Tissue remodelling in chronic bronchial diseases: From the epithelial to mesenchymal phenotype

European Respiratory Review

Volumn 23, Issue 131, 2014, Pages 118-130

  Pain, Mallory ^a   Bermudez, Olga ^b   Lacoste, Philippe ^a   Royer, Pierre Joseph ^a   Botturi, Karine ^a   Tissot, Adrien ^a   Brouard, Sophie ^a   Eickelberg, Oliver ^b   Magnan, Antoine ^a  

^a NANTES UNIVERSITY HOSPITAL   (France)

^b UNIVERSITY OF MUNICH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CORTICOSTEROID; FRIZZLED PROTEIN; GLUCOCORTICOID; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 17; INTERLEUKIN 1BETA; INTERLEUKIN 8; SONIC HEDGEHOG PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; WNT PROTEIN;

AIRWAY REMODELING; ALLERGIC ASTHMA; BRONCHIOLITIS OBLITERANS; BRONCHUS DISEASE; CHRONIC DISEASE; CHRONIC OBSTRUCTIVE LUNG DISEASE; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTRACELLULAR SIGNALING; LUNG TRANSPLANTATION; NONHUMAN; PHENOTYPE; PROTEIN EXPRESSION; REVIEW; WNT SIGNALING PATHWAY;

AIRWAY REMODELING; ANIMALS; BRONCHI; BRONCHIAL DISEASES; CHRONIC DISEASE; EPITHELIAL-MESENCHYMAL TRANSITION; FIBROBLASTS; HUMANS; PROGNOSIS; SIGNAL TRANSDUCTION;

EID: 84895479989     PISSN: 09059180     EISSN: 16000617     Source Type: Journal    
DOI: 10.1183/09059180.00004413     Document Type: Review

References (169)

1. Hay ED. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 2005; 233: 706-720.
2. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442-454.
3. Ikenouchi J, Matsuda M, Furuse M, et al. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 2003; 116: 1959-1967.
4. Ozdamar B, Bose R, Barrios-Rodiles M, et al. Regulation of the polarity protein Par6 by TGFb receptors controls epithelial cell plasticity. Science 2005; 307: 1603-1609.
5. Guarino M. Epithelial-to-mesenchymal change of differentiation. From embryogenetic mechanism to pathological patterns. Histol Histopathol 1995; 10: 171-184.
6. Vergara D, Merlot B, Lucot JP, et al. Epithelial-mesenchymal transition in ovarian cancer. Cancer Lett 2010; 291: 59-66.
7. Brabletz T, Hlubek F, Spaderna S, et al. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and b-catenin. Cells Tissues Organs 2005; 179: 56-65.
8. Usami Y, Satake S, Nakayama F, et al. Snail-associated epithelial-mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J Pathol 2008; 215: 330-339.
9. Trimboli AJ, Fukino K, de Bruin A, et al. Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 2008; 68: 937-945.
10. Yáñez-Mó M, Lara-Pezzi E, Selgas R, et al. Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003; 348: 403-413.
11. Saika S. TGFb pathobiology in the eye. Lab Invest 2006; 86: 106-115.
12. Rygiel KA, Robertson H, Marshall HL, et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 2008; 88: 112-123.
13. Selman M, Pardo A. The epithelial/fibroblastic pathway in the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2003; 29: Suppl. 3, S93-S97.
14. Selman M, Thannickal VJ, Pardo A, et al. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs 2004; 64: 405-430.
15. Willis BC, du Bois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 2006; 3: 377-382.
16. Antoniades HN, Bravo MA, Avila RE, et al. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 1990; 86: 1055-1064.
17. Giaid A, Michel RP, Stewart DJ, et al. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet 1993; 341: 1550-1554.
18. Khalil N, O'Connor R, Gold LI, et al. Biological effects of transforming growth factor-b1 in idiopathic pulmonary fibrosis may be regulated by the activation of latent transforming growth factor-b1 and the differential expression of transforming growth factor-b receptors. Chest 2001; 120: Suppl. 1, 48S.
19. Khalil N, O'Connor RN, Unruh HW, et al. Increased production and immunohistochemical localization of transforming growth factor-b in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 1991; 5: 155-162.
20. Khalil N, O'Connor RN, Flanders KC, et al. TGF-b1, but not TGF-b2 or TGF-b3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol 1996; 14: 131-138.
21. Nash JR, McLaughlin PJ, Butcher D, et al. Expression of tumour necrosis factor-a in cryptogenic fibrosing alveolitis. Histopathology 1993; 22: 343-347.
22. Pan LH, Yamauchi K, Uzuki M, et al. Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF. Eur Respir J 2001; 17: 1220-1227.
23. Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 2006; 103: 13180-13185.
24. Kasai H, Allen JT, Mason RM, et al. TGF-b1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005; 6: 56.
25. Zuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci USA 2002; 99: 6292-6297.
26. 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.
27. Holgate ST, Davies DE, Puddicombe S, et al. Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma. Eur Respir J 2003; 22: Suppl. 44, 24s-29s.
28. Flanders KC. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol 2004; 85: 47-64.
29. Borthwick LA, Parker SM, Brougham KA, et al. Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. Thorax 2009; 64: 770-777.
30. Ward C, Forrest IA, Murphy DM, et al. Phenotype of airway epithelial cells suggests epithelial to mesenchymal cell transition in clinically stable lung transplant recipients. Thorax 2005; 60: 865-871.
31. Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009; 119: 1417-1419.
32. Tanimizu N, Miyajima A. Molecularmechanismof liver development and regeneration. Int Rev Cytol 2007; 259: 1-48.
33. Johansson KA, Grapin-Botton A. Development and diseases of the pancreas. Clin Genet 2002; 62: 14-23.
34. Nakajima Y, Yamagishi T, Hokari S, et al. Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-b and bone morphogenetic protein (BMP). Anat Rec 2000; 258: 119-127.
35. Nawshad A, Lagamba D, Polad A, et al. Transforming growth factor-b signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 2005; 179: 11-23.
36. Maestro R, Dei Tos AP, Hamamori Y, et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev 1999; 13: 2207-2217.
37. Vega S, Morales AV, Ocaña OH, et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18: 1131-1143.
38. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818-829.
39. Fidler IJ, Poste G. The "seed and soil" hypothesis revisited. Lancet Oncol 2008; 9: 808.
40. Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110: 341-350.
41. Guarino M, Tosoni A, Nebuloni M. Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition. Hum Pathol 2009; 40: 1365-1376.
42. Lee JM, Dedhar S, Kalluri R, et al. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 2006; 172: 973-981.
43. Okada H, Ban S, Nagao S, et al. Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int 2000; 58: 587-597.
44. Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 1999; 250: 273-283.
45. Gibbs FE, Barraclough R, Platt-Higgins A, et al. Immunocytochemical distribution of the calcium-binding protein p9Ka in normal rat tissues: variation in the cellular location in different tissues. J Histochem Cytochem 1995; 43: 169-180.
46. Inoue T, Plieth D, Venkov CD, et al. Antibodies against macrophages that overlap in specificity with fibroblasts. Kidney Int 2005; 67: 2488-2493.
47. Le Hir M, Hegyi I, Cueni-Loffing D, et al. Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys. Histochem Cell Biol 2005; 123: 335-346.
48. Strutz F, Okada H, Lo CW, et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 1995; 130: 393-405.
49. Janda E, Lehmann K, Killisch I, et al. Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002; 156: 299-313.
50. Cano A, Pérez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76-83.
51. Huber MA, BeugH, Wirth T. Epithelial-mesenchymal transition: NF-kB takes center stage. Cell cycle 2004; 3: 1477-1480.
52. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002; 3: 155-166.
53. Peinado H, Quintanilla M, Cano A. Transforming growth factor b-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 2003; 278: 21113-21123.
54. Radisky DC. Epithelial-mesenchymal transition. J Cell Sci 2005; 118: 4325-4326.
55. Finkel T. Oxidant signals and oxidative stress. Curr Opin Cell Biol 2003; 15: 247-254.
56. Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003; 3: 276-285.
57. Morali OG, Delmas V, Moore R, et al. IGF-II induces rapid b-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene 2001; 20: 4942-4950.
58. Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 2002; 61: 1714-1728.
59. Mizuno S, Kurosawa T, Matsumoto K, et al. Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest 1998; 101: 1827-1834.
60. Nawshad A, LaGamba D, Hay ED. Transforming growth factor b (TGFb) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 2004; 49: 675-689.
61. Sridurongrit S, Larsson J, Schwartz R, et al. Signaling via the TGF-b type I receptor Alk5 in heart development. Dev Biol 2008; 322: 208-218.
62. Nawshad A, Medici D, Liu CC, et al. TGFb3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex. J Cell Sci 2007; 120: 1646-1653.
63. Hackett TL, Warner SM, Stefanowicz D, et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-b1. Am J Respir Crit Care Med 2009; 180: 122-133.
64. Heijink IH, Postma DS, Noordhoek JA, et al. House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am J Respir Cell Mol Biol 2010; 42: 69-79.
65. Gardner A, Fisher AJ, Richter C, et al. The critical role of TAK1 in accentuated epithelial to mesenchymal transition in obliterative bronchiolitis after lung transplantation. Am J Pathol 2012; 180: 2293-2308.
66. Câmara J, Jarai G. Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smaddependent and enhanced by fibronectin and TNF-a. Fibrogenesis Tissue Repair 2010; 3: 2.
67. Doerner AM, Zuraw BL. TGF-b1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1b but not abrogated by corticosteroids. Respir Res 2009; 10: 100.
68. Zhang M, Zhang Z, Pan HY, et al. TGF-b1 induces human bronchial epithelial cell-to-mesenchymal transition in vitro. Lung 2009; 187: 187-194.
69. Massagué J. How cells read TGF-b signals. Nat Rev Mol Cell Biol 2000; 1: 169-178.
70. Fuxe J, Vincent T, Garcia de Herreros A. Transcriptional crosstalk between TGF-b and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 2010; 9: 2363-2374.
71. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature 2003; 425: 577-584.
72. Thuault S, Valcourt U, Petersen M, et al. Transforming growth factor-b employs HMGA2 to elicit epithelialmesenchymal transition. J Cell Biol 2006; 174: 175-183.
73. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 2005; 132: 3151-3161.
74. Olmeda D, Jordá M, Peinado H, et al. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene 2007; 26: 1862-1874.
75. Zavadil J, Cermak L, Soto-Nieves N, et al. Integration of TGF-b/Smad and Jagged1/Notch signalling in epithelialto-mesenchymal transition. EMBO J 2004; 23: 1155-1165.
76. Dumont N, Arteaga CL. Targeting the TGF b signaling network in human neoplasia. Cancer Cell 2003; 3: 531-536.
77. Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-b signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004; 3: 1011-1022.
78. Subramanian G, Schwarz RE, Higgins L, et al. Targeting endogenous transforming growth factor b receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype1. Cancer Res 2004; 64: 5200-5211.
79. Willis BC, Borok Z. TGF-b-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007; 293: L525-L534.
80. Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-b1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9: 964-968.
81. 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.
82. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003; 15: 740-746.
83. Ellenrieder V, Hendler SF, Boeck W, et al. Transforming growth factor b1 treatment leads to an epithelialmesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res 2001; 61: 4222-4228.
84. Bates RC, Mercurio AM. Tumor necrosis factor-a stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell 2003; 14: 1790-1800.
85. Xie L, Law BK, Chytil AM, et al. Activation of the Erk pathway is required for TGF-b1-induced EMT in vitro. Neoplasia 2004; 6: 603-610.
86. Zavadil J, Böttinger EP. TGF-b and epithelial-to-mesenchymal transitions. Oncogene 2005; 24: 5764-5774.
87. Pongracz JE, Stockley RA. Wnt signalling in lung development and diseases. Respir Res 2006; 7: 15.
88. Zavadil J, Bitzer M, Liang D, et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-b. Proc Natl Acad Sci USA 2001; 98: 6686-6691.
89. Shin SY, Rath O, Zebisch A, et al. Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res 2010; 70: 6715-6724.
90. Eger A, Stockinger A, Park J, et al. b-Catenin and TGFb signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 2004; 23: 2672-2680.
91. Morin PJ. b-catenin signaling and cancer. Bioessays 1999; 21: 1021-1030.
92. Königshoff M, Eickelberg O. WNT signaling in lung disease: a failure or a regeneration signal?Am J Respir Cell Mol Biol 2010; 42: 21-31.
93. Königshoff M, Balsara N, Pfaff EM, et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One 2008; 3: e2142.
94. Timmerman LA, Grego-Bessa J, Raya A, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 2004; 18: 99-115.
95. Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004; 431: 707-712.
96. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795-801.
97. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008; 22: 2454-2472.
98. Stecca B, Ruiz I, Altaba A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol 2010; 2: 84-95.
99. Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003; 422: 313-317.
100. Bellusci S, Furuta Y, Rush MG, et al. Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Development 1997; 124: 53-63.
101. Litingtung Y, Lei L, Westphal H, et al. Sonic hedgehog is essential to foregut development. Nat Genet 1998; 20: 58-61.
102. Pepicelli CV, Lewis PM, McMahon AP. Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol 1998; 8: 1083-1086.
103. Motoyama J, Liu J, Mo R, et al. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet 1998; 20: 54-57.
104. Wang K, Pan L, Che X, et al. Sonic Hedgehog/GLI? signaling pathway inhibition restricts cell migration and invasion in human gliomas. Neurol Res 2010; 32: 975-980.
105. Li X, Deng W, Nail CD, et al. Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 2006; 25: 609-621.
106. Joost S, Almada LL, Rohnalter V, et al. GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells. Cancer Res 2012; 72: 88-99.
107. Ohta H, Aoyagi K, Fukaya M, et al. Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. Br J Cancer 2009; 100: 389-398.
108. Syn WK, Jung Y, Omenetti A, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 2009; 137: 1478-1488. e8.
109. Coon DR, Roberts DJ, Loscertales M, et al. Differential epithelial expression of SHH and FOXF1 in usual and nonspecific interstitial pneumonia. Exp Mol Pathol 2006; 80: 119-123.
110. Stewart GA, Hoyne GF, Ahmad SA, et al. Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes. J Pathol 2003; 199: 488-495.
111. Cigna N, Farrokhi Moshai E, Brayer S, et al. The hedgehog system machinery controls transforming growth factor-b-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis. Am J Pathol 2012; 181: 2126-2137.
112. Bolaños AL, Milla CM, Lira JC, et al. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2012; 303: L978-L990.
113. Bermudez O, Hennen E, Koch I, et al. Gli1 mediates lung cancer cell proliferation and sonic hedgehog-dependent mesenchymal cell activation. PLoS One 2013; 8: e63226.
114. Park KS, Martelotto LG, Peifer M, et al. A crucial requirement for Hedgehog signaling in small cell lung cancer. Nat Med 2011; 17: 1504-1508.
115. Yuan Z, Goetz JA, Singh S, et al. Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene 2007; 26: 1046-1055.
116. Chi S, Huang S, Li C, et al. Activation of the hedgehog pathway in a subset of lung cancers. Cancer Lett 2006; 244: 53-60.
117. Varnat F, Duquet A, Malerba M, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med 2009; 1: 338-351.
118. Lipinski RJ, Bijlsma MF, Gipp JJ, et al. Establishment and characterization of immortalized Gli-null mouse embryonic fibroblast cell lines. BMC Cell Biol 2008; 9: 49.
119. Polizio AH, Chinchilla P, Chen X, et al. Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gliindependent manner through coupling of smoothened to Gi proteins. Sci Signal 2011; 4: pt7.
120. Dennler S, André J, Verrecchia F, et al. Cloning of the human GLI2 promoter: transcriptional activation by transforming growth factor-b via SMAD3/b-catenin cooperation. J Biol Chem 2009; 284: 31523-31531.
121. Nolan-Stevaux O, Lau J, Truitt ML, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009; 23: 24-36.
122. Javelaud D, Pierrat MJ, Mauviel A. Crosstalk between TGF-b and hedgehog signaling in cancer. FEBS Lett 2012; 586: 2016-2025.
123. Elias JA, Lee CG, Zheng T, et al. New insights into the pathogenesis of asthma. J Clin Invest 2003; 111: 291-297.
124. Payne DNR, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 2003; 167: 78-82.
125. Cokuǧraş H, Akçakaya N, Seçkin, et al. Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma. Thorax 2001; 56: 25-29.
126. Nawijn MC, Hackett TL, Postma DS, et al. E-cadherin: gatekeeper of airway mucosa and allergic sensitization. Trends Immunol 2011; 32: 248-255.
127. Magnan A, Frachon I, Rain B, et al. Transforming growth factor b in normal human lung: preferential location in bronchial epithelial cells. Thorax 1994; 49: 789-792.
128. Nihlberg K, Larsen K, Hultgårdh-Nilsson A, et al. Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane? Respir Res 2006; 7: 50.
129. Johnson JR, Roos A, Berg T, et al. Chronic respiratory aeroallergen exposure in mice induces epithelialmesenchymal transition in the large airways. PLoS One 2011; 6: e16175.
130. Wan H, Winton HL, Soeller C, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999; 104: 123-133.
131. Runswick S, Mitchell T, Davies P, et al. Pollen proteolytic enzymes degrade tight junctions. Respirology 2007; 12: 834-842.
132. Redington AE, Madden J, Frew AJ, et al. Transforming growth factor-b 1 in asthma. Measurement in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 1997; 156: 642-647.
133. Chakir J, Shannon J, Molet S, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-b, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol 2003; 111: 1293-1298.
134. Yamaguchi M, Niimi A, Matsumoto H, et al. Sputum levels of transforming growth factor-b1 in asthma: relation to clinical and computed tomography findings. J Investig Allergol Clin Immunol 2008; 18: 202-206.
135. Vignola AM, Merendino AM, Chiappara G, et al. Markers of acute airway inflammation. Monaldi Arch Chest Dis 1997; 52: 83-85.
136. Churg A, Tai H, Coulthard T, et al. Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Am J Respir Crit Care Med 2006; 174: 1327-1334.
137. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278: 1355-1360.
138. Saetta M, Turato G, Baraldo S, et al. 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 2000; 161: 1016-1021.
139. Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 2009; 4: 435-459.
140. O'Donnell DE, Parker CM. COPD exacerbations. 3: Pathophysiology. Thorax 2006; 61: 354-361.
141. Sohal SS, Reid D, Soltani A, et al. Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Respirology 2010; 15: 930-938.
142. Acloque H, Adams MS, Fishwick K, et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 2009; 119: 1438-1449.
143. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776-1784.
144. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009; 119: 1429-1437.
145. Soltani A, Reid DW, Sohal SS, et al. Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study. Respir Res 2010; 11: 105.
146. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report-2010. J Heart Lung Transplant 2010; 29: 1104-1118.
147. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002; 166: 440-444.
148. Riise GC, Williams A, Kjellström C, et al. Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung. Eur Respir J 1998; 12: 82-88.
149. Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997; 155: 789-818.
150. Mauck KA, Hosenpud JD. The bronchial epithelium: a potential allogeneic target for chronic rejection after lung transplantation. J Heart Lung Transplant 1996; 15: 709-714.
151. Jaramillo A, Smith CR, Maruyama T, et al. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol 2003; 64: 521-529.
152. Fernández FG, Jaramillo A, Chen C, et al. Airway epithelium is the primary target of allograft rejection in murine obliterative airway disease. Am J Transplant 2004; 4: 319-325.
153. Boehler A, Estenne M. Post-transplant bronchiolitis obliterans. Eur Respir J 2003; 22: 1007-1018.
154. Yousem SA. Significance of clinically silent untreated mild acute cellular rejection in lung allograft recipients. Hum Pathol 1996; 27: 269-273.
155. Borthwick LA, McIlroy EI, Gorowiec MR, et al. Inflammation and epithelial to mesenchymal transition in lung transplant recipients: role in dysregulated epithelial wound repair. Am J Transplant 2010; 10: 498-509.
156. Hodge S, Holmes M, Banerjee B, et al. Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Am J Transplant 2009; 9: 727-733.
157. Robertson H, Ali S, McDonnell BJ, et al. Chronic renal allograft dysfunction: the role of T cell-mediated tubular epithelial to mesenchymal cell transition. J Am Soc Nephrol 2004; 15: 390-397.
158. Rastaldi MP. Epithelial-mesenchymal transition and its implications for the development of renal tubulointerstitial fibrosis. J Nephrol 2006; 19: 407-412.
159. Hertig A. [Epithelial-mesenchymal transition of the renal graft]. Nephrol Ther 2008; 4: Suppl. 1, S25-S28.
160. Bedi S, Vidyasagar A, Djamali A. Epithelial-to-mesenchymal transition and chronic allograft tubulointerstitial fibrosis. Transplant Rev (Orlando) 2008; 22: 1-5.
161. El-Gamel A, Awad M, Sim E, et al. Transforming growth factor-b1 and lung allograft fibrosis. Eur J Cardiothorac Surg 1998; 13: 424-430.
162. Elssner A, Jaumann F, Dobmann S, et al. Elevated levels of interleukin-8 and transforming growth factor-b in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant Group. Transplantation 2000; 70: 362-367.
163. Magnan A, Mege JL, Escallier JC, et al. Balance between alveolar macrophage IL-6 and TGF-b in lung-transplant recipients. Marseille and Montréal Lung Transplantation Group. Am J Respir Crit Care Med 1996; 153: 1431-1436.
164. Bergmann M, Tiroke A, Schäfer H, et al. Gene expression of profibrotic mediators in bronchiolitis obliterans syndrome after lung transplantation. Scand Cardiovasc J 1998; 32: 97-103.
165. Vanaudenaerde BM, Wuyts WA, Geudens N, et al. Broncho-alveolar lavage fluid recovery correlates with airway neutrophilia in lung transplant patients. Respir Med 2008; 102: 339-347.
166. Myerburg MM, Latoche JD, McKenna EE, et al. Hepatocyte growth factor and other fibroblast secretions modulate the phenotype of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2007; 292: L1352-L1360.
167. Vos R, Vanaudenaerde BM, Geudens N, et al. Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation? Eur Respir J 2008; 31: 1037-1045.
168. Borthwick LA, Sunny SS, Oliphant V, et al. Pseudomonas aeruginosa accentuates epithelial-to-mesenchymal transition in the airway. Eur Respir J 2011; 37: 1237-1247.
169. Strutz F. Pathogenesis of tubulointerstitial fibrosis in chronic allograft dysfunction. Clin Transplant 2009; 23: Suppl. 21, 26-32.