title: Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice.
abstract: Ozone (O₃), a commonly encountered environmental pollutant, has been shown to induce pulmonary fibrosis in different animal models; the underlying mechanism, however, remains elusive. To investigate the molecular mechanism underlying O₃-induced pulmonary fibrosis, 6- to 8-week-old C57BL/6 male mice were exposed to a cyclic O₃ exposure protocol consisting of 2 days of filtered air and 5 days of O₃ exposure (0.5 ppm, 8 h/day) for 5 and 10 cycles with or without intraperitoneal injection of IN-1233, a specific inhibitor of the type 1 receptor of transforming growth factor beta (TGF-β), the most potent profibrogenic cytokine. The results showed that O₃ exposure for 5 or 10 cycles increased the TGF-β protein level in the epithelial lining fluid (ELF), associated with an increase in the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-β-responsive gene that plays a critical role in the development of fibrosis under various pathological conditions. Cyclic O₃ exposure also increased the deposition of collagens and alpha smooth muscle actin (α-SMA) in airway walls. However, these fibrotic changes were not overt until after 10 cycles of O₃ exposure. Importantly, blockage of the TGF-β signaling pathway with IN-1233 suppressed O₃-induced Smad2/3 phosphorylation, PAI-1 expression, as well as collagens and α-SMA deposition in the lung. Our data demonstrate for the first time that O₃ exposure increases TGF-β expression and activates TGF-β signaling pathways, which mediates O₃-induced lung fibrotic responses in vivo.
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Katre
authors.forename: Carol
authors.initials: C
authors.lastname: Ballinger
authors.forename: Hasina
authors.initials: H
authors.lastname: Akhter
authors.forename: Michelle
authors.initials: M
authors.lastname: Fanucchi
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.forename: Edward
authors.initials: E
authors.lastname: Postlethwait
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010083:Oxidants, Photochemical / Q000633:toxicity*; D010126:Ozone / Q000633:toxicity*; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D058258:Serpin E2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C538835:3-((4-(6-methylpyridin-2-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D000199:Actins; D001549:Benzamides; D010083:Oxidants, Photochemical; D011804:Quinolines; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D010126:Ozone; D003094:Collagen