STAT3 and SMAD Signaling in Mouse Models of Oncostatin M-Induced Lung Extracellular Matrix Remodeling

Abstract

<p>IPF is a respiratory condition of unknown etiology that has poor survival prognosis. The stiffening of the lung associated with this condition is attributed to the irreversible turnover of healthy lung tissue into scar tissue, which affects gas exchange and can eventually lead to organ failure. Numerous studies have implicated the pro-fibrogenic growth factor TGF-β, through activation of the SMAD2/3 pathway, as a central mediator in the pathology of this condition. However, other cytokines, including members of the IL-6/gp130 family such as OSM, and other signaling pathways may be implicated in ECM accumulation in certain conditions. In particular, STAT3 activation and an impairment of the BMP-SMAD1 signaling axis is thought to contribute to lung ECM accumulation. Based on the finding that transient pulmonary overexpression of OSM induces lung ECM accumulation in C57Bl/6 mice, it was hypothesized that OSM-induced ECM remodeling would be associated with STAT3 activation and suppression of the BMP-SMAD1-signaling axis.</p> <p>Findings in this thesis revealed that transient pulmonary overexpression of OSM induces ECM remodeling in both BALB/c and C57Bl/6 mice after seven days, despite a dichotomous response in other experimental models of ECM remodeling. However, parenchyma, but not airway, pathology resolved after 28 days in AdOSM-treated BALB/c mice. Furthermore, OSM-induced ECM remodeling occurred independently of IL-6-associated inflammation as well as TGF-β/SMAD3 signaling. MLF cultures treated with OSM did not directly regulate gene expression of ECM-related genes, suggesting that other cells may be responsible for OSM-induced ECM accumulation <em>in vivo</em>. OSM overexpression <em>in vivo </em>was associated with STAT3 activation and SMAD1 suppression, and an assessment of STAT3 and SMAD signaling <em>in vitro</em> showed that OSM activated the STAT3 pathway in MLF cultures, mouse type two pneumocytes, and human airway cells, while OSM suppressed the SMAD1 pathway in mouse type two pneumocytes, and human airway cells. Collectively, this thesis shows that OSM induces novel pathways in models of lung ECM remodeling, and this may have implications for IPF pathogenesis.</p>