Role of granulocyte elastase in indomethacin-induced gastric mucosal lesion formation in rats

To investigate whether granulocyte elastase may be involved in indomethacin-induced gastric mucosal injury, we examined the effects of the granulocyte elastase inhibitors ONO-5046 and L-658,758 on gastric mucosal lesion formation in rats given indomethacin. Both gastric mucosal lesion formation and gastric mucosal vascular damage were markedly attenuated in animals with leukocytopenia and in those given granulocyte elastase inhibitors. The administration of indomethacin significantly increased gastric myeloperoxidase activity, a measure of leukocyte accumulation, 3 hours after the administration of indomethacin compared with activity in animals receiving saline solution. The administration of ONO-5046 or L-658,758 significantly prevented this increase. Histologic examinations revealed submucosal edema and marked infiltration by leukocytes, as well as widespread necrosis with loss of surface epithelium. ONO-5046 and L-658,758 markedly prevented these histologic changes. Although cimetidine significantly prevented mucosal lesion formation, it did not inhibit either granulocyte elastase release from activated neutrophils in vitro or gastric accumulation of leukocytes in vivo. These results suggest that granulocyte elastase as well as gastric acid may play an important role in the pathologic process by which indomethacin induces gastric mucosal lesions.