Objective: To investigate the mechanism by which activated leukocytes induce gastric mucosal lesions, we examined whether granulocyte elastase is involved in the formation of such lesions in a rat model of hemorrhagic shock. Design: Prospective, randomized, controlled study. Setting: Research laboratory at a university medical center. Subjects: Male Wistar rats, weighing 220 to 280 g. Interventions: Animals were subjected to hemorrhagic shock by phlebotomy. ONO- 5046, a granulocyte elastase inhibitor (300 mg/kg ip), was administered 30 mins before or after phlebotomy. The effects of antithrombotic substances and tranexamic acid on hemorrhagic shock-induced gastric mucosal lesions also were examined. The effects of granulocyte elastase on the thrombomodulin activity and 35S-glycosaminoglycan content of endothelial cells were examined, using cultured human umbilical vein endothelial cells. Measurements and Main Results: Three hours after phlebotomy, linear gastric mucosal erosions were observed. Formation of these lesions, as evaluated by the total linear length, was attenuated significantly by posttreatment as well as pretreatment of animals with ONO-5046. Administration of antithrombin III and an inactive factor Xa derivative, a selective inhibitor of thrombin generation, significantly prevented gastric mucosal lesion formation, while tranexamic acid, an inhibitor of thrombolysis, significantly worsened lesion formation. When incubated with cultured endothelial cells, granulocyte elastase markedly decreased the endothelial thrombomodulin activity and glycosaminoglycan content. These effects of granulocyte elastase were significantly decreased by ONO-5046. Conclusions: These observations strongly suggest that granulocyte elastase plays an important role in the pathogenesis of hemorrhagic shock-induced gastric mucosal lesions. Additionally, endothelial cell injury induced by granulocyte elastase may eventually lead to microthrombus formation, which in turn could be an important etiologic factor leading to ischemia in gastric mucosal lesion formation.
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