title: Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis.
abstract: Recombinant human activated protein C (rhAPC) is a natural anticoagulant with potentially important anti-inflammatory properties. In humans with severe sepsis, rhAPC treatment reduces mortality, but mechanisms responsible have not been well characterized. Accumulation of activated neutrophils in the lungs and other organs during severe infection contributes to sepsis-induced organ dysfunction, including acute inflammatory lung injury. Because neutrophils express an APC receptor, we hypothesized that immunomodulatory effects of rhAPC occur, in part, via modulation of neutrophil responses. To examine this issue, we performed a double-blinded, placebo-controlled study of rhAPC in a human model of endotoxin-induced pulmonary inflammation. Administration of rhAPC significantly reduced leukocyte accumulation to the airspaces, independent of pulmonary cytokine or chemokine release. Neutrophils recovered from bronchoalveolar lavage fluid of volunteers receiving rhAPC demonstrated decreased chemotaxis ex vivo. Decreased neutrophil chemotaxis following exposure to rhAPC was confirmed in vitro. No differences were detected in gene expression, kinase activation, cytokine release, cell survival, or apoptosis of neutrophils recovered in the presence or absence of rhAPC. These studies demonstrate that rhAPC reduces both endotoxin-induced accumulation of leukocytes in the airspaces and neutrophil chemotaxis. These rhAPC-induced effects on neutrophil function may represent a mechanism by which rhAPC improves survival in patients with sepsis.
authors.affiliation: Department of Medicine, National Jewish Medical and Research Center, D202, 1400 Jackson St, Denver, CO 80206, USA. nickj@njc.org
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Nick
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
authors.forename: Katie R
authors.initials: KR
authors.lastname: Poch
authors.forename: Brian W
authors.initials: BW
authors.lastname: Fouty
authors.forename: James
authors.initials: J
authors.lastname: O'Brien
authors.forename: Michael
authors.initials: M
authors.lastname: Gruber
authors.forename: Simona
authors.initials: S
authors.lastname: Zarini
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Katherine
authors.initials: K
authors.lastname: Kuhn
authors.forename: Don
authors.initials: D
authors.lastname: Richter
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Kast
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D000293:Adolescent; D000328:Adult; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004311:Double-Blind Method; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004731:Endotoxins; D011486:Protein C; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases