|
 |
|
|||||||
|
|||||||||
© 2006 The American Thoracic Society
Epithelial Origin of Myofibroblasts during Fibrosis in the Lung
Division of Pulmonary and Vascular Biology, and Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, Texas; Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom; and Division of Pulmonary and Critical Care Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California
Correspondence and requests for reprints should be addressed to Zea Borok, M.D., Division of Pulmonary and Critical Care Medicine, University of Southern California, IRD 620, 2020 Zonal Avenue, Los Angeles, CA 90033. E-mail: zborok{at}usc.edu
ABSTRACT
An understanding of the mechanisms underlying pulmonary fibrosis remains elusive. Once believed to result primarily from chronic inflammation, it is now clear that inflammation and chronic fibrosis, especially in diseases such as idiopathic pulmonary fibrosis/usual interstitial pneumonia, are often dissociated, and that inflammation is neither necessary nor sufficient to induce fibrosis. The origin of the primary effector cell of fibrosis in the lung, the myofibroblast, is not clearly established. Three potential sources have been hypothesized. Although conversion of resident fibroblasts and differentiation of circulating bone marrow–derived progenitors likely play a role, the possible contribution of alveolar epithelial cells (AECs), through a process termed "epithelial–mesenchymal transition" (EMT), has only recently received consideration. A process by which epithelial cells lose cell–cell attachment, polarity and epithelial-specific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, EMT plays a prominent role in fibrogenesis in adult tissues such as the kidney. This review summarizes the evidence supporting a central role for EMT in the pathogenesis of lung fibrosis, the potential for EMT in AECs in vitro and in vivo and role of transforming growth factor-ß1 in this process, and the implications of epithelium-driven fibrosis on future research and treatment. Potential pathways involved in EMT are also discussed. It is hoped that a major shift in current paradigms regarding the genesis of pulmonary fibrosis and dissection of the relevant pathways may allow development of targeted interventions that could potentially reverse the process and ameliorate the debilitating effects of abnormal repair and progressive fibrosis.
Key Words: alveolar epithelium • epithelial–mesenchymal transition • lung injury • transforming growth factor-ß
This article has been cited by other articles:
|
|
 |
|
  S. Zuyderduyn, M. B. Sukkar, A. Fust, S. Dhaliwal, and J. K. Burgess Treating asthma means treating airway smooth muscle cells Eur. Respir. J., August 1, 2008; 32(2): 265 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Weiss, J. K. Kolls, L. A. Ortiz, A. Panoskaltsis-Mortari, and D. J. Prockop Stem Cells and Cell Therapies in Lung Biology and Lung Diseases Proceedings of the ATS, July 15, 2008; 5(5): 637 - 667. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yu, M. Konigshoff, A. Jayachandran, D. Handley, W. Seeger, N. Kaminski, and O. Eickelberg Transgelin is a direct target of TGF-{beta}/Smad3-dependent epithelial cell migration in lung fibrosis FASEB J, June 1, 2008; 22(6): 1778 - 1789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Milam, V. G. Keshamouni, S. H. Phan, B. Hu, S. R. Gangireddy, C. M. Hogaboam, T. J. Standiford, V. J. Thannickal, and R. C. Reddy PPAR-{gamma} agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L891 - L901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Radisky and J. A. Przybylo Matrix Metalloproteinase-induced Fibrosis and Malignancy in Breast and Lung Proceedings of the ATS, April 15, 2008; 5(3): 316 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N Artaza, R. Singh, M. G Ferrini, M. Braga, J. Tsao, and N. F Gonzalez-Cadavid Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts J. Endocrinol., February 1, 2008; 196(2): 235 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kisseleva and D. A. Brenner Mechanisms of Fibrogenesis Experimental Biology and Medicine, February 1, 2008; 233(2): 109 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, Y. S. Kang, C. Dai, L. P. Kiss, X. Wen, and Y. Liu Epithelial-to-Mesenchymal Transition Is a Potential Pathway Leading to Podocyte Dysfunction and Proteinuria Am. J. Pathol., February 1, 2008; 172(2): 299 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Maher, A. U. Wells, and G. J. Laurent Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur. Respir. J., November 1, 2007; 30(5): 835 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Decologne, M. Kolb, P. J. Margetts, F. Menetrier, Y. Artur, C. Garrido, J. Gauldie, P. Camus, and P. Bonniaud TGF-beta1 Induces Progressive Pleural Scarring and Subpleural Fibrosis J. Immunol., November 1, 2007; 179(9): 6043 - 6051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chu, H. Xu, T. J. Ferro, and P. X. Rivera Poly(ADP-ribose) polymerase-1 regulates vimentin expression in lung cancer cells Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1127 - L1134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kono, T. Nishiuma, Y. Nishimura, Y. Kotani, T. Okada, S.-i. Nakamura, and M. Yokoyama Sphingosine Kinase 1 Regulates Differentiation of Human and Mouse Lung Fibroblasts Mediated by TGF-beta1 Am. J. Respir. Cell Mol. Biol., October 1, 2007; 37(4): 395 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Panoskaltsis-Mortari, K. V. Tram, A. P. Price, C. H. Wendt, and B. R. Blazar A New Murine Model for Bronchiolitis Obliterans Post Bone Marrow Transplant Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 713 - 723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Willis and Z. Borok TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L525 - L534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. du Bois State of the Art. Mechanisms of Scleroderma-induced Lung Disease Proceedings of the ATS, August 15, 2007; 4(5): 434 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Jain, P. W. Shaul, Z. Borok, and B. C. Willis Endothelin-1 Induces Alveolar Epithelial-Mesenchymal Transition through Endothelin Type A Receptor-Mediated Production of TGF-beta1 Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 38 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Arciniegas, M. G. Frid, I. S. Douglas, and K. R. Stenmark Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L1 - L8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. G. Neilson Plasticity, Nuclear Diapause, and a Requiem for the Terminal Differentiation of Epithelia J. Am. Soc. Nephrol., July 1, 2007; 18(7): 1995 - 1998. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Takkunen, R. Grenman, M. Hukkanen, M. Korhonen, A. Garcia de Herreros, and I. Virtanen Snail-dependent and -independent Epithelial-Mesenchymal Transition in Oral Squamous Carcinoma Cells J. Histochem. Cytochem., November 1, 2006; 54(11): 1263 - 1275. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |