A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

Abstract

Oncostatin M (OSM), a pleiotropic cytokine of the gp130 cytokine family, has been implicated in chronic allergic inflammatory and fibrotic disease states associated with tissue eosinophilia. Mouse (m)OSM induces airway eosinophilic inflammation and interstitial pulmonary fibrosis in vivo and regulates STAT6 activation in vitro. To determine the requirement of STAT6 in OSM-induced effects in vivo, we examined wild-type (WT) and STAT6-knockout (STAT6−/−) C57BL/6 mouse lung responses to transient ectopic overexpression of mOSM using an adenoviral vector (AdmOSM). Intratracheal AdmOSM elicited persistent eosinophilic lung inflammation that was abolished in STAT6−/− mice. AdmOSM also induced pronounced pulmonary remodeling characterized by goblet cell hyperplasia and parenchymal interstitial fibrosis. Goblet cell hyperplasia was STAT6 dependent; however, parenchymal interstitial fibrosis was not. OSM also induced airway hyperresponsiveness in WT mice that was abolished in STAT6−/− mice. OSM stimulated an inflammatory signature in the lungs of WT mice that demonstrated STAT6-dependent regulation of Th2 cytokines (IL-4, IL-13), chemokines (eotaxin-1/2, MCP-1, keratinocyte chemoattractant), and extracellular matrix modulators (tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-13), but STAT6-independent regulation of IL-4Rα, total lung collagen, collagen-1A1, -1A2 mRNA, and parenchymal collagen and α smooth muscle actin accumulation. Thus, overexpression of mOSM induces STAT6-dependent pulmonary eosinophilia, mucous/goblet cell hyperplasia, and airway hyperresponsiveness but STAT6-independent mechanisms of lung tissue extracellular matrix accumulation. These results also suggest that eosinophil or neutrophil accumulation in mouse lungs is not required for OSM-induced lung parenchymal collagen deposition and that OSM may have unique roles in the pathogenesis of allergic and fibrotic lung disease.

Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod‐induced psoriasis‐like inflammation

“…Overexpression of OSM after intratracheal adenovirus administration elicited persistent lung inflammation with eosinophil and B-cell accumulation in lung parenchyma [27,28]. Finally, tibial injections of AdOSM in mice promoted osteogenesis uncoupled from bone resorption [29].…”

“…Several studies have used AdOSM as a tool to overexpress mouse OSM transiently at the site of injection. For example, intra-articular injection of AdOSM was shown to induce joint inflammation [25,26].Overexpression of OSM after intratracheal adenovirus administration elicited persistent lung inflammation with eosinophil and B-cell accumulation in lung parenchyma [27,28]. Finally, tibial injections of AdOSM in mice promoted osteogenesis uncoupled from bone resorption [29].…”

Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-resistant BALB/c mice

“…12,13 We and others have previously shown that transient pulmonary elevation of OSM in C57Bl/6 mice induced rapid ECM remodeling. 13,14 In cell culture, OSM has been described as a mitogenic, anti-apoptotic factor that stimulates collagen production in human lung fibroblasts.…”

Bronchial hyperreactivity: pathogenesis and treatment options

“…Less intensive profibrotic action has been ascribed to IL-4 and IL-13. Some of the profibrotic signals may arise from extracellular matrix, epithelial cells or fibroblasts [30]. Other molecules with remodelling potential are endothelin-1 and LTC 4 inducing the expression of the collagen in lung fibroblasts.…”

“…Other molecules with remodelling potential are endothelin-1 and LTC 4 inducing the expression of the collagen in lung fibroblasts. It was also determined that oncostatine M, a pleiotropic cytokine of the gp 130 cytokine family is implicated in chronic allergic diseases, including airway remodelling [30].…”