Regulation of neutrophil migration by Activated Protein C

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): Sepsis is a serious medical condition in critical care patients caused by systemic inflammatory response resulting from infection. Severe sepsis, defined as sepsis associated with acute organ dysfunction, is an increasing cause of morbidity and mortality among children and adults, and has been one of the most significant challenges in critical care. Given the complexity of the systemic inflammatory response to infection, it is not surprising that many targeted therapies in sepsis have not been able to improve survival. Recombinant human activated protein C (rhAPC) was the first drug approved by the FDA for this indication, given the results of a large clinical trial. However, more recently its broad application has been questioned. In order to optimize the benefit of the drug, it is important to understand its mechanisms by which rhAPC exerts its beneficial effects on organ function and survival rate in sepsis. Migration of leukocytes to infection sites is vital for pathogen clearance and thus, host survival. Interaction of cell surface integrins with their counterpart ligands, which are expressed on the endothelial surface, results in the localization and adherence of circulating neutrophils to endothelial cells. This is followed by neutrophil activation and directed migration to sites of infection through the extracellular matrix. An important function of integrins is to concentrate neutrophils at the infection site, ensuring that their immune products and activities remain at this site, while minimizing unnecessary injury to uninfected tissues. During sepsis, tissue injury results from excessive infiltration and sequestration of activated neutrophils caused by dysregulation of cell surface integrins. Our preliminary data show that rhAPC inhibits neutrophil adhesion and migration on extracellular matrix proteins by directly blocking leukocyte integrins (21 and 23 integrins) on neutrophil surface. Therefore, we propose that leukocyte integrins are novel cellular receptors for APC and the specific interaction of APC with the integrins inhibits neutrophil migration. We hypothesize that the ability of rhAPC to affect neutrophil migration provides a key mechanism for its beneficial effects in sepsis. We will 1) identify specific neutrophil integrins those bind to rhAPC, 2) investigate whether blocking of the rhAPC binding integrins recapitulates the beneficial effect of rhAPC on the survival rate after sepsis, and 3) develop a novel recombinant high affinity rhAPC to the neutrophil integrins. This study should enhance our understanding of the role of APC in sepsis and would be useful in the design of a novel therapeutic approach to treat severe inflammation. PUBLIC HEALTH RELEVANCE: Project Narrative Severe sepsis, defined as sepsis associated with acute organ dysfunction, is an increasing cause of morbidity and mortality among children and adults, and has been one of the most significant challenges in critical care. Recently, a recombinant form of human activated protein C (rhAPC or drotrecogin alfa activated;known commercially as "Xigris") was approved by FDA for the treatment of severe sepsis with a high risk of mortality, but the mechanisms by which rhAPC protects septic patients remain largely unknown. This study will determine the molecular mechanisms for the interaction of APC with leukocyte integrins and its therapeutical implications in sepsis, which would lead to the design of a novel therapeutic approach to treat severe inflammation.