MRC/University Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Blood. 2011 May 12;117(19):5178-88. doi: 10.1182/blood-2010-08-304667. Epub 2011 Feb 3.
Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.
危重病患者发生医院获得性感染的风险增加。过敏毒素 C5a 可损害中性粒细胞的吞噬作用。然而，这种情况发生的机制以及与医院获得性感染的相关性仍未确定。我们旨在描述 C5a 在体外和危重病患者中抑制吞噬作用的机制，并定义 C5a 介导的功能障碍与医院获得性感染的获得之间的关系。在健康的人类中性粒细胞中，C5a 可显著抑制 RhoA 的激活，从而阻止肌动蛋白聚合和吞噬作用。PI3Kδ 介导了 RhoA 的抑制。GM-CSF 完全逆转了对 RhoA、肌动蛋白和吞噬作用的影响。在危重病患者的中性粒细胞中也观察到了类似的结果，即吞噬作用受损与 RhoA 和肌动蛋白聚合的抑制有关，并且 GM-CSF 可逆转这种抑制作用。在 60 名危重病患者的队列中，C5a 介导的中性粒细胞功能障碍（通过降低 CD88 表达来确定）是随后发生医院获得性感染的强烈预测因素（相对风险，5.8；95%置信区间，1.5-22；P =.0007），并且在生存分析中仍然独立于时间效应（危险比，5.0；95%置信区间，1.3-8.3；P =.01）。总之，这项研究为危重病患者免疫功能低下的机制提供了新的见解，并为医院获得性感染的治疗和预防提供了新的途径。
