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: Ashwini Katre, Carol Ballinger, Hasina Akhter, Michelle Fanucchi, Dae-Kee Kim, Edward Postlethwait, Rui-Ming Liu
• Journal: Inhalation toxicology (Inhal Toxicol) Vol. 23 Issue 8 Pg. 486-94 (Jul 2011) ISSN: 1091-7691 [Electronic] England
• PMID: 21689010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-((4-(6-methylpyridin-2-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamide
• Actins
• Benzamides
• Oxidants, Photochemical
• Quinolines
• Serpin E2
• Serpine2 protein, mouse
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Transforming Growth Factor beta1
• Ozone
• Collagen

Topics

• Actins (metabolism)
• Animals
• Benzamides (pharmacology)
• Bronchi (drug effects, metabolism)
• Collagen (metabolism)
• Disease Models, Animal
• Inhalation Exposure
• Male
• Mice
• Mice, Inbred C57BL
• Oxidants, Photochemical (toxicity)
• Ozone (toxicity)
• Phosphorylation
• Pulmonary Fibrosis (chemically induced, drug therapy, metabolism)
• Quinolines (pharmacology)
• Serpin E2 (metabolism)
• Signal Transduction (drug effects)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (analysis, antagonists & inhibitors, metabolism)