Analysis of pathogenic elements involved in gastric lesions induced by non‐steroidal anti‐inflammatory drugs in rats

Abstract

Pathogenesis of gastric damage induced by non-steroidal anti-inflammatory drugs (NSAID) involves multiple elements, such as deficiency of prostaglandins (PG), gastric hypermotility, neutrophil activation and luminal acid. The present study was performed to examine the effects of these elements, either alone or in combination, on the rat gastric mucosa and investigate which element is most closely associated with the gastric ulcerogenic response to NSAID. The following treatments were used to express various pathogenic elements: (i) a low dose of indomethacin (IM) to cause PG deficiency; (ii) 2-deoxy-D-glucose (2DG) to induce gastric hypermotility and acid secretion; (iii) histamine to induce acid hypersecretion; and (iv) n-formyl-Met-Leu-Phe (fMLP) to elicit neutrophil activation. When rats fasted for 18 h were subjected to each treatment alone, only 2DG caused slight macroscopic damage in the gastric mucosa within 4 h. Indomethacin showed over 90% inhibition of mucosal PG generation and fMLP increased myeloperoxidase activity four-fold greater than normal values, yet either of these treatments alone did not cause any damage in the stomach. However, the combination of IM with 2DG or His provoked severe lesions in the stomach or the duodenum, respectively, while fMLP did not modify or potentiate the mucosal ulcerogenic response to other treatments. We conclude that among various pathogenic elements only gastric hypermotility is sufficient, by itself, to induce mild damage in the mucosa, that PG deficiency may be critical in the increase of mucosal susceptibility to injury and that neutrophil activation alone is not ulcerogenic in the gastric mucosa nor does it potentiate the ulcerogenic effect of other elements. Luminal acid may be a prerequisite for later extension of damage to severe lesions.