BENEFICIAL-EFFECTS OF CYCLOSPORINE AND RAPAMYCIN IN SMALL-BOWEL ISCHEMIC-INJURY

Gut ischemia has been implicated in the pathogenesis of necrotizing en terocolitis. Cyclosporine A and rapamycin, both potent novel immunosup pressants which act on signal transduction pathways in CD4+ T-cells, c ould potentially modulate immune/inflammatory cellular reactions invol ved in tissue ischemia/reperfusion injury. We hypothesized that cyclos porine A and rapamycin would preserve mucosal cell function and attenu ate inflammatory T-cell-mediated cellular changes associated with smal l bowel ischemic injury. Forty Sprague-Dawley rats underwent 60 min of gut ischemia by vascular occlusion of the superior mesenteric vessels . Animals were randomized to four groups (n = 10): cyclosporine A (CSA , 5 mg/kg/day SQ), rapamycin (RAP, 2 mg/kg/day SQ), cyclosporine A and rapamycin (C&R), and vehicle given to controls (CON). Following 1 hr of reperfusion, small bowel was harvested for xanthine oxidase (XO, un its/mg protein) and maltase (MALT, mM substrate degraded/min/g protein ) assays. Blood was obtained from the portal vein for tumor necrosis f actor-alpha (TNF-alpha, pg/ml) assay. The results of the study are pre sented below (mean +/- SEM, , P < 0.05 versus controls). [GRAPHICS] T he results indicate that cyclosporine and rapamycin each play a signif icant role in attenuating ischemia/ reperfusion injury in the gut. The se data suggest that there are cytoprotective and anti-inflammatory me chanisms of these drugs independent of T-cell signal transduction that provide some protective effect in small bowel ischemia, Furthermore, T-cell-mediated immune mechanisms may not be associated with the adver se effects of small bowel ischemia/reperfusion injury. Additional inve stigation will be necessary in order to define the role of T-cell-medi ated immune injury in the gut and how this relates to the beneficial e ffect of immunosuppression in small bowel mucosal ischemic injury. (C) 1996 Academic Press, Inc.