenesis of emphysemaCOPD2009 6201210

    Not in our library10.1080/15412550902905953

  65. 65.

    Togo S Holz O Liu X Sugiura H Kamio K Wang X Kawasaki S Ahn Y Fredriksson K Skold CM Mueller KC Branscheid D Welker L Watz H Magnussen H Rennard SI Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanismsAm J Respir Crit Care Med2008 178248260

    Not in our library10.1164/rccm.200706-929oc

  66. 66.

    Noordhoek JA Postma DS Chong LL Vos JT Kauffman HF Timens W van Straaten JF Different proliferative capacity of lung fibroblasts obtained from control subjects and patients with emphysemaExp Lung Res2003 29291302

    Not in our library10.1080/01902140303789

  67. 67.

    Paschalaki K Starke RD Mercado N Haskard DO Barnes PJ Randi AM 59 Endothelial colony forming cells (ECFC) are senescent and dysfunctional in COPD due to reduced sirtuin-1 levelsHeart2011 97e7

    Not in our library

  68. 68.

    Giordano RJ Lahdenranta J Zhen L Chukwueke U Petrache I Langley RR Fidler IJ Pasqualini R Tuder RM Arap W Targeted induction of lung endothelial cell apoptosis causes emphysemalike changes in the mouseJ Biol Chem2008 2832944729460

    Not in our library10.1074/jbc.m804595200

  69. 69.

    Codd V Mangino M van der Harst P Braund PS Kaiser M Beveridge AJ Rafelt S Moore J Nelson C Soranzo N Zhai G Valdes AM Blackburn H Mateo Leach I de Boer RA Kimura M Aviv A Wellcome Trust Case Control ConsortiumGoodall AH Ouwehand W van Veldhuisen DJ van Gilst WH Navis G Burton PR Tobin MD Hall AS Thompson JR Spector T Samani NJ Common variants near TERC are associated with mean telomere lengthNat Genet2010 42197199

    Not in our library10.1038/ng.532

  70. 70.

    Seibold MA Wise AL Speer MC Steele MP Brown KK Loyd JE Fingerlin TE Zhang W Gudmundsson G Groshong SD Evans CM Garantziotis S Adler KB Dickey BF du Bois RM Yang IV Herron A Kervitsky D Talbert JL Markin C Park J Crews AL Slifer SH Auerbach S Roy MG Lin J Hennessy CE Schwarz MI Schwartz DA A common MUC5B promoter polymorphism and pulmonary fibrosisN Engl J Med2011 36415031512

    Not in our library10.1056/nejmoa1013660

  71. 71.

    Hersh CP Silverman EK Gascon J Bhattacharya S Klanderman BJ Litonjua AA Lefebvre V Sparrow D Reilly JJ Anderson WH Lomas DA Mariani TJ SOX5 Is a Candidate Gene for Chronic Obstructive Pulmonary Disease Susceptibility and Is Necessary for Lung DevelopmentAm J Respir Crit Care Med2011 18314821489

    Not in our library10.1164/rccm.201010-1751oc

  72. 72.

    Whitsett JA Kalinichenko VV Notch and basal cells take center stage during airway epithelial regenerationCell Stem Cell2011 8597598

    Not in our library10.1016/j.stem.2011.05.008

  73. 73.

    Ling L Nurcombe V Cool SM Wnt signaling controls the fate of mesenchymal stem cellsGene2009 43317

    Not in our library10.1016/j.gene.2008.12.008

  74. 74.

    Xu K Nieuwenhuis E Cohen BL Wang W Canty AJ Danska JS Coultas L Rossant J Wu MY Piscione TD Nagy A Gossler A Hicks GG Hui CC Henkelman RM Yu LX Sled JG Gridley T Egan SE Lunatic Fringe-mediated Notch signaling is required for lung alveogenesisAm J Physiol Lung Cell Mol Physiol2010 298L4556

    Not in our library10.1152/ajplung.90550.2008

  75. 75.

    Liu J Sato C Cerletti M Wagers A Notch signaling in the regulation of stem cell self-renewal and differentiationCurr Top Dev Biol2010 92367409

    Not in our library10.1016/s0070-2153(10)92012-7

  76. 76.

    Rock JR Gao X Xue Y Randell SH Kong YY Hogan BL Notch-dependent differentiation of adult airway basal stem cellsCell Stem Cell2011 8639648

    Not in our library10.1016/j.stem.2011.04.003

  77. 77.

    Nusse R Wnt signaling and stem cell controlCell Res2008 18523527

    Not in our library10.1038/cr.2008.47

  78. 78.

    Goss AM Morrisey EE Wnt signaling and specification of the respiratory endodermCell Cycle2010 91011

    Not in our library10.4161/cc.9.1.10272

  79. 79.

    Leslie KO Idiopathic pulmonary fibrosis may be a disease of recurrent tractional injury to the periphery of the aging lunga unifying hypothesis regarding etiology and pathogenesisArch Pathol Lab Med2011 135110

    Not in our library10.5858/arpa.2011-0511-oa

  80. 80.

    Chilosi M Poletti V Zamò A Lestani M Montagna L Piccoli P Pedron S Bertaso M Scarpa A Murer B Cancellieri A Maestro R Semenzato G Doglioni C Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosisAm J Pathol2003 16214951502

    Not in our library10.1016/s0002-9440(10)64282-4

  81. 81.
    Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis · 2008
    No notice
  82. 82.

    Königshoff M Kramer M Balsara N Wilhelm J Amarie OV Jahn A Rose F Fink L Seeger W Schaefer L Günther A Eickelberg O WNT1-inducible signalling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosisJ Clin Invest2009 119772787

    Not in our library10.1172/jci33950

  83. 83.

    Kim TH Kim SH Seo JY Chung H Kwak HJ Lee SK Yoon HJ Shin DH Park SS Sohn JW Blockade of the Wnt/β-catenin pathway attenuates bleomycin-induced pulmonary fibrosisTohoku J Exp Med2011 2234554

    Not in our library10.1620/tjem.223.45

  84. 84.

    Vuga LJ Ben-Yehudah A Kovkarova-Naumovski E Oriss T Gibson KF Feghali-Bostwick C Kaminski N WNT5A is a regulator of fibroblast proliferation and resistance to apoptosisAm J Respir Cell Mol Biol2009 41583589

    Not in our library10.1165/rcmb.2008-0201oc

  85. 85.

    Salazar KD Lankford SM Brody AR Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblastsAm J Physiol Lung Cell Mol Physiol2009 297L100211

    Not in our library10.1152/ajplung.90347.2008

  86. 86.

    Liu T Hu B Chung MJ Ullenbruch M Jin H Phan SH Telomerase regulation of myofibroblast differentiationAm J Respir Cell Mol Biol2006 34625633

    Not in our library10.1165/rcmb.2005-0252oc

  87. 87.

    Guseh JS Bores SA Stanger BZ Zhou Q Anderson WJ Melton DA Rajagopal J Notch signaling promotes airway mucous metaplasia and inhibits alveolar developmentDevelopment2009 13617511759

    Not in our library10.1242/dev.029249

  88. 88.

    Buckley S Shi W Carraro G Sedrakyan S Da Sacco S Driscoll BA Perin L de Filippo RE Warburton D The Milieu of Damaged AEC2 Stimulates Alveolar Wound Repair by Endogenous and Exogenous ProgenitorsAm J Respir Cell Mol Biol2011

    Not in our library10.1165/rcmb.2010-0325oc

  89. 89.

    Coppé JP Desprez PY Krtolica A Campisi J The senescence-associated secretory phenotype: the dark side of tumor suppressionAnnu Rev Pathol2010 599118

    Not in our library10.1146/annurev-pathol-121808-102144

  90. 90.

    Meshorer E Gruenbaum Y Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and agingJ Cell Biol2008 181913

    Not in our library10.1083/jcb.200802155

  91. 91.

    Scaffidi P Misteli T Lamin A-dependent misregulation of adult stem cells associated with accelerated ageingNat Cell Biol2008 10452459

    Not in our library10.1038/ncb1708

  92. 92.

    Espada J Varela I Flores I Ugalde AP Cadiñanos J Pendás AM Stewart CL Tryggvason K Blasco MA Freije JM López-Otín C Nuclear envelope defects cause stem cell dysfunction in premature-aging miceJ Cell Biol2008 1812735

    Not in our library10.1083/jcb.200801096

  93. 93.

    Liu H Fergusson MM Castilho RM Liu J Cao L Chen J Malide D Rovira II Schimel D Kuo CJ Gutkind JS Hwang PM Finkel T Augmented Wnt signaling in a mammalian model of accelerated agingScience2007 317803806

    Not in our library10.1126/science.1143578

  94. 94.

    Davalos AR Coppe JP Campisi J Desprez PY Senescent cells as a source of inflammatory factors for tumor progressionCancer Metastasis Rev2010 29273283

    Not in our library10.1007/s10555-010-9220-9

  95. 95.

    Laberge RM Awad P Campisi J Desprez PY Epithelial-Mesenchymal Transition Induced by Senescent FibroblastsCancer Microenviron2011

    Not in our library10.1007/s12307-011-0069-4

  96. 96.

    Chilosi M Poletti V Murer B Lestani M Cancellieri A Montagna L Piccoli P Cangi G Semenzato G Doglioni C Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63Lab Invest2002 8213351345

    Not in our library10.1097/01.lab.0000032380.82232.67

  97. 97.

    Chilosi M Zamò A Doglioni C Reghellin D Lestani M Montagna L Pedron S Ennas MG Cancellieri A Murer B Poletti V Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosisRespir Res2006 795

    Not in our library10.1186/1465-9921-7-95

  98. 98.

    Rock JR Onaitis MW Rawlins EL Lu Y Clark CP Xue Y Randell SH Hogan BL Basal cells as stem cells of the mouse trachea and human airway epitheliumProc Natl Acad Sci USA2009 1061277112775

    Not in our library10.1073/pnas.0906850106

  99. 99.

    Senoo M Pinto F Crum CP McKeon F p63 Is essential for the proliferative potential of stem cells in stratified epitheliaCell2007 129523536

    Not in our library10.1016/j.cell.2007.02.045

  100. 100.

    Plantier L Crestani B Wert SE Dehoux M Zweytick B Guenther A Whitsett JA Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosisThorax2011

    Not in our library10.1136/thx.2010.151555

  101. 101.

    Kirkham S Kolsum U Rousseau K Singh D Vestbo J Thornton DJ MUC5B is the major mucin in the gel phase of sputum in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2008 17810331039

    Not in our library10.1164/rccm.200803-391oc

  102. 102.

    Tilley AE Harvey BG Heguy A Hackett NR Wang R O'Connor TP Crystal RG Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2009 179457466

    Not in our library10.1164/rccm.200705-795oc

  103. 103.

    Wang R Ahmed J Wang G Hassan I Strulovici-Barel Y Hackett NR Crystal RG Down-regulation of the canonical Wnt β-catenin pathway in the airway epithelium of healthy smokers and smokers with COPDPLoS One2011 6e14793

    Not in our library10.1371/journal.pone.0014793

  104. 104.

    Kneidinger N Yildirim AÖ Callegari J Takenaka S Stein MM Dumitrascu R Bohla A Bracke KR Morty RE Brusselle GG Schermuly RT Eickelberg O Königshoff M Activation of the WNT/β-catenin pathway attenuates experimental emphysemaAm J Respir Crit Care Med2011 183723733

    Not in our library10.1164/rccm.200910-1560oc

  105. 105.

    Jansen JH Eijken M Jahr H Chiba H Verhaar JA van Leeuwen JP Weinans H Stretch-induced inhibition of Wnt/beta-catenin signaling in mineralizing osteoblastsJ Orthop Res2010 28390396

    Not in our library10.1002/jor.20991

  106. 106.

    Sen B Styner M Xie Z Case N Rubin CT Rubin J Mechanical loading regulates NFATc1 and beta-catenin signaling through a GSK3beta control nodeJ Biol Chem2009 2843460717

    Not in our library10.1074/jbc.m109.039453

  107. 107.
    Non-Canonical Wnt Signaling and N-Cadherin Related β-Catenin Signaling Play a Role in Mechanically Induced Osteogenic Cell Fate · 2009
    No notice
  108. 108.

    Kononov S Brewer K Sakai H Cavalcante FS Sabayanagam CR Ingenito EP Suki B Roles of mechanical forces and collagen failure in the development of elastase-induced emphysemaAm J Respir Crit Care Med2001 16419201926

    Not in our library10.1164/ajrccm.164.10.2101083

  109. 109.

    Cosio MG Saetta M Agusti A Immunologic aspects of chronic obstructive pulmonary diseaseN Engl J Med2009 36024452454

    Not in our library10.1056/nejmra0804752

  110. 110.

    Barceló B Pons J Ferrer JM Sauleda J Fuster A Agustí AGN Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smokingEur Respir J2008 31555562

    Not in our library10.1183/09031936.00010407

  111. 111.

    Saetta M Airway inflammation in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med1999 160S1720

    Not in our library10.1164/ajrccm.160.supplement_1.6

  112. 112.

    Baraldo S Saetta M To reg or not to reg: that is the question in COPDEur Respir J2008 31486488

    Not in our library10.1183/09031936.00000608

  113. 113.

    Motz GT Eppert BL Wesselkamper SC Flury JL Borchers MT Chronic cigarette smoke exposure generates pathogenic T cells capable of driving COPD-like disease in Rag2-/- miceAm J Respir Crit Care Med2010 18112231233

    Not in our library10.1164/rccm.200910-1485oc

  114. 114.

    Taraseviciene-Stewart L Douglas IS Nana-Sinkam PS Lee JD Tuder RM Nicolls MR Voelkel NF Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease?Proc Am Thorac Soc2006 3687690

    Not in our library10.1513/pats.200605-105sf

  115. 115.

    Zhou F Onizawa S Nagai A Aoshiba K Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injuryRespir Res2011 1278

    Not in our library10.1186/1465-9921-12-78

  116. 116.

    Aggarwal S Pittenger MF Human mesenchymal stem cells modulate allogeneic immune cell responsesBlood2005 10518151822

    Not in our library10.1182/blood-2004-04-1559

  117. 117.

    Krampera M Pasini A Pizzolo G Cosmi L Romagnani S Annunziato F Regenerative and immunomodulatory potential of mesenchymal stem cellsCurr Opin Pharmacol2006 6435441

    Not in our library10.1016/j.coph.2006.02.008

  118. 118.

    Le Blanc K Ringdén O Immunomodulation by mesenchymal stem cells and clinical experienceJ Intern Med2007 262509525

    Not in our library10.1111/j.1365-2796.2007.01844.x

  119. 119.

    Uccelli A Moretta L Pistoia V Mesenchymal stem cells in health and diseaseNat Rev Immunol2008

    Not in our library10.1038/nri2395

  120. 120.

    Krampera M Sartoris S Liotta F Pasini A Angeli R Cosmi L Andreini A Mosna F Bonetti B Rebellato E Testi MG Frosali F Pizzolo G Tridente G Maggi E Romagnani S Annunziato F Immune regulation by mesenchymal stem cells derived from adult spleen and thymusStem Cells Dev2007 16797810

    Not in our library10.1089/scd.2007.0024

  121. 121.

    Keyser KA Beagles KE Kiem HP Comparison of mesenchymal stem cells from different tissues to suppress T-cell activationCell Transplant2007 16555562

    Not in our library10.3727/000000007783464939

  122. 122.

    Parker SM Goriwiec MR Borthwick LA Johnson G Ward C Lordan JL Corris PA Saretzki GC Fisher AJ Airway epithelial cell senescence in the lung allograftAm J Transplant2008 815441549

    Not in our library10.1111/j.1600-6143.2008.02284.x

  123. 123.

    Ghanei M Tazelaar HD Chilosi M Harandi AA Peyman M Akbari HM Shamsaei H Bahadori M Aslani J Mohammadi A An international collaborative pathologic study of surgical lung biopsies from mustard gas-exposed patientsRespir Med2008 102825830

    Not in our library10.1016/j.rmed.2008.01.016

  124. 124.

    King MS Eisenberg R Newman JH Tolle JJ Harrell FE Jr Nian H Ninan M Lambright ES Sheller JR Johnson JE Miller RF Constrictive bronchiolitis in soldiers returning from Iraq and AfghanistanN Engl J Med2011 365222230

    Not in our library10.1056/nejmoa1101388

  125. 125.

    Maldonado F Pittelkow MR Ryu JH Constrictive bronchiolitis associated with paraneoplastic autoimmune multi-organ syndromeRespirology2009 14129133

    Not in our library10.1111/j.1440-1843.2008.01397.x

  126. 126.

    Devouassoux G Cottin V Lioté H Marchand E Frachon I Schuller A Béjui-Thivolet F Cordier JF Characterisation of severe obliterative bronchiolitis in rheumatoid arthritisEur Respir J2009 3310531061

    Not in our library10.1183/09031936.00091608

  127. 127.

    Amsellem V Gary-Bobo G Marcos E Maitre B Chaar V Validire P Stern JB Noureddine H Sapin E Rideau D Hue S Le Corvoisier P Le Gouvello S Dubois-Randé JL Boczkowski J Adnot S Telomere Dysfunction Causes Sustained Inflammation in Chronic Obstructive Pulmonary DiseaseAm J Respir Crit Care Med2011

    Not in our library10.1164/rccm.201105-0802oc

  128. 128.

    Liu G Friggeri A Yang Y Milosevic J Ding Q Thannickal VJ Kaminski N Abraham E miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosisJ Exp Med2010 20715891597

    Not in our library10.1084/jem.20100035

  129. 129.

    Pandit KV Milosevic J Kaminski N MicroRNAs in idiopathic pulmonary fibrosisTransl Res2011 157191199

    Not in our library10.1016/j.trsl.2011.01.012

  130. 130.

    Castaldi PJ Cho MH Cohn M Langerman F Moran S Tarragona N Moukhachen H Venugopal R Hasimja D Kao E Wallace B Hersh CP Bagade S Bertram L Silverman EK Trikalinos TA The COPD genetic association compendium: a comprehensive online database of COPD genetic associationsHum Mol Genet2010 19526534

    Not in our library10.1093/hmg/ddp519

  131. 131.

    Sørheim IC DeMeo DL Washko G Litonjua A Sparrow D Bowler R Bakke P Pillai SG Coxson HO Lomas DA Silverman EK Hersh CP International COPD Genetics Network InvestigatorsPolymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD COPD2010 7262268

    Not in our library10.3109/15412555.2010.496821

  132. 132.

    Hersh CP Silverman EK Gascon J Bhattacharya S Klanderman BJ Litonjua AA Lefebvre V Sparrow D Reilly JJ Anderson WH Lomas DA Mariani TJ SOX5 is a candidate gene for chronic obstructive pulmonary disease susceptibility and is necessary for lung developmentAm J Respir Crit Care Med2011 18314821489

    Not in our library10.1164/rccm.201010-1751oc

  133. 133.

    Li LJ Gao LB Lv ML Dong W Su XW Liang WB Zhang L Association between SNPs in pre-miRNA and risk of chronic obstructive pulmonary diseaseClin Biochem2011 44813816

    Not in our library10.1016/j.clinbiochem.2011.04.021

  134. 134.

    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

  135. 135.

    Morty RE Königshoff M Eickelberg O Transforming growth factor-beta signaling across agesfrom distorted lung development to chronic obstructive pulmonary diseaseProc Am Thorac Soc2009 6607613

    Not in our library10.1513/pats.200908-087rm

  136. 136.
    Activation of WNT / β-Catenin Signaling in Pulmonary Fibroblasts by TGF-β1 Is Increased in Chronic Obstructive Pulmonary Disease · 2011
    No notice
  137. 137.

    Volonte D Kahkonen B Shapiro S Di Y Galbiati F Caveolin-1 expression is required for the development of pulmonary emphysema through activation of the ATM-p53-p21 pathwayJ Biol Chem2009 28454625466

    Not in our library10.1074/jbc.c800225200

  138. 138.

    Le Saux O Teeters K Miyasato S Choi J Nakamatsu G Richardson JA Starcher B Davis EC Tam EK Jourdan-Le Saux C The role of caveolin-1 in pulmonary matrix remodeling and mechanical propertiesAm J Physiol Lung Cell Mol Physiol2008 295L1007L1017

    Not in our library10.1152/ajplung.90207.2008

  139. 139.

    Dasari A Bartholomew JN Volonte D Galbiati F Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 mitogen-activated protein kinase/Sp1-mediated activation of two GC-rich promoter elementsCancer Res2006 661080510814

    Not in our library10.1158/0008-5472.can-06-1236

  140. 140.

    Galbiati F Volonte D Brown AM Weinstein DE Ben-Ze'ev A Pestell RG Lisanti MP Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domainsJ Biol Chem2000 2752336823377

    Not in our library10.1074/jbc.m002020200

  141. 141.

    Wang XM Zhang Y Kim HP Zhou Z Feghali-Bostwick CA Liu F Ifedigbo E Xu X Oury TD Kaminski N Choi AM Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosisJ Exp Med2006 20328952906

    Not in our library10.1084/jem.20061536

  142. 142.

    Chilosi M Poletti V Murer B Semenzato G Doglioni C Lynch JPIBronchiolar epithelium in idiopathic pulmonary fibrosis/usual interstitial pneumonia In: Idiopathic pulmonary fibrosisLung Biology in health and disease2004 Marcel Dekker New York631664

    Not in our library

  143. 143.

    Mitzner W Emphysema - a disease of small airways or lung parenchyma?N Engl J Med2011 36516371639

    Not in our library10.1056/nejme1110635

  144. 144.

    Ishizawa K Kubo H Yamada M Kobayashi S Numasaki M Ueda S Suzuki T Sasaki H Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysemaFEBS Lett2004 556249252

    Not in our library10.1016/s0014-5793(03)01399-1

  145. 145.

    Huh JW Kim SY Lee JH Lee JS Ta QV Kim MJ Oh YM Lee YS Lee SD Bone marrow cells repair cigarette smoke-induced emphysema in ratsAm J Physiol Lung Cell Mol Physiol2011

    Not in our library10.1152/ajplung.00253.2010

  146. 146.

    Müller I Lymperi S Dazzi F Mesenchymal stem cell therapy for degenerative inflammatory disordersCurr Opin Organ Transplant2008 13639644

    Not in our library10.1097/mot.0b013e328317a462

  147. 147.
    Bone Marrow Stem Cells Expressing Keratinocyte Growth Factor via an Inducible Lentivirus Protects against Bleomycin-Induced Pulmonary Fibrosis · 2009
    No notice
  148. 148.

    Brooke G Cook M Blair C Han R Heazlewood C Jones B Kambouris M Kollar K McTaggart S Pelekanos R Rice A Rossetti T Atkinson K Therapeutic applications of mesenchymal stromal cellsSemin Cell Dev Biol2007 18846858

    Not in our library10.1016/j.semcdb.2007.09.012

  149. 149.

    Tzouvelekis A Antoniadis A Bouros D Stem cell therapy in pulmonary fibrosisCurr Opin Pulm Med2011

    Not in our library10.1097/mcp.0b013e328348744f

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