Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury
Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury
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DOI：
10.1016/j.freeradbiomed.2011.11.018
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发表时间：
2012-02-01
影响因子：
7.4
通讯作者：
Phillipson, Mia
中科院分区：
文献类型：
--
作者：
Jadert, Cecilia;Petersson, Joel;Phillipson, Mia
血管NO合酶产生的一氧化氮（NO）可以发挥抗炎作用，部分原因是它能够减少白细胞募集。无机硝酸盐和亚硝酸盐，从内源性或膳食来源，已成为替代底物NO形成的哺乳动物。硝酸盐的生物活化被认为需要通过口腔内细菌初始还原为亚硝酸盐。在这里，我们研究了无机硝酸盐和亚硝酸盐对微血管炎症和NSAID诱导的小肠损伤中白细胞募集的影响。我们发现，白细胞迁移的促炎趋化因子MIP-2减少70%后，7天的饮食硝酸盐补充剂，以及急性静脉注射亚硝酸盐。亚硝酸盐也减少了白细胞粘附到类似的程度，这种效果被抑制的可溶性鸟苷酸环化酶抑制剂ODQ，而对迁移的白细胞的效果没有改变这种治疗。在INF-α刺激的内皮细胞中的进一步研究表明，亚硝酸盐剂量依赖性地降低ICAM-1的表达。在接受双氯芬酸挑战的大鼠和小鼠中，膳食硝酸盐可防止小肠组织中髓过氧化物酶和P-选择素水平的增加。抗菌漱口水，消除了口服硝酸盐的减少，显着减弱了饮食中硝酸盐对P-选择素水平的保护作用。尽管急性免疫反应减弱，但清除金黄色葡萄球菌感染的总体能力并没有受到饮食硝酸盐的抑制，如无创IVIS成像所示。我们的结论是，饮食硝酸盐显着减少白细胞招募炎症的过程中，涉及衰减P-选择素和ICAM-1的上调。膳食硝酸盐的生物活化需要通过口腔硝酸盐还原菌中间形成亚硝酸盐，然后可能进一步还原为组织中的NO和其他生物活性氮氧化物。(C)2011 Elsevier Inc. All rights reserved.
Nitric oxide (NO) generated by vascular NO synthases can exert anti-inflammatory effects, partly through its ability to decrease leukocyte recruitment. Inorganic nitrate and nitrite, from endogenous or dietary sources, have emerged as alternative substrates for NO formation in mammals. Bioactivation of nitrate is believed to require initial reduction to nitrite by oral commensal bacteria. Here we investigated the effects of inorganic nitrate and nitrite on leukocyte recruitment in microvascular inflammation and in NSAID-induced small-intestinal injury. We show that leukocyte emigration in response to the proinflammatory chemokine MIP-2 is reduced by 70% after 7 days of dietary nitrate supplementation as well as by acute intravenous nitrite administration. Nitrite also reduced leukocyte adhesion to a similar extent and this effect was inhibited by the soluble guanylyl cyclase inhibitor ODQ whereas the effect on emigrated leukocytes was not altered by this treatment. Further studies in INF-alpha-stimulated endothelial cells revealed that nitrite dose-dependently reduced the expression of ICAM-1. In rats and mice subjected to a challenge with diclofenac, dietary nitrate prevented the increase in myeloperoxidase and P-selectin levels in small-intestinal tissue. Antiseptic mouthwash, which eliminates oral nitrate reduction, markedly blunted the protective effect of dietary nitrate on P-selectin levels. Despite attenuation of the acute immune response, the overall ability to clear an infection with Staphylococcus aureus was not suppressed by dietary nitrate as revealed by noninvasive IVIS imaging. We conclude that dietary nitrate markedly reduces leukocyte recruitment to inflammation in a process involving attenuation of P-selectin and ICAM-1 upregulation. Bioactivation of dietary nitrate requires intermediate formation of nitrite by oral nitrate-reducing bacteria and then probably further reduction to NO and other bioactive nitrogen oxides in the tissues. (C) 2011 Elsevier Inc. All rights reserved.