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C5a Mediates Peripheral Blood Neutrophil Dysfunction in Critically Ill Patients

¹ Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh; ² Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh; and ³ Penicuik Health Centre, Penicuik, Scotland, United Kingdom

Correspondence and requests for reprints should be addressed to A. Conway Morris, M.D., Room C2.17, MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK. E-mail: mozza{at}doctors.org.uk

Rationale: Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood.

Objectives: 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.

Methods: 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.

Measurements and Main Results: 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.

Conclusions: 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.

Key Words: complement • natural immunity • intensive care • phagocytosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Neutrophil dysfunction occurs in critical illness but remains poorly characterized. Animal models of sepsis implicate C5a in this process. What This Study Adds to the Field This study provides the first human demonstration of C5a-mediated dysfunction of peripheral blood neutrophils in critical illness. The findings demonstrate that C5a-mediated dysfunction of peripheral blood neutrophils is preventable and reversible ex vivo, suggesting potential therapeutic avenues. Provides evidence that neutrophil dysfunction persists, but is independent of C5a, in the inflamed lung.