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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3878-3885. Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-06-2140. This Article Full Text (PDF) Erratum (v105,p3785) All Versions of this Article: 2004-06-2140v1 104/13/3878    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nick, J. A Articles by Abraham, E. Search for Related Content PubMed PubMed Citation Articles by Nick, J. A Articles by Abraham, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 4, 2004 Accepted August 7, 2004 Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis Jerry A Nick*, Christopher D Coldren, Mark W Geraci, Katie R Poch, Brian W Fouty, James O'Brien, Michael Gruber, Simona Zarini, Robert C Murphy, Katherine Kuhn, Don Richter, Kelly R Kast, and Edward Abraham Department of Medicine, National Jewish Medical and Research Center, Denver, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA Department of Medicine, National Jewish Medical and Research Center, Denver, CO, USA Department of Pediatrics and Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO, USA * Corresponding author; email: nickj{at}njc.org. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: APC: braking neutrophils to benefit patients? Joseph P. Mizgerd Blood 2004 104: 3841. [Full Text] [PDF] This article has been cited by other articles: H. F. Galley, N. E. El Sakka, N. R. Webster, D. A. Lowes, and B. H. 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