Semin Respir Crit Care Med 2006; 27(6): 600-612
DOI: 10.1055/s-2006-957332
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Epithelial-Mesenchymal Interactions in Pulmonary Fibrosis

Jeffrey C. Horowitz1 , Victor J. Thannickal1
  • 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
Further Information

Publication History

Publication Date:
29 December 2006 (online)

ABSTRACT

Pulmonary fibrosis represents the sequelae of a variety of acute and chronic lung injuries of known and unknown etiologies. Tissue specimens obtained from patients with pulmonary fibrosis, regardless of the etiology, consistently show evidence of an ongoing wound-repair response. Epithelial-mesenchymal interactions have critical roles in normal lung development, tissue repair processes, and fibrosis. Current hypotheses propose that dysregulated function of, and impaired communication between, epithelial and mesenchymal cells prevent resolution of the wound-repair response and contribute to the pathobiology of pulmonary fibrosis. This hypothesis is supported by abundant evidence from patients, animal models, and cell-culture studies demonstrating abnormalities in epithelial cell and mesenchymal cell activities including proliferation, differentiation, and survival. This article reviews the aberrant epithelial and mesenchymal cellular phenotypes found in the context of pulmonary fibrosis and discusses the mechanisms that perpetuate these cellular phenotypes.

REFERENCES

  • 1 Hogan B L, Yingling J M. Epithelial/mesenchymal interactions and branching morphogenesis of the lung.  Curr Opin Genet Dev. 1998;  8 481-486
  • 2 Bostrom H, Willetts K, Pekny M et al.. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.  Cell. 1996;  85 863-873
  • 3 Bruce M C, Honaker C E, Cross R J. Lung fibroblasts undergo apoptosis following alveolarization.  Am J Respir Cell Mol Biol. 1999;  20 228-236
  • 4 Schittny J C, Djonov V, Fine A, Burri P H. Programmed cell death contributes to postnatal lung development.  Am J Respir Cell Mol Biol. 1998;  18 786-793
  • 5 Warburton D, Tefft D, Mailleux A et al.. Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny?.  Am J Respir Crit Care Med. 2001;  164(10 Pt 2) S59-S62
  • 6 Demayo F, Minoo P, Plopper C G, Schuger L, Shannon J, Torday J S. Mesenchymal-epithelial interactions in lung development and repair: are modeling and remodeling the same process?.  Am J Physiol Lung Cell Mol Physiol. 2002;  283 L510-L517
  • 7 Singer A J, Clark R A. Cutaneous wound healing.  N Engl J Med. 1999;  341 738-746
  • 8 Martin P. Wound healing: aiming for perfect skin regeneration.  Science. 1997;  276 75-81
  • 9 Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast.  Wound Repair Regen. 2005;  13 7-12
  • 10 Tomasek J J, Gabbiani G, Hinz B, Chaponnier C, Brown R A. Myofibroblasts and mechano-regulation of connective tissue remodelling.  Nat Rev Mol Cell Biol. 2002;  3 349-363
  • 11 Thannickal V J, Toews G B, White E S, Lynch III J P, Martinez F J. Mechanisms of pulmonary fibrosis.  Annu Rev Med. 2004;  55 395-417
  • 12 Rennard S I, Bitterman P B, Crystal R G. Response of the lower respiratory tract to injury. Mechanisms of repair of the parenchymal cells of the alveolar wall.  Chest. 1983;  84 735-739
  • 13 Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2002 3 http://3(www.respiratory-research.com)
  • 14 Selman M, King T E, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.  Ann Intern Med. 2001;  134 136-151
  • 15 Gross T J, Hunninghake G W. Idiopathic pulmonary fibrosis.  N Engl J Med. 2001;  345 517-525
  • 16 Kuhn C, McDonald J A. The roles of the myofibroblast in idiopathic pulmonary fibrosis: ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis.  Am J Pathol. 1991;  138 1257-1265
  • 17 Katzenstein A L, Myers J L. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification.  Am J Respir Crit Care Med. 1998;  157(4 Pt 1) 1301-1315
  • 18 Kasper M, Haroske G. Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis.  Histol Histopathol. 1996;  11 463-483
  • 19 King Jr T E, Schwarz M I, Brown K et al.. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.  Am J Respir Crit Care Med. 2001;  164 1025-1032
  • 20 Brody A R, Craighead J E. Interstitial associations of cells lining air spaces in human pulmonary fibrosis.  Virchows Arch A Pathol Anat Histol. 1976;  372 39-49
  • 21 Katzenstein A L. Pathogenesis of “fibrosis” in interstitial pneumonia: an electron microscopic study.  Hum Pathol. 1985;  16 1015-1024
  • 22 Coalson J J. The ultrastructure of human fibrosing alveolitis.  Virchows Arch A Pathol Anat Histol. 1982;  395 181-199
  • 23 Corrin B, Dewar A, Rodriguez-Roisin R, Turner-Warwick M. Fine structural changes in cryptogenic fibrosing alveolitis and asbestosis.  J Pathol. 1985;  147 107-119
  • 24 Sutinen S, Rainio P, Huhti E, Pokela R. Ultrastructure of terminal respiratory epithelium and prognosis in chronic interstitial pneumonia.  Eur J Respir Dis. 1980;  61 325-336
  • 25 Kawanami O, Ferrans V J, Crystal R G. Structure of alveolar epithelial cells in patients with fibrotic lung disorders.  Lab Invest. 1982;  46 39-53
  • 26 Chilosi M, Poletti V, Murer B et al.. Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63.  Lab Invest. 2002;  82 1335-1345
  • 27 Kuwano K, Kunitake R, Kawasaki M et al.. P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 1996;  154(2 Pt 1) 477-483
  • 28 Barbas-Filho J V, Ferreira M A, Sesso A, Kairalla R A, Carvalho C R, Capelozzi V L. Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP).  J Clin Pathol. 2001;  54 132-138
  • 29 Maeyama T, Kuwano K, Kawasaki M et al.. Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis.  Eur Respir J. 2001;  17 180-189
  • 30 Brody A R, Soler P, Basset F, Haschek W M, Witschi H. Epithelial-mesenchymal associations of cells in human pulmonary fibrosis and in BHT-oxygen-induced fibrosis in mice.  Exp Lung Res. 1981;  2 207-220
  • 31 Adamson I Y, Hedgecock C, Bowden D H. Epithelial cell-fibroblast interactions in lung injury and repair.  Am J Pathol. 1990;  137 385-392
  • 32 Sirianni F E, Milaninezhad A, Chu F S, Walker D C. Alteration of fibroblast architecture and loss of basal lamina apertures in human emphysematous lung.  Am J Respir Crit Care Med. 2006;  173 632-638
  • 33 Uhal B D, Joshi I, Hughes W F, Ramos C, Pardo A, Selman M. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung.  Am J Physiol. 1998;  275(6 Pt 1) L1192-L1199
  • 34 Plataki M, Koutsopoulos A V, Darivianaki K, Delides G, Siafakas N M, Bouros D. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis.  Chest. 2005;  127 266-274
  • 35 Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal B D. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L143-L151
  • 36 Kuwano K, Kunitake R, Maeyama T et al.. Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor.  Am J Physiol Lung Cell Mol Physiol. 2001;  280 L316-L325
  • 37 Lee C G, Cho S J, Kang M J et al.. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis.  J Exp Med. 2004;  200 377-389
  • 38 Strasser A, O'Connor L, Dixit V M. Apoptosis signaling.  Annu Rev Biochem. 2000;  69 217-245
  • 39 Hagimoto N, Kuwano K, Miyazaki H et al.. Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen.  Am J Respir Cell Mol Biol. 1997;  17 272-278
  • 40 Hagimoto N, Kuwano K, Inoshima I et al.. TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells.  J Immunol. 2002;  168 6470-6478
  • 41 Kuwano K, Hagimoto N, Kawasaki M et al.. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis.  J Clin Invest. 1999;  104 13-19
  • 42 Aoshiba K, Yasui S, Tamaoki J, Nagai A. The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice.  Am J Respir Crit Care Med. 2000;  162(2 Pt 1) 695-700
  • 43 Wallach-Dayan S B, Izbicki G, Cohen P Y, Gerstl-Golan R, Fine A, Breuer R. Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway.  Am J Physiol Lung Cell Mol Physiol. 2006;  290 L790-L796
  • 44 Schrier D J, Kunkel R G, Phan S H. The role of strain variation in murine bleomycin-induced pulmonary fibrosis.  Am Rev Respir Dis. 1983;  127 63-66
  • 45 Daly H E, Baecher-Allan C M, Barth R K, D'Angio C T, Finkelstein J N. Bleomycin induces strain-dependent alterations in the pattern of epithelial cell-specific marker expression in mouse lung.  Toxicol Appl Pharmacol. 1997;  142 303-310
  • 46 Qunn L, Takemura T, Ikushima S et al.. Hyperplastic epithelial foci in honeycomb lesions in idiopathic pulmonary fibrosis.  Virchows Arch. 2002;  441 271-278
  • 47 Deterding R R, Havill A M, Yano T et al.. Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor.  Proc Assoc Am Physicians. 1997;  109 254-268
  • 48 Dohi M, Hasegawa T, Yamamoto K, Marshall B C. Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis.  Am J Respir Crit Care Med. 2000;  162 2302-2307
  • 49 Groves R W, Schmidt-Lucke J A. Recombinant human GM-CSF in the treatment of poorly healing wounds.  Adv Skin Wound Care. 2000;  13(3 Pt 1) 107-112
  • 50 Christensen P J, Bailie M B, Goodman R E, O'Brien A D, Toews G B, Paine III R. Role of diminished epithelial GM-CSF in the pathogenesis of bleomycin-induced pulmonary fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L487-L495
  • 51 Moore B B, Coffey M J, Christensen P et al.. GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism.  J Immunol. 2000;  165 4032-4039
  • 52 Zhang F, Nielsen L D, Lucas J J, Mason R J. Transforming growth factor-beta antagonizes alveolar type II cell proliferation induced by keratinocyte growth factor.  Am J Respir Cell Mol Biol. 2004;  31 679-686
  • 53 Irigoyen J P, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y. The plasminogen activator system: biology and regulation.  Cell Mol Life Sci. 1999;  56 104-132
  • 54 Eitzman D T, McCoy R D, Zheng X et al.. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene.  J Clin Invest. 1996;  97 232-237
  • 55 Sisson T H, Hattori N, Xu Y, Simon R H. Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes.  Hum Gene Ther. 1999;  10 2315-2323
  • 56 Sisson T H, Hanson K E, Subbotina N, Patwardhan A, Hattori N, Simon R H. Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.  Am J Physiol Lung Cell Mol Physiol. 2002;  283 L1023-L1032
  • 57 Hattori N, Degen J L, Sisson T H et al.. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice.  J Clin Invest. 2000;  106 1341-1350
  • 58 Swaisgood C M, French E L, Noga C, Simon R H, Ploplis V A. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system.  Am J Pathol. 2000;  157 177-187
  • 59 Legrand C, Polette M, Tournier J M et al.. uPA/plasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration.  Exp Cell Res. 2001;  264 326-336
  • 60 Chan J C, Duszczyszyn D A, Castellino F J, Ploplis V A. Accelerated skin wound healing in plasminogen activator inhibitor-1-deficient mice.  Am J Pathol. 2001;  159 1681-1688
  • 61 Lazar M H, Christensen P J, Du M et al.. Plasminogen activator inhibitor-1 impairs alveolar epithelial repair by binding to vitronectin.  Am J Respir Cell Mol Biol. 2004;  31 672-678
  • 62 Van Leer C, Stutz M, Haeberli A, Geiser T. Urokinase plasminogen activator released by alveolar epithelial cells modulates alveolar epithelial repair in vitro.  Thromb Haemost. 2005;  94 1257-1264
  • 63 Phan S H. The myofibroblast in pulmonary fibrosis.  Chest. 2002;  122(Suppl 6) 286S-289S
  • 64 Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases.  J Pathol. 2003;  200 500-503
  • 65 Chambers R C, Leoni P, Kaminski N, Laurent G J, Heller R A. Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching.  Am J Pathol. 2003;  162 533-546
  • 66 Schmidt M, Sun G, Stacey M A, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.  J Immunol. 2003;  171 380-389
  • 67 Quan T E, Cowper S, Wu S P, Bockenstedt L K, Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood.  Int J Biochem Cell Biol. 2004;  36 598-606
  • 68 Phillips R J, Burdick M D, Hong K et al.. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.  J Clin Invest. 2004;  114 438-446
  • 69 Moore B B, Kolodsick J E, Thannickal V J et al.. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.  Am J Pathol. 2005;  166 675-684
  • 70 Hashimoto N, Jin H, Liu T, Chensue S W, Phan S H. Bone marrow-derived progenitor cells in pulmonary fibrosis.  J Clin Invest. 2004;  113 243-252
  • 71 Willis B C, Liebler J M, Luby-Phelps K et al.. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis.  Am J Pathol. 2005;  166 1321-1332
  • 72 Yao H W, Xie Q M, Chen J Q, Deng Y M, Tang H F. TGF-beta1 induces alveolar epithelial to mesenchymal transition in vitro.  Life Sci. 2004;  76 29-37
  • 73 Kasai H, Allen J T, Mason R M, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005 6: 56 http://(www.respiratory-research.com)
  • 74 Kotaru C, Schoonover K J, Trudeau J B et al.. Regional fibroblast heterogeneity in the lung: implications for remodeling.  Am J Respir Crit Care Med. 2006;  173(11) 1208-1215
  • 75 Chang H Y, Chi J T, Dudoit S et al.. Diversity, topographic differentiation, and positional memory in human fibroblasts.  Proc Natl Acad Sci USA. 2002;  99 12877-12882
  • 76 Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar.  Am J Pathol. 1995;  146 56-66
  • 77 Kissin E Y, Lemaire R, Korn J H, Lafyatis R. Transforming growth factor beta induces fibroblast fibrillin-1 matrix formation.  Arthritis Rheum. 2002;  46 3000-3009
  • 78 Tanaka T, Yoshimi M, Maeyama T, Hagimoto N, Kuwano K, Hara N. Resistance to Fas-mediated apoptosis in human lung fibroblast.  Eur Respir J. 2002;  20 359-368
  • 79 Buhling F, Wille A, Rocken C et al.. Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respir Res 2005 6: 37 http://(www.respiratory-research.com)
  • 80 Moodley Y P, Misso N L, Scaffidi A K et al.. Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs.  Am J Respir Cell Mol Biol. 2003;  29 490-498
  • 81 Frankel S K, Cosgrove G P, Cha S I et al.. TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis.  Am J Respir Cell Mol Biol. 2006;  34 293-304
  • 82 Moodley Y P, Caterina P, Scaffidi A K et al.. Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis.  J Pathol. 2004;  202 486-495
  • 83 Horowitz J C, Cui Z, Moore T A et al.. Constitutive activation of prosurvival signaling in alveolar mesenchymal cells isolated from patients with nonresolving acute respiratory distress syndrome.  Am J Physiol Lung Cell Mol Physiol. 2006;  290 L415-L425
  • 84 Matsuyama W, Watanabe M, Shirahama Y et al.. Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis.  Am J Pathol. 2006;  168 866-877
  • 85 Chodon T, Sugihara T, Igawa H H, Funayama E, Furukawa H. Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance.  Am J Pathol. 2000;  157 1661-1669
  • 86 Jelaska A, Korn J H. Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis.  Arthritis Rheum. 2000;  43 2230-2239
  • 87 Horowitz J C, Lee D Y, Waghray M et al.. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor.  J Biol Chem. 2004;  279 1359-1367
  • 88 Zhang H Y, Phan S H. Inhibition of myofibroblast apoptosis by transforming growth factor beta(1).  Am J Respir Cell Mol Biol. 1999;  21 658-665
  • 89 Grinnell F, Zhu M, Carlson M A, Abrams J M. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue.  Exp Cell Res. 1999;  248 608-619
  • 90 Zhu Y K, Umino T, Liu X D et al.. Contraction of fibroblast-containing collagen gels: initial collagen concentration regulates the degree of contraction and cell survival.  In Vitro Cell Dev Biol Anim. 2001;  37 10-16
  • 91 Xia H, Nho R S, Kahm J, Kleidon J, Henke C A. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway.  J Biol Chem. 2004;  279 33024-33034
  • 92 Thannickal V J, Lee D Y, White E S et al.. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase.  J Biol Chem. 2003;  278 12384-12389
  • 93 Kobayashi T, Liu X, Wen F Q et al.. Smad3 mediates TGF-beta1 induction of VEGF production in lung fibroblasts.  Biochem Biophys Res Commun. 2005;  327 393-398
  • 94 Vittal R, Horowitz J C, Moore B B et al.. Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury.  Am J Pathol. 2005;  166 367-375
  • 95 Khalil N, Xu Y D, O'Connor R, Duronio V. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK.  J Biol Chem. 2005;  280 43000-43009
  • 96 Matsuoka H, Arai T, Mori M et al.. A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2002;  283 L103-L112
  • 97 Lappi-Blanco E, Soini Y, Paakko P. Apoptotic activity is increased in the newly formed fibromyxoid connective tissue in bronchiolitis obliterans organizing pneumonia.  Lung. 1999;  177 367-376
  • 98 Jordana M, Schulman J, McSharry C et al.. Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue.  Am Rev Respir Dis. 1988;  137 579-584
  • 99 Raghu G, Chen Y Y, Rusch V, Rabinovitch P S. Differential proliferation of fibroblasts cultured from normal and fibrotic human lungs.  Am Rev Respir Dis. 1988;  138 703-708
  • 100 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).  Chest. 1992;  102 832-837
  • 101 Ramos C, Montano M, Garcia-Alvarez J et al.. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression.  Am J Respir Cell Mol Biol. 2001;  24 591-598
  • 102 Marshall R P, McAnulty R J, Laurent G J. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor.  Am J Respir Crit Care Med. 2000;  161 1999-2004
  • 103 Moodley Y P, Scaffidi A K, Misso N L et al.. Fibroblasts isolated from normal lungs and those with idiopathic pulmonary fibrosis differ in interleukin-6/gp130-mediated cell signaling and proliferation.  Am J Pathol. 2003;  163 345-354
  • 104 Border W A, Noble N A. Transforming growth factor beta in tissue fibrosis.  N Engl J Med. 1994;  331 1286-1292
  • 105 Xaubet A, Marin-Arguedas A, Lario S et al.. Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2003;  168 431-435
  • 106 Khalil N, Parekh T V, O'Connor R et al.. Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis.  Thorax. 2001;  56 907-915
  • 107 Sime P J, Xing Z, Graham F L, Csaky K G, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung.  J Clin Invest. 1997;  100 768-776
  • 108 Bonniaud P, Margetts P J, Kolb M et al.. Progressive transforming growth factor {beta}1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor.  Am J Respir Crit Care Med. 2005;  171 889-898
  • 109 Bonniaud P, Kolb M, Galt T et al.. Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis.  J Immunol. 2004;  173 2099-2108
  • 110 Kelley J, Shull S, Walsh J J, Cutroneo K R, Absher M. Auto-induction of transforming growth factor-beta in human lung fibroblasts.  Am J Respir Cell Mol Biol. 1993;  8 417-424
  • 111 Kelley J, Fabisiak J P, Hawes K, Absher M. Cytokine signaling in lung: transforming growth factor-beta secretion by lung fibroblasts.  Am J Physiol. 1991;  260(2 Pt 1) L123-L128
  • 112 Breen E, Shull S, Burne S et al.. Bleomycin regulation of transforming growth factor-beta mRNA in rat lung fibroblasts.  Am J Respir Cell Mol Biol. 1992;  6 146-152
  • 113 Bergeron A, Soler P, Kambouchner M et al.. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10.  Eur Respir J. 2003;  22 69-76
  • 114 Coker R K, Laurent G J, Jeffery P K, du Bois R M, Black C M, McAnulty R J. Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung.  Thorax. 2001;  56 549-556
  • 115 Kapanci Y, Desmouliere A, Pache J C, Redard M, Gabbiani G. Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Possible role of transforming growth factor beta and tumor necrosis factor alpha.  Am J Respir Crit Care Med. 1995;  152(6 Pt 1) 2163-2169
  • 116 Khalil N, O'Connor R N, Flanders K C, Unruh H. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study.  Am J Respir Cell Mol Biol. 1996;  14 131-138
  • 117 Xu Y D, Hua J, Mui A, O'Connor R, Grotendorst G, Khalil N. Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2003;  285 L527-L539
  • 118 Yoo J, Ghiassi M, Jirmanova L et al.. Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation.  J Biol Chem. 2003;  278 43001-43007
  • 119 Yanagisawa K, Osada H, Masuda A et al.. Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-beta in human normal lung epithelial cells.  Oncogene. 1998;  17 1743-1747
  • 120 Solovyan V T, Keski-Oja J. Proteolytic activation of latent TGF-beta precedes caspase-3 activation and enhances apoptotic death of lung epithelial cells.  J Cell Physiol. 2006;  207 445-453
  • 121 Varga J, Rosenbloom J, Jimenez S A. Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts.  Biochem J. 1987;  247 597-604
  • 122 Eickelberg O, Kohler E, Reichenberger F et al.. Extracellular matrix deposition by primary human lung fibroblasts in response to TGF-beta1 and TGF-beta3.  Am J Physiol. 1999;  276(5 Pt 1) L814-L824
  • 123 Thannickal V J, Fanburg B L. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1.  J Biol Chem. 1995;  270 30334-30338
  • 124 Shiratori M, Michalopoulos G, Shinozuka H, Singh G, Ogasawara H, Katyal S L. Hepatocyte growth factor stimulates DNA synthesis in alveolar epithelial type II cells in vitro.  Am J Respir Cell Mol Biol. 1995;  12 171-180
  • 125 Nishimura S, Takahashi M, Ota S, Hirano M, Hiraishi H. Hepatocyte growth factor accelerates restitution of intestinal epithelial cells.  J Gastroenterol. 1998;  33 172-178
  • 126 Inoue T, Okada H, Kobayashi T et al.. Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice.  FASEB J. 2003;  17 268-270
  • 127 Dworkin L D, Gong R, Tolbert E et al.. Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury.  Kidney Int. 2004;  65 409-419
  • 128 Mizuno S, Matsumoto K, Li M Y, Nakamura T. HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis.  FASEB J. 2005;  19 580-582
  • 129 Taniyama Y, Morishita R, Nakagami H et al.. Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamsters.  Circulation. 2000;  102 246-252
  • 130 Marchand-Adam S, Marchal J, Cohen M et al.. Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2003;  168 1156-1161
  • 131 Matsumoto K, Tajima H, Okazaki H, Nakamura T. Negative regulation of hepatocyte growth factor gene expression in human lung fibroblasts and leukemic cells by transforming growth factor-beta 1 and glucocorticoids.  J Biol Chem. 1992;  267 24917-24920
  • 132 Hattori N, Mizuno S, Yoshida Y et al.. The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism.  Am J Pathol. 2004;  164 1091-1098
  • 133 Eickelberg O, Pansky A, Koehler E et al.. Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts.  FASEB J. 2001;  15 797-806
  • 134 Nagahori T, Dohi M, Matsumoto K et al.. Interferon-gamma upregulates the c-Met/hepatocyte growth factor receptor expression in alveolar epithelial cells.  Am J Respir Cell Mol Biol. 1999;  21 490-497
  • 135 Rubin J S, Osada H, Finch P W, Taylor W G, Rudikoff S, Aaronson S A. Purification and characterization of a newly identified growth factor specific for epithelial cells.  Proc Natl Acad Sci USA. 1989;  86 802-806
  • 136 Finch P W, Rubin J S, Miki T, Ron D, Aaronson S A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth.  Science. 1989;  245(4919) 752-755
  • 137 Deterding R R, Jacoby C R, Shannon J M. Acidic fibroblast growth factor and keratinocyte growth factor stimulate fetal rat pulmonary epithelial growth.  Am J Physiol. 1996;  271(4 Pt 1) L495-L505
  • 138 Bao S, Wang Y, Sweeney P et al.. Keratinocyte growth factor induces Akt kinase activity and inhibits Fas-mediated apoptosis in A549 lung epithelial cells.  Am J Physiol Lung Cell Mol Physiol. 2005;  288 L36-L42
  • 139 Portnoy J, Pan T, Dinarello C A et al.. Alveolar type II cells inhibit fibroblast proliferation: role of IL-1alpha.  Am J Physiol Lung Cell Mol Physiol. 2006;  290 L307-L316
  • 140 Marchand-Adam S, Plantier L, Bernuau D et al.. Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta.  Am J Respir Cell Mol Biol. 2005;  32 470-477
  • 141 Li X, Rayford H, Uhal B D. Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice.  Am J Pathol. 2003;  163 2523-2530
  • 142 Otsuka M, Takahashi H, Shiratori M, Chiba H, Abe S. Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist.  Thorax. 2004;  59 31-38
  • 143 Wang R, Zagariya A, Ang E, Ibarra-Sunga O, Uhal B D. Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction.  Am J Physiol. 1999;  277(6 Pt 1) L1245-L1250
  • 144 Papp M, Li X, Zhuang J, Wang R, Uhal B D. Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG II.  Am J Physiol Lung Cell Mol Physiol. 2002;  282 L713-L718
  • 145 Uhal B D, Gidea C, Bargout R et al.. Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism.  Am J Physiol. 1998;  275(5 Pt 1) L1013-L1017
  • 146 Nguyen L, Ward W F, Ts'ao C H, Molteni A. Captopril inhibits proliferation of human lung fibroblasts in culture: a potential antifibrotic mechanism.  Proc Soc Exp Biol Med. 1994;  205 80-84
  • 147 Ketteler M, Noble N A, Border W A. Transforming growth factor-beta and angiotensin II: the missing link from glomerular hyperfiltration to glomerulosclerosis?.  Annu Rev Physiol. 1995;  57 279-295
  • 148 Campbell S E, Katwa L C. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts.  J Mol Cell Cardiol. 1997;  29 1947-1958
  • 149 Cantin A M, North S L, Fells G A, Hubbard R C, Crystal R G. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis.  J Clin Invest. 1987;  79 1665-1673
  • 150 Cantin A M, Hubbard R C, Crystal R G. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis.  Am Rev Respir Dis. 1989;  139 370-372
  • 151 Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis.  Eur Respir J. 1994;  7 431-436
  • 152 Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis: adjunctive therapy to maintenance immunosuppression.  Am J Respir Crit Care Med. 1997;  156 1897-1901
  • 153 Demedts M, Behr J, Buhl R et al.. High-dose acetylcysteine in idiopathic pulmonary fibrosis.  N Engl J Med. 2005;  353 2229-2242
  • 154 Hunninghake G W. Antioxidant therapy for idiopathic pulmonary fibrosis.  N Engl J Med. 2005;  353 2285-2287
  • 155 Thannickal V J, Fanburg B L. Reactive oxygen species in cell signaling.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L1005-L1028
  • 156 Thannickal V J, Aldweib K D, Fanburg B L. Tyrosine phosphorylation regulates H2O2 production in lung fibroblasts stimulated by transforming growth factor beta1.  J Biol Chem. 1998;  273 23611-23615
  • 157 Waghray M, Cui Z, Horowitz J C et al.. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts.  FASEB J. 2005;  19 854-856
  • 158 Charbeneau R P, Peters-Golden M. Eicosanoids: mediators and therapeutic targets in fibrotic lung disease.  Clin Sci (Lond). 2005;  108 479-491
  • 159 Borok Z, Gillissen A, Buhl R et al.. Augmentation of functional prostaglandin E levels on the respiratory epithelial surface by aerosol administration of prostaglandin E.  Am Rev Respir Dis. 1991;  144 1080-1084
  • 160 Petkova D K, Clelland C A, Ronan J E, Lewis S, Knox A J. Reduced expression of cyclooxygenase (COX) in idiopathic pulmonary fibrosis and sarcoidosis.  Histopathology. 2003;  43 381-386
  • 161 Wilborn J, Bailie M, Coffey M, Burdick M, Strieter R, Peters-Golden M. Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.  J Clin Invest. 1996;  97 1827-1836
  • 162 Keerthisingam C B, Jenkins R G, Harrison N K et al.. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice.  Am J Pathol. 2001;  158 1411-1422
  • 163 Peters-Golden M, Bailie M, Marshall T et al.. Protection from pulmonary fibrosis in leukotriene-deficient mice.  Am J Respir Crit Care Med. 2002;  165 229-235
  • 164 Bitterman P B, Wewers M D, Rennard S I, Adelberg S, Crystal R G. Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators.  J Clin Invest. 1986;  77 700-708
  • 165 Lama V, Moore B B, Christensen P, Toews G B, Peters-Golden M. Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent.  Am J Respir Cell Mol Biol. 2002;  27 752-758
  • 166 Pan T, Mason R J, Westcott J Y, Shannon J M. Rat alveolar type II cells inhibit lung fibroblast proliferation in vitro.  Am J Respir Cell Mol Biol. 2001;  25 353-361
  • 167 Kohyama T, Ertl R F, Valenti V et al.. Prostaglandin E(2) inhibits fibroblast chemotaxis.  Am J Physiol Lung Cell Mol Physiol. 2001;  281 L1257-L1263
  • 168 White E S, Atrasz R G, Dickie E G et al.. Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity.  Am J Respir Cell Mol Biol. 2005;  32 135-141
  • 169 Kolodsick J E, Peters-Golden M, Larios J, Toews G B, Thannickal V J, Moore B B. Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation.  Am J Respir Cell Mol Biol. 2003;  29 537-544
  • 170 Goldstein R H, Polgar P. The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts.  J Biol Chem. 1982;  257 8630-8633
  • 171 Ghosh M, Stewart A, Tucker D E, Bonventre J V, Murphy R C, Leslie C C. Role of cytosolic phospholipase A(2) in prostaglandin E(2) production by lung fibroblasts.  Am J Respir Cell Mol Biol. 2004;  30 91-100
  • 172 Ehrenreich H, Anderson R W, Fox C H et al.. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages.  J Exp Med. 1990;  172 1741-1748
  • 173 Shahar I, Fireman E, Topilsky M et al.. Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases.  Int J Immunopharmacol. 1999;  21 759-775
  • 174 Shi-Wen X, Chen Y, Denton C P et al.. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts.  Mol Biol Cell. 2004;  15 2707-2719
  • 175 Goto T, Yanaga F, Ohtsuki I. Studies on the endothelin-1-induced contraction of rat granulation tissue pouch mediated by myofibroblasts.  Biochim Biophys Acta. 1998;  1405(1-3) 55-66
  • 176 Xu S W, Howat S L, Renzoni E A et al.. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK.  J Biol Chem. 2004;  279 23098-23103
  • 177 Giaid A, Michel R P, Stewart D J, Sheppard M, Corrin B, Hamid Q. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis.  Lancet. 1993;  341 1550-1554
  • 178 Saleh D, Furukawa K, Tsao M S et al.. Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of proinflammatory cytokines.  Am J Respir Cell Mol Biol. 1997;  16 187-193
  • 179 Hocher B, Schwarz A, Fagan K A et al.. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice.  Am J Respir Cell Mol Biol. 2000;  23 19-26
  • 180 Park S H, Saleh D, Giaid A, Michel R P. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist.  Am J Respir Crit Care Med. 1997;  156(2 Pt 1) 600-608
  • 181 McGowan S E. Extracellular matrix and the regulation of lung development and repair.  FASEB J. 1992;  6 2895-2904
  • 182 Bienkowski R S, Gotkin M G. Control of collagen deposition in mammalian lung.  Proc Soc Exp Biol Med. 1995;  209 118-140
  • 183 Frisch S M, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis.  J Cell Biol. 1994;  124 619-626
  • 184 Hadden H L, Henke C A. Induction of lung fibroblast apoptosis by soluble fibronectin peptides.  Am J Respir Crit Care Med. 2000;  162(4 Pt 1) 1553-1560
  • 185 Serini G, Bochaton-Piallat M L, Ropraz P et al.. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1.  J Cell Biol. 1998;  142 873-881
  • 186 Swartz M A, Tschumperlin D J, Kamm R D, Drazen J M. Mechanical stress is communicated between different cell types to elicit matrix remodeling.  Proc Natl Acad Sci USA. 2001;  98 6180-6185
  • 187 Eckes B, Krieg T. Regulation of connective tissue homeostasis in the skin by mechanical forces.  Clin Exp Rheumatol. 2004;  22(Suppl 33) S73-S76
  • 188 Hinz B, Gabbiani G. Mechanisms of force generation and transmission by myofibroblasts.  Curr Opin Biotechnol. 2003;  14 538-546
  • 189 Selman M, Ruiz V, Cabrera S et al.. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis: a prevailing nondegradative lung microenvironment?.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L562-L574
  • 190 Legrand C, Gilles C, Zahm J M et al.. Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling.  J Cell Biol. 1999;  146 517-529
  • 191 Lee S L, Dickson R B, Lin C Y. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease.  J Biol Chem. 2000;  275 36720-36725
  • 192 Hardie W D, Le Cras T D, Jiang K, Tichelaar J W, Azhar M, Korfhagen T R. Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2004;  286 L741-L749
  • 193 Larios J M, Budhiraja R, Fanburg B L, Thannickal V J. Oxidative protein cross-linking reactions involving L-tyrosine in transforming growth factor-beta1-stimulated fibroblasts.  J Biol Chem. 2001;  276 17437-17441
  • 194 Siegel P M, Massague J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer.  Nat Rev Cancer. 2003;  3 807-821
  • 195 Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis.  J Clin Invest. 2003;  112 1776-1784
  • 196 Willis B C, Liebler J M, Luby-Phelps K et al.. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-{beta}1: potential role in idiopathic pulmonary fibrosis.  Am J Pathol. 2005;  166 1321-1332
  • 197 Zeisberg M, Bottiglio C, Kumar N et al.. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models.  Am J Physiol Renal Physiol. 2003;  285 F1060-F1067

Jeffrey C HorowitzM.D. 

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center

6301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109

Email: jchorow@umich.edu

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