Fox-Robichaud A, Payne D, Hasan S U, Ostrovsky L, Fairhead T, Reinhardt P, Kubes P
Immunology Research Group, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
J Clin Invest. 1998 Jun 1;101(11):2497-505. doi: 10.1172/JCI2736.
Inhaled nitric oxide (NO) is being used more and more in intensive care units as a modality to improve the outcome of patients with pulmonary complications. Our objective was to demonstrate that inhaled NO could impact upon a distally inflamed microvasculature-improving perfusion, leukocyte adhesive interactions, and endothelial dysfunction. Using intravital microscopy to visualize ischemia/reperfusion of postcapillary venules, we were able to demonstrate that the reduction in perfusion, the dramatic increase in leukocyte rolling, adhesion, and emigration, and the endothelial dysfunction could all be significantly abrogated with 80 ppm, but not 20 ppm inhaled NO. Perfusing whole blood directly over an inert P-selectin and CD18 ligand substratum incorporated in a flow chamber recruited the same number of rolling and adhering leukocytes from NO-ventilated and non-NO-ventilated animals, suggesting that inhaled NO was not directly affecting leukocytes. To demonstrate that inhaled NO was actually reaching the peripheral microvasculature in vivo, we applied a NO synthase inhibitor locally to the feline mesentery and demonstrated that the vasoconstriction, as well as leukocyte recruitment, were essentially abolished by inhaled NO, suggesting that a NO-depleted peripheral microvasculature could be replenished with inhaled NO in vivo. Finally, inhaled NO at the same concentration that was effective in ischemia/reperfusion did not affect vascular alterations, leukocyte recruitment, and endothelial dysfunction associated with endotoxemia in the feline mesentery. In conclusion, our data for the first time demonstrate a role for inhaled NO as a therapeutic delivery system to the peripheral microvasculature, showing tremendous efficacy as an antiadhesive, antivasoconstrictive, and antipermeabilizing molecule in NO-depleted tissues, but not normal microvessels or vessels that have an abundance of NO (LPS-treated). The notion that blood borne molecules have NO carrying capacity is conceptually consistent with our observations.
吸入一氧化氮（NO）在重症监护病房中越来越多地被用作改善肺部并发症患者预后的一种方式。我们的目的是证明吸入NO可对远端炎症性微血管产生影响，改善灌注、白细胞黏附相互作用和内皮功能障碍。利用活体显微镜观察毛细血管后微静脉的缺血/再灌注情况，我们能够证明，吸入80 ppm而非20 ppm的NO可显著消除灌注减少、白细胞滚动、黏附和移出的急剧增加以及内皮功能障碍。将全血直接灌注在流动腔室中掺入的惰性P-选择素和CD18配体基质上，从接受NO通气和未接受NO通气的动物中募集到的滚动和黏附白细胞数量相同，这表明吸入的NO并未直接影响白细胞。为了证明吸入的NO实际上在体内到达了外周微血管，我们将一种NO合酶抑制剂局部应用于猫的肠系膜，并证明吸入的NO基本消除了血管收缩以及白细胞募集，这表明体内可通过吸入NO补充外周微血管中消耗的NO。最后，在缺血/再灌注中有效的相同浓度的吸入NO并未影响猫肠系膜中与内毒素血症相关的血管改变、白细胞募集和内皮功能障碍。总之，我们的数据首次证明了吸入NO作为外周微血管治疗递送系统的作用，显示出其作为抗黏附、抗血管收缩和抗通透性分子在NO消耗组织中具有巨大疗效，但在正常微血管或具有大量NO的血管（经脂多糖处理）中则不然。血源性分子具有携带NO能力这一观点在概念上与我们的观察结果一致。
