Mucosal adaptation to aspirin induced gastric damage in humans. Studies on blood flow, gastric mucosal growth, and neutrophil activation.

Abstract

The gastropathy associated with the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin is a common side effect of this class of drugs, but the precise mechanisms by which they cause mucosal damage have not been fully explained. During continued use of an injurious substance, such as aspirin, the extent of gastric mucosal damage decreases and this phenomenon is named gastric adaptation. To assess the extent of mucosal damage by aspirin and subsequent adaptation the effects of 14 days of continuous, oral administration of aspirin (2 g per day) to eight healthy male volunteers was studied. To estimate the rate of mucosal damage, gastroscopy was performed before (day 0) and at days 3, 7, 14 of aspirin treatment. Gastric microbleeding and gastric mucosal blood flow were measured using laser Doppler flowmeter and mucosal biopsy specimens were taken for the estimation of tissue DNA synthesis and RNA and DNA concentration. In addition, the activation of neutrophils in peripheral blood was assessed by measuring their ability to associate with platelets. Aspirin induced acute damage mainly in gastric corpus, reaching at day 3 about 3.5 on the endoscopic Lanza score but lessened to about 15 at day 14 pointing to the occurrence of gastric adaptation. Mucosal blood flow increased at day 3 by about 50% in the gastric corpus and by 88% in the antrum. The in vitro DNA synthesis and RNA concentration, an index of mucosal growth, were reduced at day 3 but then increased to reach about 150% of initial value at the end of aspirin treatment. The gastric microbleeding rate rose from about 0-38 mi/day at day 0 to about 7-7 mi/day at day 3 but then decreased significantly to virtually normal values at the end of the study. The neutrophil/platelet adherence showed significant increase during aspirin treatment. It is concluded that the treatment with aspirin in humans induces gastric adaptation to this agent, which entails the increase in mucosal blood flow, the rise in neutrophil activation, and the enhancement in mucosal growth.

Recent Advances in Gastrointestinal Pathophysiology: Role of Heat Shock Proteins in Mucosal Defense and Ulcer Healing.

“…Konturek et al 68) reported that gastric mucosa increases its resistance to damage caused by aspirin during repeated administration of aspirin. Jin et al 69) observed that the increase in HSP (mainly HSP70) expression correlated with mucosal resistance that observed after repeated administration of aspirin.…”

Effect of Helicobacter pylori eradication on cyclooxygenase 2 (COX‐2) and inducible nitric oxide synthase (iNOS) expression during gastric adaptation to aspirin (ASA) in humans

“…Gastric adaptation to aspirin (ASA), i.e., resolution of mucosal damage despite continued exposure to the drug, is well documented (Graham et al, 1983;Ivey, 1988; J.W. Konturek et al, 1994; S.J. Konturek et al, 1981).…”

“…Direct damage of mucosal cells, reduction of prostaglandin formation and-although discussed controversially-reduced microcirculation contribute to the deleterious effects of NSAIDs on gastroduodenal mucosa (Graham et al, 1983;Ivey, 1988;J.W. Konturek et al, 1994; S.J.…”

Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides

“…This is in keeping with the lesser degree of injury caused by the aspirin dose used in this study compared with the other more extensive injury models. Similarly, measurable increases in TGF-␣ and epidermal growth factor also occur in adapted stomachs only after multiple doses of aspirin and not after a single injurious dose (Doljanin et al, 1996;Konturek et al, 1994aKonturek et al, , 1998aRomano et al, 1996). It is possible that the increments in mucosal RegI (and indeed TGF-␣ and epidermal growth factor) that occur as a result of each adapting dose finally culminate as an "effective" increase only after several episodes of daily injury-this would help to explain the lag time of several days required for the onset of adaptation St John et al, 1973;Wallace et al, 1995).…”

“…Several studies in both humans and experimental animals using histologic assessments and incorporation of 3 [H]thymidine and bromodeoxyuridine conclude that enhanced proliferation likely contributes to the mechanism of reduced injury that is characteristic of gastric mucosal adaptation (Baumgartner et al, 1986;Eastwood and Quimby, 1982;Konturek et al, 1994a;Lev et al, 1972;Levi et al, 1992;Romano et al, 1996;Shorrock et al, 1990). A role A, mRNA expression of regenerating protein (RegI) and its receptor (Regr) in the gastric mucosa of control, single-dose, and adapted rats 4 hours after the last dose of vehicle or aspirin.…”