A Rat Model of Ischemic Enteritis: Pathogenic Importance of Enterobacteria, iNOS/NO, and COX-2/PGE2.

BACKGROUND: We introduced a rat model of ischemic enteritis and investigated the roles of enterobacteria, Nitric Oxide (NO), and Prostaglandins (PGs) in its pathogenesis. METHODS: Male rats were used after 18 h of fasting. Ischemic enteritis was induced by partial ligation of the superior mesenteric artery (SMA). Under ether anesthesia, SMA was isolated, and a stenosis was made by placing a needle (23 guage) on the vessel and ligating both the vessel and needle, and then a needle was removed from the ligature. Animals were then fed normally after surgery. Various drugs such as antibiotics, cyclooxygenase (COX) inhibitors, NO synthase (NOS) inhibitors and PGE2 were administered for 2 days after surgery. RESULTS: Stenosis of the SMA caused mucosal ischemia and damaged the small intestine, particularly the ileum, within 3 days. The development of enteritis was accompanied by mucosal invasion of enterobacteria, with the bacterial count being significantly increased 8 h after surgery. The severity of enteritis was prevented by the prior administration of ampicillin, L-NAME, or aminoguanidine, but aggravated by that of indomethacin or rofecoxib. The deleterious effects of indomethacin were antagonized by the co-administration of PGE2; these effects were mimicked by AE1-329, an EP4 agonist, and abrogated by AE3-208, an EP4 antagonist. The expression of iNOS and COX-2 was up-regulated in the small intestine in a time-dependent manner after ischemia caused by stenosis of the SMA, with increases in the mucosal contents of NO and PGE2. CONCLUSION: These results suggest that enterobacteria played a major pathogenic role in this model of ischemic enteritis, and that iNOS/NO was deleterious in the pathogenesis of these lesions, while COX-2/PGE2 prevented the development of ischemic enteritis by activating EP4 receptors.

Pathogenic importance of cysteinyl leukotrienes in development of gastric lesions induced by ischemia/reperfusion in mice.

We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT(1)R) antagonist] as well as 1-[[5'-(3''-methoxy-4''-ethoxycarbonyl-oxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT(1)R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT(1)R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT(1)R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT(1)R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.

A novel model of ischemic enteritis induced in rats by stenosis of the superior mesenteric artery.

AIMS: We established a new model of ischemic enteritis in rats and evaluated its usefulness for screening prophylactic drugs. MAIN METHODS: Male SD rats were used after 18 h of fasting. Under ether anesthesia, the superior mesenteric artery (SMA) was exposed, and a calibrated stenosis was produced by placing a needle on a blood vessel, ligating both the vessel and needle, and then removing the needle from the ligature. KEY FINDINGS: The stenosis caused severe damage on the anti-mesenteric side of the small intestine within 3 days; the severity of the damage increased with the gauge of a needle. No damage occurred in the small intestine following the stenosis with a needle of less than 21 gauge. Multiple hemorrhagic lesions occurred at an incidence of 100% when a 23-gauge needle was used. The development of enteritis was accompanied by enterobacterial invasion in the mucosa, with an up-regulation of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. The ischemia-induced enteritis was significantly prevented by repeated treatment with aminoguanidine (a selective iNOS inhibitor), L-NAME (a nonselective NOS inhibitor), ampicillin, and aztreonam (a gram-negative bacterium antibiotic), but not vancomycin (a gram-positive bacterium antibiotic). SIGNIFICANCE: These results showed that a novel model of ischemic enteritis is induced in rats by stenosis of the SMA, this model may be useful for screening drugs against ischemic enteritis, and gram-negative bacteria as well as iNOS/NO are involved in the pathogenesis of enteritis in this model.

A novel model of ischemic enteritis induced in rats by stenosis of the superior mesenteric artery.

AIMS: We established a new model of ischemic enteritis in rats and evaluated its usefulness for screening prophylactic drugs. MAIN METHODS: Male SD rats were used after 18 h of fasting. Under ether anesthesia, the superior mesenteric artery (SMA) was exposed, and a calibrated stenosis was produced by placing a needle on a blood vessel, ligating both the vessel and needle, and then removing the needle from the ligature. KEY FINDINGS: The stenosis caused severe damage on the anti-mesenteric side of the small intestine within 3 days; the severity of the damage increased with the gauge of a needle. No damage occurred in the small intestine following the stenosis with a needle of less than 21 gauge. Multiple hemorrhagic lesions occurred at an incidence of 100% when a 23-gauge needle was used. The development of enteritis was accompanied by enterobacterial invasion in the mucosa, with an up- regulation of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. The ischemia-induced enteritis was significantly prevented by repeated treatment with aminoguanidine (a selective iNOS inhibitor), L-NAME (a nonselective NOS inhibitor), ampicillin, and aztreonam (a gram- negative bacterium antibiotic), but not vancomycin (a gram-positive bacterium antibiotic). SIGNIFICANCE: These results showed that a novel model of ischemic enteritis is induced in rats by stenosis of the SMA, this model may be useful for screening drugs against ischemic enteritis, and gram-negative bacteria as well as iNOS/NO are involved in the pathogenesis of enteritis in this model.