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Fibrotic Response of Tissue Remodeling in COPD

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Abstract

Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) involves diverse processes characterized by epithelial disruption, smooth muscle hypertrophy/hyperplasia, airway wall fibrosis, and alveolar destruction. According to the accepted current theory of COPD pathogenesis, tissue remodeling in COPD is predominantly a consequence of an imbalance between proteolytic and antiproteolytic activities. However, most of the studies carried out during the last few years have focused on mechanisms related to degradation of extracellular matrix (ECM) structural proteins, neglecting those involved in ECM protein deposition. This review revisits some of the latest findings related to fibrotic changes that occur in the airway wall of COPD patients, as well as the main cellular phenotypes relevant to these processes.

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References

  1. Lopez AD, Murray CC (1998) The global burden of disease, 1990–2020. Nat Med 4:1241–1243

    PubMed  CAS  Google Scholar 

  2. Terzano C, Conti V, Di Stefano F, Petroianni A, Ceccarelli D, Graziani E, Mariotta S, Ricci A, Vitarelli A, Puglisi G, De Vito C, Villari P, Allegra L (2010) Comorbidity, hospitalization, and mortality in COPD: results from a longitudinal study. Lung 188:321–329

    PubMed  Google Scholar 

  3. Zandvoort A, Postma DS, Jonker MR, Noordhoek JA, Vos JT, van der Geld YM, Timens W (2006) Altered expression of the Smad signalling pathway: implications for COPD pathogenesis. Eur Respir J 28:533–541

    PubMed  CAS  Google Scholar 

  4. Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, Maestrelli P, Cavallesco G, Papi A, Fabbri LM (2000) Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161:1016–1021

    PubMed  CAS  Google Scholar 

  5. Atzori L, Lucattelli M, Scotton CJ, Laurent GJ, Bartalesi B, De Cunto G, Lunghi B, Chambers RC, Lungarella G (2009) Absence of proteinase-activated receptor-1 signaling in mice confers protection from fMLP-induced goblet cell metaplasia. Am J Respir Cell Mol Biol 41:680–687

    PubMed  CAS  Google Scholar 

  6. Zanini A, Chetta A, Saetta M, Baraldo S, Castagnetti C, Nicolini G, Neri M, Olivieri D (2009) Bronchial vascular remodelling in patients with COPD and its relationship with inhaled steroid treatment. Thorax 64:1019–1024

    PubMed  CAS  Google Scholar 

  7. Rufino R, Madi K, Souza HS, Costa CH, Saito EH, Silva JR (2007) Quantitative assessment of elastic fibers in chronic obstructive pulmonary disease. J Bras Pneumol 33:502–509

    PubMed  Google Scholar 

  8. Falk JA, Martin UJ, Scharf S, Criner GJ (2007) Lung elastic recoil does not correlate with pulmonary hemodynamics in severe emphysema. Chest 132:1476–1484

    PubMed  Google Scholar 

  9. Murarescu ED, Eloae-Zugun F, Mihailovici MS (2008) Experimental COPD induced by solid combustible burn smoke in rats: a study of the emphysematous changes of the pulmonary parenchyma. Rom J Morphol Embryol 49:495–505

    PubMed  Google Scholar 

  10. Inoue K, Koike E, Yanagisawa R, Takano H (2010) Extensive analysis of elastase-induced pulmonary emphysema in rats: ALP in the lung, a new biomarker for disease progression? J Clin Biochem Nutr 46:168–176

    PubMed  CAS  Google Scholar 

  11. Chaouat A, Naeije R, Weitzenblum E (2008) Pulmonary hypertension in COPD. Eur Respir J 32:1371–1385

    PubMed  CAS  Google Scholar 

  12. Chung KF, Adcock IM (2008) Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J 31:1334–1356

    PubMed  CAS  Google Scholar 

  13. Leopold JG, Gough J (1957) The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax 12:219–235

    PubMed  CAS  Google Scholar 

  14. Churg A, Zhou S, Preobrazhenska O, Tai H, Wang R, Wright JL (2009) Expression of profibrotic mediators in small airways versus parenchyma after cigarette smoke exposure. Am J Respir Cell Mol Biol 40:268–276

    PubMed  CAS  Google Scholar 

  15. Shapiro SD (1995) The pathogenesis of emphysema: the elastase:antielastase hypothesis 30 years later. Proc Assoc Am Physicians 107:346–352

    PubMed  CAS  Google Scholar 

  16. Baraldo S, Bazzan E, Zanin ME, Turato G, Garbisa S, Maestrelli P, Papi A, Miniati M, Fabbri LM, Zuin R, Saetta M (2007) Matrix metalloproteinase-2 protein in lung periphery is related to COPD progression. Chest 132:1733–1740

    PubMed  CAS  Google Scholar 

  17. Ilumets H, Rytila P, Demedts I, Brusselle GG, Sovijarvi A, Myllarniemi M, Sorsa T, Kinnula VL (2007) Matrix metalloproteinases-8, -9 and -12 in smokers and patients with stage 0 COPD. Int J Chron Obstruct Pulmon Dis 2:369–379

    PubMed  CAS  Google Scholar 

  18. Brajer B, Batura-Gabryel H, Nowicka A, Kuznar-Kaminska B, Szczepanik A (2008) Concentration of matrix metalloproteinase-9 in serum of patients with chronic obstructive pulmonary disease and a degree of airway obstruction and disease progression. J Physiol Pharmacol 59(Suppl 6):145–152

    PubMed  Google Scholar 

  19. Chen Y, Chen P, Hanaoka M, Droma Y, Kubo K (2008) Enhanced levels of prostaglandin E2 and matrix metalloproteinase-2 correlate with the severity of airflow limitation in stable COPD. Respirology 13:1014–1021

    PubMed  Google Scholar 

  20. Lowrey GE, Henderson N, Blakey JD, Corne JM, Johnson SR (2008) MMP-9 protein level does not reflect overall MMP activity in the airways of patients with COPD. Respir Med 102:845–851

    PubMed  Google Scholar 

  21. Wallace AM, Sandford AJ, English JC, Burkett KM, Li H, Finley RJ, Muller NL, Coxson HO, Pare PD, Abboud RT (2008) Matrix metalloproteinase expression by human alveolar macrophages in relation to emphysema. COPD 5:13–23

    PubMed  Google Scholar 

  22. Cheng SL, Yu CJ, Yang PC (2009) Genetic polymorphisms of cytochrome p450 and matrix metalloproteinase in chronic obstructive pulmonary disease. Biochem Genet 47:591–601

    PubMed  CAS  Google Scholar 

  23. Deshmukh HS, McLachlan A, Atkinson JJ, Hardie WD, Korfhagen TR, Dietsch M, Liu Y, Di PY, Wesselkamper SC, Borchers MT, Leikauf GD (2009) Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am J Respir Crit Care Med 180:834–845

    PubMed  CAS  Google Scholar 

  24. Hunninghake GM, Cho MH, Tesfaigzi Y, Soto-Quiros ME, Avila L, Lasky-Su J, Stidley C, Melen E, Soderhall C, Hallberg J, Kull I, Kere J, Svartengren M, Pershagen G, Wickman M, Lange C, Demeo DL, Hersh CP, Klanderman BJ, Raby BA, Sparrow D, Shapiro SD, Silverman EK, Litonjua AA, Weiss ST, Celedon JC (2009) MMP12, lung function, and COPD in high-risk populations. N Engl J Med 361:2599–2608

    PubMed  CAS  Google Scholar 

  25. McAloon CJ, Wood AM, Gough SC, Stockley RA (2009) Matrix metalloprotease polymorphisms are associated with gas transfer in alpha 1 antitrypsin deficiency. Ther Adv Respir Dis 3:23–30

    PubMed  Google Scholar 

  26. Qu P, Du H, Wang X, Yan C (2009) Matrix metalloproteinase 12 overexpression in lung epithelial cells plays a key role in emphysema to lung bronchioalveolar adenocarcinoma transition. Cancer Res 69:7252–7261

    PubMed  CAS  Google Scholar 

  27. Schirmer H, Basso da Silva L, Teixeira PJ, Moreira JS, Moreira AL, Simon D (2009) Matrix metalloproteinase gene polymorphisms: lack of association with chronic obstructive pulmonary disease in a Brazilian population. Genet Mol Res 8:1028–1034

    PubMed  CAS  Google Scholar 

  28. Wong S, Belvisi MG, Birrell MA (2009) MMP/TIMP expression profiles in distinct lung disease models: implications for possible future therapies. Respir Res 10:72

    PubMed  Google Scholar 

  29. Haq I, Chappell S, Johnson SR, Lotya J, Daly L, Morgan K, Guetta-Baranes T, Roca J, Rabinovich R, Millar AB, Donnelly SC, Keatings V, MacNee W, Stolk J, Hiemstra PS, Miniati M, Monti S, O’Connor CM, Kalsheker N (2010) Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population. BMC Med Genet 11:7

    PubMed  Google Scholar 

  30. Lee SY, Kim MJ, Kang HG, Yoo SS, Choi YY, Lee WK, Cha SI, Kim CH, Jung TH, Park JY (2010) Polymorphisms in matrix metalloproteinase-1, -9 and -12 genes and the risk of chronic obstructive pulmonary disease in a Korean population. Respiration 80:133–138

    PubMed  CAS  Google Scholar 

  31. Louhelainen N, Stark H, Mazur W, Rytila P, Djukanovic R, Kinnula VL (2010) Elevation of sputum matrix metalloproteinase-9 persists up to 6 months after smoking cessation: a research study. BMC Pulm Med 10:13

    PubMed  Google Scholar 

  32. Churg A, Tai H, Coulthard T, Wang R, Wright JL (2006) Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Am J Respir Crit Care Med 174:1327–1334

    PubMed  CAS  Google Scholar 

  33. Girod CE, King TE Jr (2005) COPD: a dust-induced disease? Chest 128:3055–3064

    PubMed  Google Scholar 

  34. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350:2645–2653

    PubMed  CAS  Google Scholar 

  35. Jeffery PK (2001) Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 164:S28–S38

    PubMed  CAS  Google Scholar 

  36. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, GOLD Scientific Committee (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 163:1256–1276

    PubMed  CAS  Google Scholar 

  37. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM (2000) Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161:1720–1745

    PubMed  CAS  Google Scholar 

  38. Petecchia L, Sabatini F, Varesio L, Camoirano A, Usai C, Pezzolo A, Rossi GA (2009) Bronchial airway epithelial cell damage following exposure to cigarette smoke includes disassembly of tight junction components mediated by the extracellular signal-regulated kinase 1/2 pathway. Chest 135:1502–1512

    PubMed  CAS  Google Scholar 

  39. Tilley AE, Harvey BG, Heguy A, Hackett NR, Wang R, O’Connor TP, Crystal RG (2009) Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 179:457–466

    PubMed  CAS  Google Scholar 

  40. Lapperre TS, Sont JK, van Schadewijk A, Gosman MM, Postma DS, Bajema IM, Timens W, Mauad T, Hiemstra PS, GLUCOLD Study Group (2007) Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir Res 8:25

    Google Scholar 

  41. Araya J, Cambier S, Markovics JA, Wolters P, Jablons D, Hill A, Finkbeiner W, Jones K, Broaddus VC, Sheppard D, Barzcak A, Xiao Y, Erle DJ, Nishimura SL (2007) Squamous metaplasia amplifies pathologic epithelial–mesenchymal interactions in COPD patients. J Clin Invest 117:3551–3562

    PubMed  CAS  Google Scholar 

  42. Bolton SJ, Pinnion K, Oreffo V, Foster M, Pinkerton KE (2009) Characterisation of the proximal airway squamous metaplasia induced by chronic tobacco smoke exposure in spontaneously hypertensive rats. Respir Res 10:118

    PubMed  Google Scholar 

  43. Polosukhin VV, Lawson WE, Milstone AP, Egunova SM, Kulipanov AG, Tchuvakin SG, Massion PP, Blackwell TS (2007) Association of progressive structural changes in the bronchial epithelium with subepithelial fibrous remodeling: a potential role for hypoxia. Virchows Arch 451:793–803

    PubMed  Google Scholar 

  44. Innes AL, Woodruff PG, Ferrando RE, Donnelly S, Dolganov GM, Lazarus SC, Fahy JV (2006) Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 130:1102–1108

    PubMed  CAS  Google Scholar 

  45. Haswell LE, Hewitt K, Thorne D, Richter A, Gaca MD (2010) Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: a potential model of goblet cell hyperplasia. Toxicol In Vitro 24:981–987

    PubMed  CAS  Google Scholar 

  46. Williams OW, Sharafkhaneh A, Kim V, Dickey BF, Evans CM (2006) Airway mucus: from production to secretion. Am J Respir Cell Mol Biol 34:527–536

    PubMed  CAS  Google Scholar 

  47. Hirst SJ, Walker TR, Chilvers ER (2000) Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma. Eur Respir J 16:159–177

    PubMed  CAS  Google Scholar 

  48. Shao J, Xia ZW, Li YZ, Yu SC, Deng WW (2006) Expression of cellular phenotype switching markers-matrix protein Gla, mRNA and collagen I, III and V of human airway smooth muscle cells in vitro after TGF-beta1 stimulation. Zhonghua Er Ke Za Zhi 44:531–534

    PubMed  Google Scholar 

  49. Xie M, Liu XS, Xu YJ, Zhang ZX, Bai J, Ni W, Chen SX (2007) ERK1/2 signaling pathway modulates the airway smooth muscle cell phenotype in the rat model of chronic asthma. Respiration 74:680–690

    PubMed  CAS  Google Scholar 

  50. Halayko AJ, Tran T, Gosens R (2008) Phenotype and functional plasticity of airway smooth muscle: role of caveolae and caveolins. Proc Am Thorac Soc 5:80–88

    PubMed  CAS  Google Scholar 

  51. Dekkers BG, Schaafsma D, Nelemans SA, Zaagsma J, Meurs H (2007) Extracellular matrix proteins differentially regulate airway smooth muscle phenotype and function. Am J Physiol Lung Cell Mol Physiol 292:L1405–L1413

    PubMed  CAS  Google Scholar 

  52. Dekkers BG, Schaafsma D, Tran T, Zaagsma J, Meurs H (2009) Insulin-induced laminin expression promotes a hypercontractile airway smooth muscle phenotype. Am J Respir Cell Mol Biol 41:494–504

    PubMed  CAS  Google Scholar 

  53. Dekkers BG, Maarsingh H, Meurs H, Gosens R (2009) Airway structural components drive airway smooth muscle remodeling in asthma. Proc Am Thorac Soc 6:683–692

    PubMed  CAS  Google Scholar 

  54. Pera T, Gosens R, Lesterhuis AH, Sami R, Toorn M, Zaagsma J, Meurs H (2010) Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype. Respir Res 11:48

    PubMed  Google Scholar 

  55. Panettieri RA Jr, Kotlikoff MI, Gerthoffer WT, Hershenson MB, Woodruff PG, Hall IP, Banks-Schlegel S, National Heart, Lung and Blood Institute (2008) Airway smooth muscle in bronchial tone, inflammation, and remodeling: basic knowledge to clinical relevance. Am J Respir Crit Care Med 177:248–252

    PubMed  Google Scholar 

  56. Jarai G, Sukkar M, Garrett S, Duroudier N, Westwick J, Adcock I, Chung KF (2004) Effects of interleukin-1beta, interleukin-13 and transforming growth factor-beta on gene expression in human airway smooth muscle using gene microarrays. Eur J Pharmacol 497:255–265

    PubMed  CAS  Google Scholar 

  57. Fernandes DJ, Bonacci JV, Stewart AG (2006) Extracellular matrix, integrins, and mesenchymal cell function in the airways. Curr Drug Targets 7:567–577

    PubMed  CAS  Google Scholar 

  58. Parameswaran K, Willems-Widyastuti A, Alagappan VK, Radford K, Kranenburg AR, Sharma HS (2006) Role of extracellular matrix and its regulators in human airway smooth muscle biology. Cell Biochem Biophys 44:139–146

    PubMed  CAS  Google Scholar 

  59. Schuliga M, Ong SC, Soon L, Zal F, Harris T, Stewart AG (2010) Airway smooth muscle remodels pericellular collagen fibrils: implications for proliferation. Am J Physiol Lung Cell Mol Physiol 298:L584–L592

    PubMed  CAS  Google Scholar 

  60. James AL, Wenzel S (2007) Clinical relevance of airway remodelling in airway diseases. Eur Respir J 30:134–155

    PubMed  CAS  Google Scholar 

  61. Malmstrom J, Larsen K, Malmstrom L, Tufvesson E, Parker K, Marchese J, Williamson B, Hattan S, Patterson D, Martin S, Graber A, Juhasz HP, Westergren-Thorsson G, Marko-Varga G (2004) Proteome annotations and identifications of the human pulmonary fibroblast. J Proteome Res 3:525–537

    PubMed  Google Scholar 

  62. Zandvoort A, Postma DS, Jonker MR, Noordhoek JA, Vos JT, Timens W (2008) Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD. Respir Res 9:83

    PubMed  Google Scholar 

  63. Hallgren O, Nihlberg K, Dahlback M, Bjermer L, Eriksson LT, Erjefalt JS, Lofdahl CG, Westergren-Thorsson G (2010) Altered fibroblast proteoglycan production in COPD. Respir Res 11:55

    PubMed  Google Scholar 

  64. Roberts AB, McCune BK, Sporn MB (1992) TGF-beta: regulation of extracellular matrix. Kidney Int 41:557–559

    PubMed  CAS  Google Scholar 

  65. Schiller M, Javelaud D, Mauviel A (2004) TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35:83–92

    PubMed  CAS  Google Scholar 

  66. Morty RE, Konigshoff M, Eickelberg O (2009) Transforming growth factor-beta signaling across ages: from distorted lung development to chronic obstructive pulmonary disease. Proc Am Thorac Soc 6:607–613

    PubMed  CAS  Google Scholar 

  67. Sugiura H, Ichikawa T, Liu X, Kobayashi T, Wang XQ, Kawasaki S, Togo S, Kamio K, Mao L, Ann Y, Ichinose M, Rennard SI (2009) N-acetyl-L-cysteine inhibits TGF-beta1-induced profibrotic responses in fibroblasts. Pulm Pharmacol Ther 22:487–491

    PubMed  CAS  Google Scholar 

  68. Araya J, Nishimura SL (2010) Fibrogenic reactions in lung disease. Annu Rev Pathol 5:77–98

    PubMed  CAS  Google Scholar 

  69. Camara J, Jarai G (2010) Epithelial–mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis Tissue Repair 3(1):2

    PubMed  Google Scholar 

  70. Kranenburg AR, Willems-Widyastuti A, Moori WJ, Sterk PJ, Alagappan VK, de Boer WI, Sharma HS (2006) Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am J Clin Pathol 126:725–735

    PubMed  CAS  Google Scholar 

  71. Lagente V, Manoury B, Nenan S, Le Quement C, Martin-Chouly C, Boichot E (2005) Role of matrix metalloproteinases in the development of airway inflammation and remodeling. Braz J Med Biol Res 38:1521–1530

    PubMed  CAS  Google Scholar 

  72. Li H, Cui D, Ma N, Lu L, Gao Y, Cui X, Wang D (2002) The effect of extracellular matrix remodeling on airflow obstruction in a rat model of chronic obstructive pulmonary disease. Zhonghua Jie He He Hu Xi Za Zhi 25:403–407

    PubMed  Google Scholar 

  73. Li H, Cui D, Tong X, Ma N, Gao Y, Cui X, Lu L, Wang D, Liang Y (2002) The role of matrix metalloproteinases in extracellular matrix remodelling in chronic obstructive pulmonary disease rat models. Zhonghua Nei Ke Za Zhi 41:393–398

    PubMed  CAS  Google Scholar 

  74. Hogg JC, McDonough JE, Gosselink JV, Hayashi S (2009) What drives the peripheral lung-remodeling process in chronic obstructive pulmonary disease? Proc Am Thorac Soc 6:668–672

    PubMed  Google Scholar 

  75. Papakonstantinou E, Karakiulakis G (2009) The ‘sweet’ and ‘bitter’ involvement of glycosaminoglycans in lung diseases: pharmacotherapeutic relevance. Br J Pharmacol 157:1111–1127

    PubMed  CAS  Google Scholar 

  76. Klagas I, Goulet S, Karakiulakis G, Zhong J, Baraket M, Black JL, Papakonstantinou E, Roth M (2009) Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD. Eur Respir J 34:616–628

    PubMed  CAS  Google Scholar 

  77. van Straaten JF, Coers W, Noordhoek JA, Huitema S, Flipsen JT, Kauffman HF, Timens W, Postma DS (1999) Proteoglycan changes in the extracellular matrix of lung tissue from patients with pulmonary emphysema. Mod Pathol 12:697–705

    PubMed  Google Scholar 

  78. Noordhoek JA, Postma DS, Chong LL, Menkema L, Kauffman HF, Timens W, van Straaten JF, van der Geld YM (2005) Different modulation of decorin production by lung fibroblasts from patients with mild and severe emphysema. COPD 2:17–25

    PubMed  Google Scholar 

  79. Hogg JC, Timens W (2009) The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 4:435–459

    PubMed  CAS  Google Scholar 

  80. Bracke KR, Dentener MA, Papakonstantinou E, Vernooy JH, Demoor T, Pauwels NS, Cleutjens J, van Suylen RJ, Joos GF, Brusselle GG, Wouters EF (2010) Enhanced deposition of low-molecular-weight hyaluronan in lungs of cigarette smoke-exposed mice. Am J Respir Cell Mol Biol 42:753–761

    PubMed  CAS  Google Scholar 

  81. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, Noble PW (1996) Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest 98:2403–2413

    PubMed  CAS  Google Scholar 

  82. Khan AI, Kerfoot SM, Heit B, Liu L, Andonegui G, Ruffell B, Johnson P, Kubes P (2004) Role of CD44 and hyaluronan in neutrophil recruitment. J Immunol 173:7594–7601

    PubMed  CAS  Google Scholar 

  83. Dentener MA, Louis R, Cloots RH, Henket M, Wouters EF (2006) Differences in local versus systemic TNFalpha production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNFalpha release. Thorax 61:478–484

    PubMed  CAS  Google Scholar 

  84. Cantor JO (2007) Potential therapeutic applications of hyaluronan in the lung. Int J Chron Obstruct Pulmon Dis 2:283–288

    PubMed  CAS  Google Scholar 

  85. Scotton CJ, Chambers RC (2007) Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest 132:1311–1321

    PubMed  Google Scholar 

  86. Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjoland A, Hallgren O, Marko-Varga G, Bjermer L (2010) Pathological airway remodelling in inflammation. Clin Respir J 4(Suppl 1):1–8

    PubMed  CAS  Google Scholar 

  87. Phan SH (2008) Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5:334–337

    PubMed  Google Scholar 

  88. Kaarteenaho-Wiik R, Paakko P, Sormunen R (2009) Ultrastructural features of lung fibroblast differentiation into myofibroblasts. Ultrastruct Pathol 33:6–15

    PubMed  Google Scholar 

  89. Watsky MA, Weber KT, Sun Y, Postlethwaite A (2010) New insights into the mechanism of fibroblast to myofibroblast transformation and associated pathologies. Int Rev Cell Mol Biol 282:165–192

    PubMed  CAS  Google Scholar 

  90. McAnulty RJ (2007) Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol 39:666–671

    PubMed  CAS  Google Scholar 

  91. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210

    PubMed  CAS  Google Scholar 

  92. Wicks J, Haitchi HM, Holgate ST, Davies DE, Powell RM (2006) Enhanced upregulation of smooth muscle related transcripts by TGF beta2 in asthmatic (myo) fibroblasts. Thorax 61:313–319

    PubMed  CAS  Google Scholar 

  93. Choe MM, Sporn PH, Swartz MA (2006) Extracellular matrix remodeling by dynamic strain in a three-dimensional tissue-engineered human airway wall model. Am J Respir Cell Mol Biol 35:306–313

    PubMed  CAS  Google Scholar 

  94. Singh SR, Hall IP (2008) Airway myofibroblasts and their relationship with airway myocytes and fibroblasts. Proc Am Thorac Soc 5:127–132

    PubMed  CAS  Google Scholar 

  95. Michalik M, Pierzchalska M, Legutko A, Ura M, Ostaszewska A, Soja J, Sanak M (2009) Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture. Med Sci Monit 15:194–201

    Google Scholar 

  96. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171:380–389

    PubMed  CAS  Google Scholar 

  97. Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM (2007) Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 282:22910–22920

    PubMed  CAS  Google Scholar 

  98. Andersson-Sjoland A, de Alba CG, Nihlberg K, Becerril C, Ramirez R, Pardo A, Westergren-Thorsson G, Selman M (2008) Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 40:2129–2140

    PubMed  Google Scholar 

  99. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110:341–350

    PubMed  CAS  Google Scholar 

  100. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z (2005) Induction of epithelial–mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 166:1321–1332

    PubMed  CAS  Google Scholar 

  101. Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z (2005) TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 5:56

    Google Scholar 

  102. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 103:13180–13185

    PubMed  CAS  Google Scholar 

  103. Kim JH, Jang YS, Eom KS, Hwang YI, Kang HR, Jang SH, Kim CH, Park YB, Lee MG, Hyun IG, Jung KS, Kim DG (2007) Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci 22:898–904

    PubMed  CAS  Google Scholar 

  104. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA, Chapman HA (2009) Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest 119:213–224

    PubMed  CAS  Google Scholar 

  105. Zhang M, Zhang Z, Pan HY, Wang DX, Deng ZT, Ye XL (2009) TGF-beta1 induces human bronchial epithelial cell-to-mesenchymal transition in vitro. Lung 187:187–194

    PubMed  CAS  Google Scholar 

  106. Ramos C, Becerril C, Montano M, Garcia-De-Alba C, Ramirez R, Checa M, Pardo A, Selman M (2010) FGF-1 reverts epithelial-mesenchymal transition induced by TGF-{beta}1 through MAPK/ERK kinase pathway. Am J Physiol Lung Cell Mol Physiol 299(2):L222–L231

    PubMed  CAS  Google Scholar 

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Salazar, L.M., Herrera, A.M. Fibrotic Response of Tissue Remodeling in COPD. Lung 189, 101–109 (2011). https://doi.org/10.1007/s00408-011-9279-2

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