283: Suppression of SMAD-1 signaling pathway in mouse lung tissue remodelling by oncostatin M

Abstract

Introduction Abnormal remodeling of the extracellular matrix (ECM) in lung tissue marks the pathology and compromises lung function in diseases such as pulmonary fibrosis and severe asthma. Various cytokine networks, including TGF-beta and gp130 cytokines, have been shown to modulate the ECM. More recent work has suggested a protective role for bone morphogenetic proteins (BMP) in pulmonary fibrosis. We have previously shown that over-expression of Oncostatin M (OSM), one member of the gp130 cytokine family, induces ECM remodeling in mouse lung that remains evident in SMAD3−/− and IL-6−/− mice. Here we examine the regulation of BMP/SMAD1 signaling pathways upon transient pulmonary over-expression of OSM. Methods: C57Bl/6 mice were intubated with adenovirus vector encoding OSM (AdOSM) to induce transient pulmonary over-expression for 7 days. Lungs were processed for histology, immunohistochemistry, RNA analysis for ECM proteins (collagen) and BMP-associated proteins (BMP-2, BMP-4, BMP-7, gremlin), or for protein analysis by immunoblot for (activated) pSTAT3, pSMAD1/5/8 and BMPReceptor2. Results: AdOSM induced ECM remodeling as indicated by increased parenchymal collagen (PSR stain), coll1a1 and coll1a2 mRNA levels. Immunoblots of signaling responses in total lung homogenates showed increased levels of pSTAT3, but decreased levels of pSMAD1/5/8 and BMPR2 in AdOSM-treated mice. Immunohistochemistry showed a marked reduction of pSMAD1/5/8 detected in airway epithelial cells due to AdOSM, whereas pSTAT3 was up-regulated in airway epithelial and other cells. Levels of mRNA of BMP-2 and BMP-4 were reduced whereas gremlin mRNA was increased in total lungs of AdOSM-treated compared to control (AdDl70) mice. Conclusions: Transient over-expression of OSM induces rapid ECM remodeling in mouse lungs and caused marked suppression of BMP-2/4 mRNA, BMPR2 and pSMAD1 signaling. Such effects would decrease the putative protective function of BMPs in lung fibrosis. Thus OSM-induced suppression of the SMAD1 signaling, in context of STAT3 activation, may reflect a novel pathway that contributes to lung ECM remodeling. This work was supported by the Canadian Institutes for Health Research.