Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs
Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs
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DOI：
10.1016/s0014-2999(01)01327-9
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发表时间：
2001-10-19
影响因子：
5
通讯作者：
Whittle, BJR
中科院分区：
文献类型：
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作者：
Evans, SM;Whittle, BJR
本实验观察了诱导型一氧化氮合酶（iNOS）、超氧化物歧化酶（SOD）和腔菌脂多糖（LPS）形成的一氧化氮（NO）在非甾体抗炎药所致大鼠肠损伤中的作用。给药（皮下注射）或p.o.）吲哚美辛（10 mg kg（-1））、氟比洛芬（40 mg kg（-1））或双氯芬酸（40 mg kg（-1））可增加空肠中放射性标记白蛋白的血管渗漏，24 h后测定，与诱导型一氧化氮合酶（iNOS）的诱导有关，通过放射性标记L-精氨酸的转化进行评估。用氨苄青霉素（200 mg kg（-1）天（-1），p.o.）、甲硝唑（200 mg kg（-1）天（-1），p.o.）预处理，或多粘菌素B（15 mg/kg/天，S.C.），抑制吲哚美辛诱导的损伤形成，减少微血管渗漏，并阻止iNOS活性的表达。给予高选择性iNOS抑制剂GW 273629（（R）-2-氨基-4，4-二氧代-6（1-亚氨基乙基氨基）-4-硫代己酸; 5 me kg（-1），s.c.），18 h后，同样防止了肠道病变并减弱了微血管渗漏。与聚乙二醇结合的超氧化物歧化酶（3000 U kg（-1），静脉注射），抑制消炎痛引起的损伤和微血管渗漏，但不抑制iNOS活性的表达。这些发现表明，非甾体抗炎药损害粘膜完整性，导致管腔细菌移位。这引起iNOS诱导，导致涉及NO和超氧化物的微血管损伤。(C)2001 Elsevier Science B. V.保留所有权利。
The role of nitric oxide (NO) formed by inducible NO synthase (iNOS), superoxide and the lipopolysaccharide from luminal bacteria in non-steroidal anti-inflammatory drug-induced intestinal injury was investigated in the rat. Administration (s.c. or p.o.) of indomethacin (10 mg kg(-1)), flurbiprofen (40 mg kg(-1)) or diclofenac (40 mg kg(-1)) increased the vascular leakage of radiolabelled albumin in the jejunum, determined after 24 h, associated with the induction of iNOS, assessed by the conversion of radiolabelled L-arginine. Pre-treatment with ampicillin(200 mg kg(-1) day(-1), p.o,), metronidazole(200 mg kg(-1) day(-1), p.o.), or polymixin B (15 mg kg(-1) day(-1), S.C.), inhibited indomethacin-induced lesion formation, reduced microvascular leakage and prevented the expression of iNOS activity. Administration of the highly selective iNOS inhibitor, GW273629 ((R)-2-amino-4,4-dioxo-6(1-iminioethylamino)-4-thiahexanoic acid; 5 me kg(-1), s.c.), 18 h after indomethacin, likewise prevented the intestinal lesions and attenuated the microvascular leakage. Superoxide dismutase conjugated with polyethylene glycol (3000 U kg(-1), i.v.), inhibited the indomethacin-induced lesions and microvascular leak-age, but not the expression of iNOS activity. These findings suggest that non-steroidal anti-inflammatory drugs compromise mucosal integrity, leading to luminal bacterial translocation. This provokes iNOS induction, leading to microvascular injury involving both NO and superoxide. (C) 2001 Elsevier Science B.V. All rights reserved.