title: Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-resistant BALB/c mice.
abstract: Adverse health outcomes in pulmonary fibrosis are associated with extracellular matrix (ECM) accumulation. Although transforming growth factor-β (TGF-β) has been reported to be an important regulator of fibrosis pathogenesis, TGF-β-independent pathways may also be involved. Here, we investigated responses of putative relatively fibrosis-resistant BALB/c mice to transient pulmonary overexpression of oncostatin M (OSM) using an adenovirus vector encoding OSM (AdOSM) and compared responses with the relatively fibrosis-prone C57Bl/6 strain. Interestingly, BALB/c mice showed similar ECM accumulation and collagen 1A1 and 3A1 mRNA elevation to C57Bl/6 mice 7 days after endotracheal administration of AdOSM. TGF-β1 mRNA levels and pSMAD2 signal were not regulated in either strain in total lung extracts. In contrast to C57Bl/6 mice, BALB/c mice lacked eosinophil, Th2 cytokine, and pro-inflammatory cytokine elevation in the broncholveolar space. OSM overexpression induced STAT3 activation and SMAD1/5/8 signaling suppression in lung from both mice strains, which was associated with a downregulation of BMPR2 and BMP ligands, and increased expression of the BMP antagonist gremlin. Although we also observed STAT3 activation and SMAD1/5/8 signaling suppression in mouse lung fibroblast cultures in vitro upon OSM stimulation, immunohistochemistry analyses indicated that the AdOSM-induced pSMAD1/5/8 signal suppression was primarily localized to the airway epithelium. Other gp130 cytokines including IL-6, LIF, CT-1, but not IL-31, also induced STAT3 activation and SMAD1/5/8 signaling suppression in C10 mouse lung epithelial cells and BEAS 2B bronchial epithelial cells, and we found that pharmacological inhibition of STAT3 activation reversed OSM-induced SMAD1/5/8 signaling suppression in vitro. The results demonstrate that OSM induces ECM accumulation in fibrosis-resistant BALB/c mouse lung in the absence of Th2 inflammation or TGF-β signaling, and highlight a dichotomy of STAT3 activation versus SMAD1 suppression in this process.
authors.affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Wong
authors.affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Botelho
authors.affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Rodrigues
authors.affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Richards
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D008024:Ligands; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053683:Oncostatin M / Q000378:metabolism*; D011658:Pulmonary Fibrosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051898:Smad1 Protein / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D008024:Ligands; D050796:STAT3 Transcription Factor; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C494087:Stat3 protein, mouse; D053683:Oncostatin M