Beneficial effects of cyclosporine and rapamycin in small bowel ischemic injury.
Gut ischemia has been implicated in the pathogenesis of necrotizing enterocolitis. Cyclosporine A and rapamycin, both potent novel immunosuppressants which act on signal transduction pathways in CD4+ T-cells, could potentially modulate immune/inflammatory cellular reactions involved in tissue ischemia/reperfusion injury. We hypothesized that cyclosporine A and rapamycin would preserve mucosal cell function and attenuate inflammatory T-cell-mediated cellular changes associated with small 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, units/mg protein) and maltase (MALT, mM substrate degraded/min/g protein) assays. Blood was obtained from the portal vein for tumor necrosis factor-alpha (TNF-alpha, pg/ml) assay. The results of the study are presented below (mean +/- SEM, *, P < 0.05 versus controls). (Table in text) The results indicate that cyclosporine and rapamycin each play a significant role in attenuating ischemia/reperfusion injury in the gut. These data suggest that there are cytoprotective and anti-inflammatory mechanisms 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 adverse effects of small bowel ischemia/reperfusion injury. Additional investigation will be necessary in order to define the role of T-cell-mediated immune injury in the gut and how this relates to the beneficial effect of immunosuppression in small bowel mucosal ischemic injury.
Department of Pediatric Surgery, Children's Regional Medical Center, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden 08103, USA.
R N
RN
Puglisi
L
L
Strande
M
M
Santos
G
G
Schulte
C W
CW
Hewitt
T V
TV
Whalen
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology; D007421:Intestine, Small / Q000098:blood supply* / Q000201:enzymology; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D011090:Polyenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*; D020123:Sirolimus; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D014969:Xanthine Oxidase / Q000187:drug effects / Q000378:metabolism; D000520:alpha-Glucosidases / Q000187:drug effects / Q000378:metabolism
D007166:Immunosuppressive Agents; D011090:Polyenes; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D014969:Xanthine Oxidase; D000520:alpha-Glucosidases; D020123:Sirolimus