Activated Protein C in Sepsis

Sepsis, also known as systemic inflammatory response syndrome (SIRS) by infection, is a serious medical condition caused by inflammatory response which leads to secretion of pro- and anti-inflammatory cytokines, activation and migration of leukocytes, activation of coagulation and inhibition of fibrinolysis, and increased apoptosis. 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 activated protein C (rhAPC or drotrecogin alfa activated; commercially as “Xigris”) was approved by FDA for the treatment severe sepsis and a high risk of mortality.

Despite the ability of rhAPC to improve survival among patients with severe sepsis, the mechanisms by which APC protects septic patients remain largely unknown. Although initial hypotheses focused on antithrombotic and profibrinolytic functions of APC in sepsis, other agents that also have potent effects on such pathways did not demonstrate the same clinical benefit in severe sepsis as was seen with rhAPC. Excessive sequestration and infiltration of neutrophils through dysregulated cell surface adhesion molecules, integrins, is another known factor that contributes to tissue injury and the pathophysiology of sepsis.

Crystal structure of human activated protein C.

Therefore, we hypothesize that the ability of rhAPC to affect neutrophil functions, particularly those associated with neutrophil migration, provides an additional potential mechanism for its beneficial effects in sepsis. We will determine the effects of rhAPC on the integrin mediated neutrophil migration. We will also test anti-adhesion agents against leukocyte integrins, together with rhAPC and the advantages of the combined therapy in sepsis. This study should enhance our understanding of the role of APC in sepsis and would be useful in the design of a new therapeutic approach.

References

  1. GF Elphick, PP Sarangi, Y-M Hyun, JA Hollenbaugh, A Ayala, WL Biffl, H-L Chung, AR Rezaie, JL McGrath, DJ Topham, JS Reichner, and Kim M. 2009 Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood Feb 24. [Epub ahead of print].
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