title: 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.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Dominik K
authors.initials: DK
authors.lastname: Fritz
authors.forename: Christine
authors.initials: C
authors.lastname: Kerr
authors.forename: Ramzi
authors.initials: R
authors.lastname: Fattouh
authors.forename: Alba
authors.initials: A
authors.lastname: Llop-Guevara
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
authors.forename: Carl D
authors.initials: CD
authors.lastname: Richards
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology*; D006965:Hyperplasia; D017563:Lung Diseases, Interstitial / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053683:Oncostatin M / Q000008:administration & dosage* / Q000235:genetics; D011657:Pulmonary Eosinophilia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C508352:Osm protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D053683:Oncostatin M