Beneficial effects of GW274150 treatment on the development of experimental colitis induced by dinitrobenzene sulfonic acid
Beneficial effects of GW274150 treatment on the development of experimental colitis induced by dinitrobenzene sulfonic acid
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DOI：
10.1016/j.ejphar.2004.11.041
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发表时间：
2005-01-10
影响因子：
5
通讯作者：
Cuzzocrea, S
中科院分区：
文献类型：
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作者：
Di Paola, R;Mazzon, E;Cuzzocrea, S
炎症性肠病与诱导型一氧化氮合酶(INOS)的表达有关。氧化和亚硝化应激，以及结肠内白细胞的渗透。在这里，我们研究了选择性诱导型一氧化氮合酶抑制剂(S)-2-amino-(1-iminoethylamino)-5-thiopentanoic酸(GW274150)对二硝基苯磺酸诱导的实验性结肠炎的影响。与二硝基苯磺酸处理的小鼠相比，GW274150(5 mg/kg ip)处理的二硝基苯磺酸诱导的结肠炎小鼠的结肠损伤程度和严重程度的组织学SIPS的比率显著降低。经二硝基苯磺酸处理的小鼠出现出血性腹泻和体重减轻。二硝基苯磺酸给药后4d。结肠粘膜呈大面积坏死。硝基酪氨酸和多聚(ADP-核糖)(PAR)免疫组织化学显示炎症的结肠中有强烈的染色。用GW274150治疗二硝基苯磺酸引起的小鼠出血性腹泻和体重下降的程度明显减轻。GW274150还可显著减轻(I)结肠损伤程度，(Ii)髓过氧化物酶(MPO)活性(粘膜)升高。(Iii)染色增加。(4)二硝基苯磺酸在结肠中引起的PARP激活。因此。GW274150治疗可减轻二硝基苯磺酸引起的结肠炎程度。我们认为GW274150选择性抑制iNOS活性可能有助于炎症性肠病的治疗。(C)2004爱思唯尔B.V.保留所有权利。
Inflammatory bowel disease is associated with inducible nitric oxide synthase (iNOS) expression. oxidative and nitrosative stress, and leukocyte infiltration in the colon. Here, we investigate the effects of the selective iNOS-inhibitor (S)-2-amino-(1-iminoethylamino)-5-thiopentanoic acid (GW274150) on the development of experimental colitis induced by dinitrobenzene sulfonic acid. When compared to dinitrobenzene sulfonic acid-treated mice, GW274150 (5 mg/kg i.p.)-treated mice subjected to dinitrobenzene sulfonic ACID-induced colitis experienced a significantly lower rate of the extent and severity of the histological sips of colon injury. Dinitrobenzene sulfonic acid-treated mice experienced hemorrhagic diarrhoea and weight loss. At 4 days after the administration of dinitrobenzene sulfonic acid. the mucosa of the colon exhibited large areas of necrosis. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) (PAR) showed an intense staining in the inflamed colon. Treatment of dinitrobenzene sulfonic acid-treated mice with GW274150 significantly reduced the degree of hemorrhagic diarrhoea and weight loss caused by administration of dinitrobenzene sulfonic acid. GW274150 also caused a substantial reduction of (i) the degree of colon injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa). (iii) the increase in staining. (immunohistochemistry) for nitrotyrosine, as well as (iv) PARP activation caused by dinitrobenzene sulfonic acid in the colon. Thus. GW274150 treatment reduced the degree of colitis caused by dinitrobenzene sulfonic acid. We propose that selective inhibition of iNOS activity with GW274150 may be useful in the treatment of inflammatory bowel disease. (C) 2004 Elsevier B.V. All rights reserved.