O001 Regulation of tissue remodelling by Oncostatin M in mouse lung is IL-6- and SMAD3-independent

IntroductionRemodeling of extracellular matrix (ECM) in lungs occurs with various chronic inflammatory conditions including idiopathic pulmonary fibrosis and allergic airway disease. Although TGFbeta/SMAD signaling and other molecules are recognized as important in controlling ECM deposition, the gp130 cytokine (or IL-6/LIF cytokine) family including Oncostatin M (OSM) and IL-6 have also been implicated. OSM is a potent regulator of ECM in Balb/C and C57Bl/6 mouse lungs. Since OSM markedly induces IL-6 in vivo, here we tested the requirement for IL-6 using IL-6-/- mice and, in parallel, effects in SMAD3-/- mice in this system.MethodsWe used Adenovirus vector encoding murine OSM (AdOSM), to over-express OSM (endotracheal administration) and examined accumulation of collagen in lung tissue by histology, mRNA levels, chemokine levels in lung lavage and recruitment of CD45+collagen1+fibrocytes using Flow cytometry of whole lung mononuclear cell populations, with an n=5 for each treatment in the separate mouse lines.ResultsIn wild type mice, using empty vector Addel70 as a control treatment, AdOSM markedly induced mRNA levels of collagen1A1, 1A2, elastin, fibronectin, MMP13, TIMP-1, and IL-6 at Days 5 and 7 while TIMP-3 was reduced. Activated STAT3 was evident at day 2 and 7 as assessed by Western blots of individual mouse lung homogenates and immuno-histochemistry of tissue sections. Analysis of tissue at Day 7 and 14 showed increased collagen (picrosirus red stain) in parenchyma as well as around smaller airways. Collagen accumulation was still evident in IL-6-/- as well as SMAD3-/- lungs. FACS analysis showed significant elevation of CD45+coll1+fibrocyte accumulation in lung at day 7, however the fibrocyte chemokine SDF-1 (CXCL12) expression was reduced at the RNA and protein level in lungs.ConclusionOver-expression of OSM induces ECM in lungs that did not require IL-6 ligand nor SMAD3 signaling systems. ECM deposition was associated with increased fibrocyte accumulation that appeared independent of the chemokine SDF-1. The results suggest unique activities of OSM in lung tissue remodeling and a potential role in inflammatory lung diseases. (Supported by the Canadian Institutes for Health Research).