Laboratório de Farmacologia Bioquímica e Celular, Departamento de Farmacologia, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brasil.
Shock. 2011 Jan;35(1):17-27. doi: 10.1097/SHK.0b013e3181e37ea8.
Sepsis results from an overwhelming response to infection and is a major contributor to death in intensive care units worldwide. In recent years, we and others have shown that neutrophil functionality is impaired in sepsis. This correlates with sepsis severity and contributes to aggravation of sepsis by precluding bacterial clearance. Nitric oxide (NO) is a major contributor to the impairment of neutrophil function in sepsis. However, attempts to inhibit NO synthesis in sepsis resulted in increased death despite restoring neutrophil migration. This could be in part attributed to a reduction of the NO-dependent microbicidal activity of neutrophils. In sepsis, the beneficial effects resulting from the inhibition of soluble guanylyl cyclase (sGC), a downstream target of NO, have long been appreciated but poorly understood. However, the effects of sGC inhibition on neutrophil function in sepsis have never been addressed. In the present study, we show that TLR activation in human neutrophils leads to decreased chemotaxis, which correlated with chemotactic receptor internalization and increased G protein-coupled receptor kinase 2 expression, in a process involving the NO-sGC-protein kinase G axis. We also demonstrate that inhibition of sGC activity increased survival in a murine model of sepsis, which was paralleled by restored neutrophil migratory function and increased bacterial clearance. Finally, the beneficial effect of sGC inhibition could also be demonstrated in mice treated after the onset of sepsis. Our results suggest that the beneficial effects of sGC inhibition in sepsis could be at least in part attributed to a recovery of neutrophil functionality.
脓毒症是由感染引起的全身性过度反应，是全球重症监护病房死亡的主要原因。近年来，我们和其他人已经表明，脓毒症患者的中性粒细胞功能受损。这与脓毒症的严重程度相关，并通过阻止细菌清除而加重脓毒症。一氧化氮（NO）是导致脓毒症中性粒细胞功能障碍的主要因素。然而，尽管恢复了中性粒细胞的迁移能力，抑制脓毒症中 NO 的合成仍导致死亡率增加。这在一定程度上归因于中性粒细胞的 NO 依赖性杀菌活性的降低。在脓毒症中，抑制一氧化氮合酶（sGC）的有益效果长期以来一直受到重视，但却知之甚少，sGC 是 NO 的下游靶点。然而，sGC 抑制对脓毒症中性粒细胞功能的影响从未得到解决。在本研究中，我们表明 TLR 在人中性粒细胞中的激活导致趋化性降低，这与趋化性受体内化和 G 蛋白偶联受体激酶 2 表达增加有关，该过程涉及 NO-sGC-蛋白激酶 G 轴。我们还证明，抑制 sGC 活性可增加脓毒症小鼠模型的存活率，同时恢复中性粒细胞迁移功能并增加细菌清除率。最后，sGC 抑制的有益作用也可以在脓毒症发病后给予小鼠治疗时得到证明。我们的研究结果表明，sGC 抑制在脓毒症中的有益作用至少部分归因于中性粒细胞功能的恢复。
