Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA, USA.
Vasc Med. 2012 Dec;17(6):379-85. doi: 10.1177/1358863X12459790. Epub 2012 Sep 26.
Resuscitation from hemorrhagic shock induces endothelial dysfunction and activates inflammatory cascades leading to organ damage. Following restoration of blood flow to ischemic vascular beds, leukocyte-endothelium interactions leading to leukocyte infiltration into the vascular wall occur very early due, in part, to the loss of endothelium-derived nitric oxide (NO). The mechanism by which ischemia-reperfusion injury impairs endothelium-derived NO is not completely understood. We hypothesized that inhibition of Rho-kinase could exert beneficial effects following hemorrhagic shock by preserving endothelial function and attenuating leukocyte trafficking in the microcirculation. Using intravital microscopy, we found that resuscitation from hemorrhage acutely increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. Treatment of mice with the Rho-kinase inhibitor fasudil, markedly attenuated leukocyte-endothelium interaction in response to hemorrhage/reinfusion. The beneficial effect of fasudil was not observed in endothelial nitric oxide synthase (eNOS)(-/-) mice. In conclusion, inhibition of Rho-kinase prevents inflammatory leukocyte trafficking in the microcirculation via an eNOS-dependent mechanism. Our data support a role for Rho-kinase inhibitors in the treatment of ischemia-reperfusion injury.
失血性休克复苏会引起血管内皮功能障碍，并激活炎症级联反应，导致器官损伤。在缺血性血管床血流恢复后，由于内皮细胞衍生的一氧化氮（NO）的丧失，白细胞-内皮细胞相互作用导致白细胞浸润血管壁会很早发生。缺血再灌注损伤导致内皮细胞衍生的 NO 功能障碍的机制尚不完全清楚。我们假设，抑制 Rho 激酶可能通过维持血管内皮功能和减轻微循环中的白细胞迁移，在失血性休克后发挥有益作用。通过活体显微镜观察，我们发现从出血中复苏会急性增加小鼠内脏微循环中滚动和黏附的白细胞数量。用 Rho 激酶抑制剂法舒地尔治疗可显著减轻对出血/再灌注的白细胞-内皮细胞相互作用。内皮型一氧化氮合酶（eNOS）（-/-）小鼠未观察到法舒地尔的有益作用。总之，抑制 Rho 激酶通过依赖 eNOS 的机制防止炎症性白细胞在微循环中的迁移。我们的数据支持 Rho 激酶抑制剂在治疗缺血再灌注损伤中的作用。
