Fox-Robichaud A, Payne D, Kubes P
Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Am J Physiol. 1999 Dec;277(6):L1224-31. doi: 10.1152/ajplung.1999.277.6.L1224.
Nitric oxide (NO), in addition to being a potent vasodilator, also prevents leukocyte adhesion in the microvasculature. Based on the antiadhesive properties of NO and work suggesting that NO is transported by proteins in the circulation, we tested the possibility that inhaled NO could impart antiadhesive effects in peripheral microvessels. We also determined the underlying mechanisms of actions. Three well-established models that induce local microvascular changes (either endothelium or leukocyte) were used. Hydrogen peroxide (H(2)O(2); 100 microM) was superfused onto the cat mesentery to induce an endothelium-derived, P-selectin- and platelet-activating factor-dependent, oxidant-dependent leukocyte recruitment. In a second series of experiments, the cat mesentery was superfused with histamine (100 microM) to induce rapid endothelium-derived, P-selectin- and platelet-activating factor-dependent, oxidant-independent leukocyte recruitment. Finally, in a third series of experiments to target the leukocyte (but not the endothelium) directly in the periphery, the chemotactic molecule leukotriene B(4) (20 nM) was superfused onto the cat mesentery. The above experiments were performed with and without cats breathing NO (80 parts/million). Intravital microscopy was used to visualize the mesenteric microcirculation. Inhaled NO reduced the increased leukocyte rolling and adhesion associated with H(2)O(2) superfusion of the feline mesentery via a cGMP-dependent mechanism. In contrast, inhaled NO had no effect on the histamine-induced increase in leukocyte rolling flux but partially inhibited the subsequent adhesion. The leukocyte chemotactic mediator leukotriene B(4) induced a significant increase in leukocyte adhesion, but NO inhalation did not impair this chemotactically induced leukocyte recruitment. These data suggest that inhaled NO can reach the endothelium in the distal microvasculature and alter the response to an oxidative and a nonoxidative activator of endothelium but imparts no antiadhesive effect directly on circulating leukocytes.
一氧化氮（NO）除了是一种强效血管舒张剂外，还能防止白细胞在微血管中黏附。基于NO的抗黏附特性以及有研究表明NO在循环中由蛋白质运输，我们测试了吸入NO在外周微血管中产生抗黏附作用的可能性。我们还确定了其潜在的作用机制。使用了三种成熟的诱导局部微血管变化（内皮或白细胞）的模型。将过氧化氢（H₂O₂；100微摩尔）灌注到猫肠系膜上，以诱导内皮源性、P选择素和血小板活化因子依赖性、氧化剂依赖性的白细胞募集。在第二系列实验中，将组胺（100微摩尔）灌注到猫肠系膜上，以诱导快速的内皮源性、P选择素和血小板活化因子依赖性、非氧化剂依赖性的白细胞募集。最后，在第三系列实验中，为了直接在外周靶向白细胞（而非内皮），将趋化分子白三烯B₄（20纳摩尔）灌注到猫肠系膜上。上述实验在猫呼吸NO（百万分之80）和不呼吸NO的情况下进行。采用活体显微镜观察肠系膜微循环。吸入NO通过依赖环磷酸鸟苷（cGMP）的机制减少了与猫肠系膜H₂O₂灌注相关的白细胞滚动和黏附增加。相比之下，吸入NO对组胺诱导的白细胞滚动通量增加没有影响，但部分抑制了随后的黏附。白细胞趋化介质白三烯B₄诱导白细胞黏附显著增加，但吸入NO并未损害这种趋化诱导的白细胞募集。这些数据表明，吸入的NO可以到达远端微血管的内皮，并改变对内皮氧化和非氧化激活剂的反应，但对循环中的白细胞没有直接的抗黏附作用。
