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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3841.
APC: braking neutrophils to benefit patients?HARVARD SCHOOL OF PUBLIC HEALTH
Higher plasma concentrations of activated protein C (APC) associate with improved survival during sepsis, and exogenous APC decreases neutrophil chemotaxis and recruitment, suggesting that the actions of APC on neutrophils may be a critical determinant of outcome during severe sepsis.
The mechanisms by which APC protects septic patients remain speculative. Neutrophils express receptors for APC, and recombinant APC inhibits neutrophil chemotaxis in vitro.2 Nick and colleagues hypothesized that rhAPC may decrease neutrophil recruitment in tissues, and in the current issue they report results confirming this hypothesis. rhAPC or saline was administered by intravenous infusion to healthy human volunteers, and a bolus of bacterial lipopolysaccharide was delivered to the air spaces of the lungs by instillation. rhAPC decreased neutrophil recruitment to the alveolar air spaces, measured using bronchoalveolar lavage. Furthermore, neutrophils recovered from the air spaces of subjects receiving rhAPC were defective in chemotaxis in vitro when compared with neutrophils recovered from subjects receiving saline. Supporting a direct effect of APC on neutrophils, Nick et al confirmed that rhAPC in vitro is sufficient to decrease chemotaxis of normal blood neutrophils in a dose-response fashion. Therefore, rhAPC decreases the ability of human neutrophils to migrate toward chemokines in vitro and to an inflammatory site in vivo. Excessive sequestration and emigration of neutrophils can contribute to tissue injury and the pathophysiology of sepsis. Is the ability of APC to decrease neutrophil recruitment responsible for the beneficial effects of endogenous and exogenous1 APC during sepsis? Several facts bear consideration. First, it cannot be determined from these studies whether neutrophil recruitment is indeed diminished by APC during sepsis. A single instillation of lipopolysaccharide in the lungs differs meaningfully from severe systemic infection. Second, decreasing neutrophil recruitment may or may not benefit patients with severe sepsis. While neutrophils can damage tissue, they also kill bacteria. More than half of the patients in the study by Liaw et al were diagnosed with primary infections in the lung. Decreased neutrophil recruitment in the lungs, as in the study by Nick et al, could adversely affect pulmonary host defenses. Thus, the influence of APC on neutrophil recruitment may be beneficial or detrimental during infection, determined by the degree to which neutrophils are effecting tissue injury and bacterial killing, and by the degree to which tissue injury or bacterial burden is pathogenetic. Third, APC is more than just an inhibitor of neutrophil chemotaxis. Effects of APC on cells other than neutrophils (such as endothelial cells or monocytes) or on processes other than chemotaxis (such as coagulation, fibrinolysis, apoptosis, or gene expression) may significantly contribute to protection during infection. The studies in this issue of Blood demonstrate that APC associates with improved survival during severe sepsis and diminishes neutrophil recruitment. These important findings raise the question of whether endogenous and exogenous APC benefits patients with severe sepsis by limiting neutrophil recruitment. References
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
