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Effects of Recombinant Human Activated Protein C in Human Models of Endotoxin Administration

Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Edward Abraham, M.D., Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C272, Denver, CO 80262. E-mail: edward.abraham{at}uchsc.edu

ABSTRACT

Alterations in the generation of activated protein C (APC) as well as in the interactions of APC with the endothelial protein C receptor are present in severe sepsis and acute lung injury. Administration of recombinant human activated protein C (rhAPC) improves the survival of critically ill patients with sepsis, but the mechanisms by which rhAPC produces benefit are not well defined. Human models of systemic and pulmonary endotoxin exposure may provide important insights into the mechanisms of action of rhAPC in critical illness. In volunteers given systemic endotoxin, rhAPC had minimal effects on physiologic parameters, including blood pressure, markers of inflammation, and measures of sepsis-induced coagulopathy. In contrast, in the setting of pulmonary endotoxin exposure, rhAPC decreased neutrophil migration into the airspaces and also diminished neutrophil chemotaxis. Administration of rhAPC did not affect other parameters of neutrophil function, including kinase activation, production of proinflammatory cytokines, or apoptosis. Such results indicate that the effects of rhAPC in inhibiting the infiltration of neutrophils into the lungs and other inflammatory sites may contribute to its beneficial effects in sepsis.

Key Words: activated protein C • endotoxemia • endotoxin • protein C • sepsis • sepsis syndrome

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