APC: braking neutrophils to benefit patients?

Comment on Nick et al, page 3878, and comment on Liaw et al, page 3958

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 observation that recombinant human activated protein C (rhAPC) improves survival among patients with severe sepsis¹  has intensified interest in the biology of APC in infection. Previous studies of endogenous APC were limited by the resolution of available assays. In the present issue, Liaw and colleagues used a more sensitive antibody capture assay system to accurately quantify APC concentrations in plasma samples from patients with severe sepsis. Circulating APC was detected in all patients. Liaw et al postulated that the variability in plasma APC concentrations may be due to differences in the ability to activate protein C and may be functionally significant. Consistent with this, APC concentrations were higher in plasma from patients who survived sepsis compared with those who did not. Alongside evidence that exogenous APC improves survival,¹  these results suggest that endogenous APC serves protective functions, and more is better, 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.