The effects of sirolimus on target organs during mesenteric ischemia and reperfusion damage in an experimental rat model.

BACKGROUND

Mesenteric ischemia and reperfusion (I/R) syndrome (MIRS) has been considered a clinicopathologic entity associated with a variety of clinically severe conditions with decreased intestinal blood flow and has been known to induce I/R damage in various organs. Sirolimus (SRL), a macrolide antibiotic isolated from a strain of Streptomyces hygroscopicus, is a potent and nonnephrotoxic immunosuppressant.

OBJECTIVE

This study was designed to investigate the potential impact of sirolimus on MIRS-induced I/R damage in renal, intestinal, pulmonary, and hepatic tissues in an experimental rat model.

METHODS

Twenty-four male Sprague-Dawley rats, aged 6 to 8 weeks and weighing 280 (±20 g), were studied. Using computer-generated random numbers, rats were assigned to 1 of the following 3 groups: group 1 (I/R group, n = 8), group 2 (I/R + sirolimus group, n = 8), and group 3 (control group, n = 8). Sirolimus, in a 1 mg/mL (60 mL) solution, was administered intraperitoneally in a dose of 1.5 mg/kg/d to the rats assigned to group 2 starting from 3 days before the surgical procedure. In surgery, a laparotomy was performed to clamp the superior mesenteric artery and, thus, induce bowel ischemia in groups 1 and 2. After 60 minutes of ischemia, the microvascular clamp on the superior mesenteric artery was removed for 3 hours of reperfusion. Soon after experimental induction of MIRS, bowel, lung, kidney, and liver specimens from each animal were harvested for both biochemical and histopathologic analysis.

RESULTS

There were statistically significant differences between groups 1 and 3 with regard to degrees of intestinal (P < 0.001), hepatic (P = 0.001), renal (P < 0.001), and pulmonary (P = 0.01) I/R damage. The lung specimens from group 2 had less inflammation and perivascular edema formation compared with specimens from group 1, but no statistical significance was observed between the groups (P < 0.33). There were statistically significant differences between groups 1 and 2 with regard to degrees of intestinal, hepatic, and renal I/R damage (P = 0.001 for all).

CONCLUSIONS

The findings of the present study demonstrate the attenuating effects of sirolimus on I/R damage in the intestine and remote organs, including the liver and kidney in the setting of MIRS in an experimental rat model. As a therapeutic implication, the utility of sirolimus may be of clinical value in procedures associated with a high likelihood of I/R damage, including major abdominal operations and renal transplantation. However, whether these results apply to humans is unclear. Additional experimental and clinical studies are warranted to confirm the clinical utility of sirolimus in conditions potentially associated with I/R damage.