Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis.
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-beta 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.
Mozaffarian
Afsaneh
A
Department of Inflammation, Amgen, Inc., Seattle, WA 98119, USA.
Brewer
Avery W
AW
Trueblood
Esther S
ES
Luzina
Irina G
IG
Todd
Nevins W
NW
Atamas
Sergei P
SP
Arnett
Heather A
HA
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D053683:Oncostatin M / Q000276:immunology / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D053683:Oncostatin M