C5a mediates peripheral blood neutrophil dysfunction in critically ill patients.
C5a mediates peripheral blood neutrophil dysfunction in critically ill patients.
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DOI：
10.1164/rccm.200812-1928oc
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发表时间：
2009-07-01
影响因子：
24.7
通讯作者：
Simpson AJ
中科院分区：
文献类型：
--
作者：
Conway Morris A;Kefala K;Wilkinson TS;Dhaliwal K;Farrell L;Walsh T;Mackenzie SJ;Reid H;Davidson DJ;Haslett C;Rossi AG;Sallenave JM;Simpson AJ
危重病人极易感染医院获得性感染。危重病患者的中性粒细胞功能仍知之甚少。目的探讨危重病患者外周血中性粒细胞(PBN)功能障碍的特点和机制。以确定发炎的肺是否造成额外的吞噬功能障碍。前瞻性采集疑似呼吸机相关性肺炎患者和年龄性别匹配的志愿者的血液和支气管肺泡灌洗液；中性粒细胞功能的实验室分析。研究对象包括72名患者和21名志愿者。患者PBN的吞噬能力比志愿者低36%(P<；0.0001)。在几个生物学上可信的候选者中，只有激活的补体与PBN吞噬功能受损显著相关(P<；0.0001)。吞噬功能与血清C3a呈负相关，与PBN表面C5a受体1型(CD88)表达呈正相关。C5a在体外可抑制PBN的吞噬功能，显著下调CD88的表达。C5a介导的吞噬损伤可通过阻断CD88或磷脂酰肌醇3-激酶而被阻止，并被粒细胞-巨噬细胞集落刺激因子完全逆转。C5a还削弱了PBN对铜绿假单胞菌的杀灭和迁移，表明这种作用并不限于吞噬作用。患者的支气管肺泡灌洗液白细胞功能也明显受损，灌洗上清液使健康中性粒细胞吞噬功能降低43%(P=0.0001)。但灌洗液不影响CD88的表达，CD88抗体不能阻断灌洗液介导的吞噬功能损伤。危重病患者存在明显的PBN功能障碍，其主要由激活的补体介导。此外，严重的补体非依赖性中性粒细胞功能障碍发生在发炎的肺中。
Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood. To characterize and define mechanisms of peripheral blood neutrophil (PBN) dysfunction in critically ill patients. To determine whether the inflamed lung contributes additional phagocytic impairment. Prospective collection of blood and bronchoalveolar lavage fluid from patients with suspected ventilator-associated pneumonia and from age- and sex-matched volunteers; laboratory analysis of neutrophil functions. Seventy-two patients and 21 volunteers were included. Phagocytic capacity of PBNs was 36% lower in patients than in volunteers (P < 0.0001). From several biologically plausible candidates only activated complement was significantly associated with impaired PBN phagocytosis (P < 0.0001). Phagocytosis was negatively correlated with serum C3a and positively correlated with expression of C5a receptor type 1 (CD88) on PBNs. C5a recapitulated impaired PBN phagocytosis and significantly down-regulated CD88 expression in vitro. C5a-mediated phagocytic impairment was prevented by blocking either CD88 or phosphoinositide 3-kinase, and completely reversed by granulocyte-macrophage colony-stimulating factor. C5a also impaired killing of Pseudomonas aeruginosa by, and migration of, PBNs, indicating that effects were not restricted to phagocytosis. Bronchoalveolar lavage fluid leukocytes from patients also demonstrated significantly impaired function, and lavage supernatant reduced phagocytosis in healthy neutrophils by 43% (P = 0.0001). However, lavage fluid did not affect CD88 expression and lavage-mediated impairment of phagocytosis was not blocked by anti-CD88 antibody. Critically ill patients have significant dysfunction of PBNs, which is mediated predominantly by activated complement. Further, profound complement-independent neutrophil dysfunction occurs in the inflamed lung.