ROLE OF GRANULOCYTE ELASTASE IN THE FORMATION OF HEMORRHAGIC SHOCK-INDUCED GASTRIC-MUCOSAL LESIONS IN THE RAT

Objective: To investigate the mechanism by which activated leukocytes induce gastric mucosal lesions, we examined whether granulocyte elasta se is involved in the formation of such lesions in a rat model of hemo rrhagic shock. Design: Prospective, randomized, controlled study. Sett ing: Research laboratory at a university medical center, Subjects: Mal e Wistar rats, weighing 220 to 280 g. Interventions: Animals were subj ected to hemorrhagic shock by phlebotomy. ONO-5046, a granulocyte elas tase inhibitor (300 mg/kg ip), was administered 30 mins before or afte r phlebotomy, The effects of antithrombotic substances and tranexamic acid on hemorrhagic shock-induced gastric mucosal lesions also were ex amined, The effects of granulocyte elastase on the thrombomodulin acti vity and S-35-glycosaminoglycan content of endothelial cells were exam ined, using cultured human umbilical vein endothelial cells. Measureme nts and Main Results: Three hours after phlebotomy, linear gastric muc osal erosions were observed. Formation of these lesions, as evaluated by the total linear length, was attenuated significantly by posttreatm ent as well as pretreatment of animals with ONO-5046, Administration o f antithrombin III and an inactive factor Xa derivative, a selective i nhibitor of thrombin generation, significantly prevented gastric mucos al lesion formation, while tranexamic acid, an inhibitor of thrombolys is, significantly worsened lesion formation, When incubated with cultu red endothelial cells, granulocyte elastase markedly decreased the end othelial thrombomodulin activity and glycosaminoglycan content, These effects of granulocyte elastase were significantly decreased by ONO-50 46. Conclusions: These observations strongly suggest that granulocyte elastase plays an important role in the pathogenesis of hemorrhagic sh ock-induced gastric mucosal lesions, Addition ally, endothelial cell i njury induced by granulocyte elastase may eventually lead to microthro mbus formation, which in turn could be an important etiologic factor l eading to ischemia in gastric mucosal lesion formation.