C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients
C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients
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DOI：
10.1182/blood-2010-08-304667
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发表时间：
2011-05-12
期刊：
影响因子：
20.3
通讯作者：
Simpson, A. John
中科院分区：
文献类型：
--
作者：
Morris, Andrew Conway;Brittan, Mairi;Simpson, A. John
危重病人发生院内感染的风险较高。过敏毒素C5a损害中性粒细胞的吞噬作用。然而，发生这种情况的机制和获得医院感染的相关性仍然不确定。我们的目的是表征C5a在体外和危重患者中抑制吞噬的机制，并确定C5a介导的功能障碍与获得院内感染之间的关系。在健康人中性粒细胞中，C5a显著抑制RhoA活化，阻止肌动蛋白聚合和吞噬作用。RhoA抑制是由PI3K δ介导的。对RhoA、肌动蛋白和吞噬的影响被GMCSF完全逆转。在危重患者的中性粒细胞中也进行了类似的观察，即吞噬功能受损与RhoA和肌动蛋白聚合的抑制有关，并被GM-CSF逆转。在60例危重患者队列中，c5a介导的中性粒细胞功能障碍（由CD88表达减少决定）是随后获得医院感染的一个强有力的预测因素（相对风险，5.8；95%可信区间，1.5-22;P = 0.0007），并且通过生存分析评估，与时间效应无关（风险比，5.0；95%可信区间，1.3-8.3;P = 0.01）。总之，这项研究为危重疾病中免疫功能低下的机制提供了新的见解，并为治疗和预防医院感染提供了新的途径。[血液杂志];2011;117(19):5178-5188。]
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 PI3K delta. The effects on RhoA, actin, and phagocytosis were fully reversed by GMCSF. 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. (Blood. 2011; 117(19): 5178-5188)