Toxicology
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Lung mechanics, hemodynamics and blood chemistries were assessed in sheep (Ovis aries) before, and up to 24 h following, a 15-20 min exposure to either air (control) or approximately 500 ppm nitrogen dioxide (NO2). Histopathologic examinations of lung tissues were performed 24 h after exposure. Nose-only and lung-only routes of exposure were compared for effects on NO2 pathogenesis. ⋯ The qualitative responses of this large animal species to high-level NO2 supports the concept of size dependent species sensitivity to NO2. In addition, when inspired minute ventilation was used as a dose-determinant, a linear relationship between NO2 dose and lung resistance was found. The importance of these findings, NO2 dose-determinants, and the utility of sheep as a large animal inhalation model are discussed.
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Human inhalation exposures to relatively high mass concentrations of the oxidant gas nitrogen dioxide (NO2) can result in a variety of pulmonary disorders, including life-threatening pulmonary edema, pneumonia, and bronchiolitis obliterans. Inasmuch as most experimental studies to date have examined NO2-induced lung injury following exposures to near ambient or supra-ambient concentrations of NO2, e.g., < or = 50 ppm, little detailed information about the pulmonary injurious responses following the acute inhalation of higher NO2 concentrations that are more commensurate with some actual human exposure conditions is currently available. Described in this report are the results from a series of investigations in which various aspects of the inhalation toxicity of high concentrations of NO2 have been examined in laboratory rats. ⋯ Comparisons of results obtained from this and the first component studies additionally revealed that brief exposures to the very high concentrations of NO2 are more hazardous than longer duration exposures to lower concentrations. In a third study series, we examined pre-exposure, exposure, and post-exposure modifiers of NO2-induced lung injury, including dietary taurine, minute ventilation, and post-exposure exercise. Results from these studies indicated: (i) dietary taurine does not protect the rat lung against high concentration NO2 exposure, (ii) the severity of acute lung injury in response to NO2 inhalation is increased by an increase in minute ventilation during exposure, and (iii) the performance of exercise after NO2 exposure can significantly enhance the injurious response to NO2.(ABSTRACT TRUNCATED AT 400 WORDS)
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Comparative Study
Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease.
The pyrrolizidine alkaloid (PA) monocrotaline (MCT) is thought to be activated in the liver to monocrotaline pyrrole (MCTP) which is then transported to the lungs where it causes a pulmonary vascular syndrome characterized by elevated pulmonary artery pressure and right ventricular hypertrophy. We have found that, as opposed to Sprague-Dawley (SD) rats, Fischer 344 (F344) strain rats are resistant to the ventricular hypertrophy and pressure changes induced by MCT. To determine whether this strain difference might be related to differences in hepatic activation of MCT to MCTP, we compared the response of SD and F344 rats to treatment with MCT or MCTP. ⋯ MCTP treated SD rats had similar vascular and parenchymal alterations as those treated with MCT but with a lesser inflammatory component. We conclude that the strain differences in cardiac and pulmonary vascular responses to MCT also occur with MCTP treatment. This, combined with the similarity in alveolar parenchymal response to both PAs in both strains, suggests that these differences are related to the pulmonary vascular response rather than differences in hepatic metabolism.
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Dermal intoxication of mice with bis(2-chloroethyl)sulphide and the protective effect of flavonoids.
The influence of dermal application of sulphur mustard (SM) on hepatic lipid peroxidation and the protective effect of flavonoids in SM toxicity was investigated. SM applied on the skin of mice (0.25 or 0.5 LD50) depleted glutathione (GSH) in blood and liver. ⋯ Survival time of mice with 1 LD50 SM applied dermally was increased by GN and HR to a greater extent than by vitamin E or sodium thiosulphate probably due to one or more of the analgesic, anti-inflammatory, antihepatotoxic, antihistaminic, mast cell stabilization, lipid peroxidation inhibitory and free radical scavenging actions of the flavonoids. The present study indicates that dermally applied SM can induce lipid peroxidation and GSH depletion, and flavonoids may be beneficial in reducing the toxicity.
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The effects of cold-restraint as a physiological stressor on the glutathione (GSH) content of the liver and other tissues were examined in male mice. Mice of the ICR, NIH, ND/4, and B6C3F1 strains subjected to cold-restraint for 2 or 3 h experienced a loss of hepatic GSH concentrations ranging from approximately 15 to 50%. Though 3 of these strains (ICR, NIH, and B6C3F1) experienced hypothermia as result of the cold-restraint treatment, with average decreases in core body temperature ranging from 3.3 to 9.8 degrees C, hepatic GSH levels were depressed in the ND/4 mouse in the absence of changes in core body temperature. ⋯ In addition to its effects on liver GSH and NPSH concentrations, 1.5 h of cold-restraint stress significantly depressed plasma, heart, kidney, and lung NPSH concentrations. The extent of NPSH depression was equivalent to the GSH depression in the liver, heart, and kidney, despite the observation that the normal contribution of GSH to total NPSH content in these tissues ranged from a high of 89% (liver) to a low of 49% (heart). These results with cold-restraint in the ND/4 mouse suggest that other stressors may significantly depress cellular concentrations of GSH and other thiols, and may thereby render the affected tissues more susceptible to the toxicity of free radicals, electrophilic xenobiotic metabolites, or reactive oxygen species.