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.
Puglisi
R N
RN
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.
Strande
L
L
Santos
M
M
Schulte
G
G
Hewitt
C W
CW
Whalen
T V
TV
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