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16 January 2001 | Volume 134 Issue 2 | Pages 136-151
Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast–myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies.
Author and Article Information
From Instituto Nacional de Enfermedades Respiratorias and Universidad Nacional Autónoma de México, Mexico City, Mexico; and the University of California, San Francisco, San Francisco, California.
Acknowledgments: The authors thank Dr. Iasha Sznajder for providing the impetus for the writing of this manuscript.
Requests for Single Reprints: Moisés Selman, MD, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Mexico DF, Mexico; e-mail, mselman{at}conacyt.mx.
Current Author Addresses: Dr. Selman: Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Mexico DF, Mexico.
Dr. King: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, 1001 Potrero Avenue, Room 5H22, San Francisco, CA 94110.
Dr. Pardo: Facultad de Ciencias, UNAM, Apartado Postal 21-630, Coyoacan, Mexico DF 04000, Mexico. REVIEW
Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy
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D. M. Brass, J. Tomfohr, I. V. Yang, and D. A. Schwartz Using Mouse Genomics to Understand Idiopathic Interstitial Fibrosis Proceedings of the ATS, January 1, 2007; 4(1): 92 - 100. [Abstract] [Full Text] [PDF]
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P. Markart, C. Ruppert, M. Wygrecka, R. Schmidt, M. Korfei, H. Harbach, I. Theruvath, U. Pison, W. Seeger, A. Guenther, et al. Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias Eur. Respir. J., January 1, 2007; 29(1): 134 - 137. [Abstract] [Full Text] [PDF]
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A. Churg, H. Tai, T. Coulthard, R. Wang, and J. L. Wright Cigarette Smoke Drives Small Airway Remodeling by Induction of Growth Factors in the Airway Wall Am. J. Respir. Crit. Care Med., December 15, 2006; 174(12): 1327 - 1334. [Abstract] [Full Text] [PDF]
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H. Matsuoka, T. H. Sisson, T. Nishiuma, and R. H. Simon Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 705 - 713. [Abstract] [Full Text] [PDF]
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J. Gauldie, M. Kolb, K. Ask, G. Martin, P. Bonniaud, and D. Warburton Smad3 Signaling Involved in Pulmonary Fibrosis and Emphysema Proceedings of the ATS, November 1, 2006; 3(8): 696 - 702. [Abstract] [Full Text] [PDF]
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C. Ramos, M. Montano, C. Becerril, J. Cisneros-Lira, L. Barrera, V. Ruiz, A. Pardo, and M. Selman Acidic fibroblast growth factor decreases {alpha}-smooth muscle actin expression and induces apoptosis in human normal lung fibroblasts Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L871 - L879. [Abstract] [Full Text] [PDF]
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Q. Ye, B. Chen, Z. Tong, S. Nakamura, R. Sarria, U. Costabel, and J. Guzman Thalidomide reduces IL-18, IL-8 and TNF-{alpha} release from alveolar macrophages in interstitial lung disease Eur. Respir. J., October 1, 2006; 28(4): 824 - 831. [Abstract] [Full Text] [PDF]
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G. Raghu, D. Weycker, J. Edelsberg, W. Z. Bradford, and G. Oster Incidence and Prevalence of Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 810 - 816. [Abstract] [Full Text] [PDF]
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C. D. Cool, S. D. Groshong, P. R. Rai, P. M. Henson, J. S. Stewart, and K. K. Brown Fibroblast Foci Are Not Discrete Sites of Lung Injury or Repair: The Fibroblast Reticulum Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 654 - 658. [Abstract] [Full Text] [PDF]
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B. S. Lu, A. D. Yu, X. Zhu, E. R. Garrity Jr, W. T. Vigneswaran, and S. M. Bhorade Sequential gene expression profiling in lung transplant recipients with chronic rejection. Chest, September 1, 2006; 130(3): 847 - 854. [Abstract] [Full Text] [PDF]
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M. M. Kelly, R. Leigh, S. E. Gilpin, E. Cheng, G. E. M. Martin, K. Radford, G. Cox, and J. Gauldie Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 557 - 565. [Abstract] [Full Text] [PDF]
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Y. Ishii, S. Fujimoto, and T. Fukuda Gefitinib Prevents Bleomycin-induced Lung Fibrosis in Mice Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 550 - 556. [Abstract] [Full Text] [PDF]
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R. Lebtahi, S. Moreau, S. Marchand-Adam, M.-P. Debray, M. Brauner, P. Soler, J. Marchal, O. Raguin, A. Gruaz-Guyon, J.-C. Reubi, et al. Increased Uptake of 111In-Octreotide in Idiopathic Pulmonary Fibrosis J. Nucl. Med., August 1, 2006; 47(8): 1281 - 1287. [Abstract] [Full Text] [PDF]
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C. Neurohr, S. L. Nishimura, and D. Sheppard Activation of Transforming Growth Factor-beta by the Integrin {alpha}vbeta8 Delays Epithelial Wound Closure Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 252 - 259. [Abstract] [Full Text] [PDF]
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A. K. Lovgren, L. A. Jania, J. M. Hartney, K. K. Parsons, L. P. Audoly, G. A. FitzGerald, S. L. Tilley, and B. H. Koller COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L144 - L156. [Abstract] [Full Text] [PDF]
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R. M. du Bois Fibroblastic foci: time to be counted? Chest, July 1, 2006; 130(1): 3 - 5. [Full Text] [PDF]
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N. Enomoto, T. Suda, M. Kato, Y. Kaida, Y. Nakamura, S. Imokawa, M. Ida, and K. Chida Quantitative analysis of fibroblastic foci in usual interstitial pneumonia. Chest, July 1, 2006; 130(1): 22 - 29. [Abstract] [Full Text] [PDF]
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M Molina-Molina, A Serrano-Mollar, O Bulbena, L Fernandez-Zabalegui, D Closa, A Marin-Arguedas, A Torrego, J Mullol, C Picado, and A Xaubet Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis Thorax, July 1, 2006; 61(7): 604 - 610. [Abstract] [Full Text] [PDF]
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T. E. King Jr and M. Selman Introduction Proceedings of the ATS, June 1, 2006; 3(4): 283 - 284. [Full Text] [PDF]
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E. G. Tzortzaki, A. V. Koutsopoulos, K. I. Dambaki, I. Lambiri, M. Plataki, M. K. Gordon, D. R. Gerecke, and N. M. Siafakas Active Remodeling in Idiopathic Interstitial Pneumonias: Evaluation of Collagen Types XII and XIV J. Histochem. Cytochem., June 1, 2006; 54(6): 693 - 700. [Abstract] [Full Text] [PDF]
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G. Y. Park and J. W. Christman Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L797 - L805. [Abstract] [Full Text] [PDF]
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M. Inayama, Y. Nishioka, M. Azuma, S. Muto, Y. Aono, H. Makino, K. Tani, H. Uehara, K. Izumi, A. Itai, et al. A Novel I{kappa}B Kinase-beta Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice Am. J. Respir. Crit. Care Med., May 1, 2006; 173(9): 1016 - 1022. [Abstract] [Full Text] [PDF]
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A. Prasse, D. V. Pechkovsky, G. B. Toews, W. Jungraithmayr, F. Kollert, T. Goldmann, E. Vollmer, J. Muller-Quernheim, and G. Zissel A Vicious Circle of Alveolar Macrophages and Fibroblasts Perpetuates Pulmonary Fibrosis via CCL18 Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 781 - 792. [Abstract] [Full Text] [PDF]
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G. R. S. Budinger, G. M. Mutlu, J. Eisenbart, A. C. Fuller, A. A. Bellmeyer, C. M. Baker, M. Wilson, K. Ridge, T. A. Barrett, V. Y. Lee, et al. Proapoptotic Bid is required for pulmonary fibrosis PNAS, March 21, 2006; 103(12): 4604 - 4609. [Abstract] [Full Text] [PDF]
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G. Raghu, S. T.-Y. Yang, C. Spada, J. Hayes, and C. A. Pellegrini Sole Treatment of Acid Gastroesophageal Reflux in Idiopathic Pulmonary Fibrosis: A Case Series Chest, March 1, 2006; 129(3): 794 - 800. [Abstract] [Full Text] [PDF]
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S. K. Frankel, G. P. Cosgrove, S.-I. Cha, C. D. Cool, M. W. Wynes, B. L. Edelman, K. K. Brown, and D. W. H. Riches TNF-{alpha} Sensitizes Normal and Fibrotic Human Lung Fibroblasts to Fas-Induced Apoptosis Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 293 - 304. [Abstract] [Full Text] [PDF]
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I. Dell'Aica, L. Sartor, P. Galletti, D. Giacomini, A. Quintavalla, F. Calabrese, C. Giacometti, E. Brunetta, F. Piazza, C. Agostini, et al. Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-Triggered Pulmonary Fibrosis by a 4-Alkyliden-beta-lactam with a Galloyl Moiety J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 539 - 546. [Abstract] [Full Text] [PDF]
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P. Pignatti, G. Brunetti, D. Moretto, M.-R. Yacoub, M. Fiori, B. Balbi, A. Balestrino, G. Cervio, S. Nava, and G. Moscato Role of the Chemokine Receptors CXCR3 and CCR4 in Human Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., February 1, 2006; 173(3): 310 - 317. [Abstract] [Full Text] [PDF]
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J. Portnoy, T. Pan, C. A. Dinarello, J. M. Shannon, J. Y. Westcott, L. Zhang, and R. J. Mason Alveolar type II cells inhibit fibroblast proliferation: role of IL-1{alpha} Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L307 - L316. [Abstract] [Full Text] [PDF]
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