title: C5a mediates peripheral blood neutrophil dysfunction in critically ill patients.
abstract: BACKGROUND
  Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Conway Morris
authors.forename: Kallirroi
authors.initials: K
authors.lastname: Kefala
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wilkinson
authors.forename: Kevin
authors.initials: K
authors.lastname: Dhaliwal
authors.forename: Lesley
authors.initials: L
authors.lastname: Farrell
authors.forename: Tim
authors.initials: T
authors.lastname: Walsh
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Mackenzie
authors.forename: Hamish
authors.initials: H
authors.lastname: Reid
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
authors.forename: Chris
authors.initials: C
authors.lastname: Haslett
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson