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Title: Effect of angiotensin-IV on the survival and toxicity of sulphur mustard-treated mice
Keywords: Sulphur Mustard, Inflammation, Angiotensin, Pulmonary, Mouse Model
Issue Date: 14-Aug-2009
Citation: SEOW JOSEFINA (2009-08-14). Effect of angiotensin-IV on the survival and toxicity of sulphur mustard-treated mice. ScholarBank@NUS Repository.
Abstract: Sulphur mustard (SM) is an alkylating agent with cytotoxic, mutagenic and vesicating properties. The underlying mechanisms of SM pathology are not fully understood. Inhalation of SM can lead to persistent and clinically significant lung disease, including bronchial mucosal injury, many years after exposure. There is no known medical countermeasure for SM-induced respiratory injuries. We hypothesized that inflammatory mechanisms play an essential role in SM pathogenesis and interrupting the inflammatory cascade may ameliorate SM-induced injuries, especially in the lungs. Previous studies have shown des-aspartate-angiotensin I (DAA-1) treatment over 14 days was able to increase survival numbers of mice intoxicated intranasally with 2-chlorethyl-ethyl sulfide (CEES), a less toxic analog of SM. DAA-1, a bioactive angiotensin peptide, was known to have an effect on the angiotensin II proinflammatory pathway. This project aimed to complement this previous work. The main of the project is to determine if interrupting the angiotensin II inflammatory pathway with angiotensin IV (ANG-IV) treatment could improve survival rate of SM-intoxicated mice and protect against SM-induced pulmonary biochemical and histopathological changes. ANG-IV have been shown to effectively modify angiotensin II pathways. DAA-1 and losartan were also investigated alongside ANG-IV treatment. We developed an intranasal SM mice model to study survival rate and pulmonary damages in intoxicated animals. A single LD80 SM was administered (0.006mg/mouse) and treatments were given 60 minutes before SM administration, followed by a daily dose for 14 days post-SM. The effectiveness of different drugs in improving survival rate, mediating weight loss and reducing pulmonary inflammation of the intoxicated animals were evaluated over 21 days. It was observed that treatment with 150 nm/kg/day ANG-IV and 150 nm/kg/day DAA-1 improved survival rate and reduced body weight loss of SM intoxicated mice and were effective in lowering pulmonary inflammatory markers (MPO and histopathology) caused by SM intoxication. SM-intoxicated mice treated with either ANG-IV or DAA-1 showed considerable suppression of pulmonary edema, parenchymal damage and concurrent reduction in MPO (neutrophil infiltration indicator). We also demonstrated that ANG-IV exerted its protective action via both AT4 and AT1 receptors as divalinal ANG-IV (AT4 antagonist) and losartan (AT1 antagonist) were able to antagonize its protective effects in SM intoxicated mice. Hence, the results of this study supported our hypothesis that SM-induced pulmonary damages can be mediated by attenuating inflammation via the angiotensin II pathway at the injury site. These anti-inflammatory compounds may represent a novel and specific therapeutic strategy for treatment of SM-induced pulmonary lesions and understanding its pathogenesis.
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