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

Abstract

BackgroundExposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury.MethodsBalb/C mice were exposed to Cl2 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 Cl2, 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 Cl2 exposure.ResultsMice exposed to Cl2 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 Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 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 Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU.ConclusionOur data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.

Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness

“…In addition to preventing neutrophil influx and changes in KC, DMTU completely prevented AHR in Rn and H. However, DMTU was unable to prevent AHR in G. Similarly, Shalaby et al (39) demonstrated that DMTU prevented neutrophil accumulation in BAL fluid as well as AHR in both the central and peripheral lung compartments in an allergic model of asthma in mice exposed to birch pollen extract. In a model of irritant-induced asthma using Cl 2 gas, DMTU was also effective in reducing AHR in both peripheral and central lung (25). Our findings suggest a role for oxidative stress, likely associated with neutrophil populations, following OD exposure.…”

“…*P Ͻ 0.05, **P Ͻ 0.01, and ***P Ͻ 0.001; n ϭ 5-6/group. burden, we utilized an antioxidant, DMTU, that has been shown to prevent pulmonary neutrophilia following inhalation of chlorine gas (25). We found that DMTU prevented ODinduced airway inflammation in lung tissue and prevented neutrophilia.…”

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

“…Chlorine exposure produces changes in lung function, including altered airway resistance, elastance, and reactivity to methacholine (7, c P Ͻ 0.01 vs. corresponding unexposed; d P Ͻ 0.05 vs. corresponding unexposed. 10,13,24,26,35,40). These changes are complex and appear to depend on the dose of chlorine as well as the species and strain of the animal.…”

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

“…At the age of 12 wk, airway responsiveness to methacholine challenge was measured as described by McGovern et al (27). The mice were anesthetized and paralyzed using i.p.…”