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Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice
- Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice
- Katre A.; Ballinger C.; Akhter H.; Fanucchi M.; Kim D.-K.; Postlethwait E.; Liu R.-M.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- Inhalation Toxicology
- Inhalation Toxicology vol. 23, no. 8, pp. 486 - 494
- SCI; SCIE; SCOPUS
- Document Type
- 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-ββ), the most potent profibrogenic cytokine. The results showed that O3 exposure for 5 or 10 cycles increased the TGF-ββ protein level in the epithelial lining fluid (ELF), associated with an increase in the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-ββ-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 (αα-SMA) in airway walls. However, these fibrotic changes were not overt until after 10 cycles of O3 exposure. Importantly, blockage of the TGF-ββ signaling pathway with IN-1233 suppressed O3-induced Smad2/3 phosphorylation, PAI-1 expression, as well as collagens and αα-SMA deposition in the lung. Our data demonstrate for the first time that O3 exposure increases TGF-ββ expression and activates TGF-ββ signaling pathways, which mediates O3-induced lung fibrotic responses in vivo. © 2011 Informa Healthcare USA, Inc.
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