Fibrotic footprint of Oncostatin M-induced pulmonary disease

Abstract Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and modulation of extracellular matrix (ECM). Recently, we observed that OSM is elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis as well as scleroderma. In mice, delivery of OSM to the lungs results in recruitment of inflammatory cells and an increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease. We used genetically modified mice to show that the fibrotic response is largely independent of B and T lymphocytes, eosinophils and mast cells. To investigate the relationship between OSM-induced inflammation and OSM-induced fibrosis, we used both protein and genomic array approaches to generate a "fibrotic footprint" for OSM. While the IL-4/IL-13 and TGF-β pathways are generally intertwined in fibrosis, we show that OSM is capable of driving lung fibrosis independent of these pathways. For comparison, we show the expression patterns of OSM versus bleomycin-induced lung fibrosis to highlight the unique mechanisms underlying disease pathogenesis. The demonstration that OSM is a potent mediator of lung inflammation and ECM accumulation, and upregulated in patients, provides a rationale for targeting OSM in human disease.