Ketotifen abrogates local and systemic consequences of rat intestinal ischemia–reperfusion injury

Abstract

Mast cell-derived vasoactive and pro-inflammatory mediators, particularly histamine, might contribute to local tissue damage and multiorgan dysfunction induced by intestinal ischemia/reperfusion (I/R). The purpose of the present study was to evaluate the effects of the mast cell stabilizer, ketotifen, on leukocyte adhesion within, and tissue leakage from the mucosal villous microcirculation after intestinal I/R. Superior mesenteric arteries of untreated and ketotifen-pretreated (1 mg/kg orally twice daily for 3 days, and 90 min prior to ischemia) Piebald-Viral-Glaxo (PVG) rats were clamped for 30 min (n = 12 per group; sham operated controls n = 12). Mucosal surfaces of exteriorized ileal segments were visualized, and leukocyte adherence in, and macromolecular leakage (MML) from individual villi were followed for 2 h after clamp removal using in vivo microscopy. Blood pressure and heart rate were monitored, and lung tissue damage was assessed by histology. Ten untreated animals subjected to intestinal I/R failed to survive the reperfusion period, leukocyte adhesion (P < 0.001) and MML (P < 0.001) were increased at all time-points and blood flow stasis eventually ensued. In contrast, all ketotifen-pretreated I/R animals survived the duration of the study. Ketotifen abrogated I/R-induced leukocyte adherence within the villus mucosal capillaries and supplying arterioles and largely prevented pulmonary injury, yet surprisingly had no effect on intestinal vascular leakage. This is the first study to demonstrate that ketotifen is a powerful inhibitor of I/R-induced leukocyte adhesion and can prevent localized and reduce remote organ damage after intestinal I/R injury. However, its effects are manifested in the absence of any influence on intestinal I/R-induced vascular leakage.