Nitric oxide, superoxide radicals and mast cells in pathogenesis of indomethacin-induced small intestinal lesions in rats.
Nitric oxide, superoxide radicals and mast cells in pathogenesis of indomethacin-induced small intestinal lesions in rats.
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一氧化氮、超氧自由基和肥大细胞在吲哚美辛引起的大鼠小肠病变发病机制中的作用。
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发表时间：
1999
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通讯作者：
K. Takeuchi
中科院分区：
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作者：
A. Konaka;M. Nishijima;A. Tanaka;T. Kunikata;S. Kato;K. Takeuchi
我们研究了吲哚美辛诱导的小肠病变的发病机制，与一氧化氮（NO），超氧自由基和肥大细胞。大鼠接受吲哚美辛（1-6 mg/kg）s.c.每天一次，持续3天，并在最后一次给予消炎痛后24小时检查小肠是否有病变。吲哚美辛引起小肠出血性病变，主要是在空肠和回肠，在剂量和时间依赖性的方式，伴随着粘膜微血管通透性的增加。结果表明，诱导型一氧化氮合酶（iNOS）活性随其mRNA的表达、髓过氧化物酶（MPO）活性和硫代巴比妥酸反应物（TRBAS）的表达而增加，且iNOS活性的变化先于MPO活性和TRBAS的变化及病变的发展。吲哚美辛诱导的这些病变可通过氨基胍（一种选择性iNOS抑制剂）、地塞米松（一种iNOS mRNA转录抑制剂）、别嘌呤醇（一种黄嘌呤氧化酶抑制剂）、羟基脲（一种中性粒细胞还原剂）和FR 167653（一种白细胞介素-1/肿瘤坏死因子-α生成抑制剂）以及16，16-二甲基前列腺素E2 β来预防。同样，肥大细胞稳定剂FPL-52694和色甘酸二钠和脂氧合酶抑制剂TMK-688也降低了这些病变的严重程度，但不受tripelennamine（组胺H1受体拮抗剂）或methysergide（5-羟色胺受体拮抗剂）的影响。这些结果表明：1）吲哚美辛诱导的小肠损伤的致病机制涉及超氧自由基以及由iNOS产生的NO，2）NO的有害作用可以通过过氧亚硝酸盐的细胞毒性作用来解释，过氧亚硝酸盐是在超氧自由基存在下由NO产生的，和3）肥大细胞也可以参与小肠溃疡的过程，尽管负责的介质仍然不确定。
We investigated the pathogenic mechanism of indomethacin-induced small intestinal lesions, in relation to nitric oxide (NO), superoxide radicals and mast cells. Rats received indomethacin (1-6 mg/kg) s.c. once daily for 3 days, and the small intestine was examined for lesions 24 hr after the final administration of indomethacin. Indomethacin caused hemorrhagic lesions in the small intestine, mostly in the jejunum and ileum, in dose- and time-dependent manners, with concomitant increase of mucosal microvascular permeability. This treatment also caused an increase of inducible NO synthase (iNOS) activity with the expression of its mRNA, myeloperoxidase (MPO) activity as well as thiobarbituric acid reactants (TRBAS) in the mucosa, and the changes in iNOS activity preceded those in MPO activity and TRBAS as well as lesion development. These lesions induced by indomethacin were prevented by aminoguanidine (a selective inhibitor of iNOS), dexamethasone (an inhibitor of iNOS mRNA transcription), allopurinol (a xanthine oxidase inhibitor), hydroxyurea (a neutrophil reducing agent) and FR167653 (an inhibitor of interleukin-1/tumor necrosis factor-alpha production) as well as 16,16-dimethyl prostaglandin E2ń. Likewise, the severity of these lesions was also reduced by mast cell stabilizers FPL-52694 and disodium cromoglycate and a lipoxygenase inhibitor TMK-688, but not affected by tripelennamine (a histamine H1-receptor antagonist) or methysergide (a serotonin receptor antagonist). These results suggest that: 1) the pathogenic mechanism of indomethacin-induced small intestinal lesions involves superoxide radicals as well as NO produced by iNOS, 2) the deleterious effect of NO may be accounted for by the cytotoxic action of peroxynitrite, produced from NO in the presence of superoxide radicals, and 3) the mast cells may also be involved in the process of small intestinal ulceration, although the mediator responsible remains undefined.