HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mozaffarian, A. Articles by Arnett, H. A. Search for Related Content PubMed PubMed Citation Articles by Mozaffarian, A. Articles by Arnett, H. A.

Mechanisms of Oncostatin M-Induced Pulmonary Inflammation and Fibrosis

Afsaneh Mozaffarian^*, Avery W. Brewer, Esther S. Trueblood, Irina G. Luzina, Nevins W. Todd, Sergei P. Atamas and Heather A. Arnett^1,*

^* Department of Inflammation and Department of Pathology, Amgen, Inc., Seattle, WA 98119; and University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201

Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and the modulation of extracellular matrix. In this study, we demonstrate that OSM is up-regulated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and scleroderma, and investigate the pathological consequences of excess OSM in the lungs. Delivery of OSM to the lungs of mice results in a significant recruitment of inflammatory cells, as well as a dose-dependent increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease. To better understand the relationship between OSM-induced inflammation and OSM-induced fibrosis, we used genetically modified mice and show that the fibrotic response is largely independent of B and T lymphocytes, eosinophils, and mast cells. We further explored the mechanisms of OSM-induced inflammation and fibrosis using both protein and genomic array approaches, generating a "fibrotic footprint" for OSM that shows modulation of various matrix metalloproteinases, extracellular matrix components, and cytokines previously implicated in fibrosis. In particular, although the IL-4/IL-13 and TGF-β pathways have been shown to be important and intertwined of fibrosis, we show that OSM is capable of inducing lung fibrosis independently of these pathways. The demonstration that OSM is a potent mediator of lung inflammation and extracellular matrix accumulation, combined with the up-regulation observed in patients with pulmonary fibrosis, may provide a rationale for therapeutically targeting OSM in human disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Heather A. Arnett, Department of Inflammation, Amgen Corporation, 1201 Amgen Court West, Seattle, WA 98119. E-mail address: harnett{at}amgen.com

² Abbreviations used in this paper: OSM, oncostatin M; OSMR, OSM receptor; ECM, extracellular matrix; RA, rheumatoid arthritis; BAL, bronchoalveolar lavage; MMP, matrix metalloproteinase; TIMP, tissue inhibitors of metalloproteinase; SSc, systemic sclerosis; IPF, idiopathic pulmonary fibrosis; MSA, mouse serum albumin; TLDA, TaqMan Low Density Array; HRPT; hypoxanthine phosphoribosyltransferase; CTGF, connective tissue growth factor; OPG, osteoprotegerin.

This article has been cited by other articles:

				W. D. Hardie, S. W. Glasser, and J. S. Hagood Emerging Concepts in the Pathogenesis of Lung Fibrosis Am. J. Pathol., July 1, 2009; 175(1): 3 - 16. [Abstract] [Full Text] [PDF]