Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma

BACKGROUND: Exposure to chlorine (Cl(2)) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl(2)-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury. METHODS: Balb/C mice were exposed to Cl(2 )gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl(2), airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl(2 )exposure. RESULTS: Mice exposed to Cl(2 )had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl(2 )exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl(2)-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl(2 )prevented lipid peroxidation in the lung. Following Cl(2 )exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl(2 )exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU. CONCLUSION: Our data show that the anti-oxidant DMTU is effective in attenuating Cl(2 )induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.