Cellular Mechanisms of Sepsis and Organ Failure

Washington University, Saint Louis MO

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Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Patients with sepsis are characterized by defects in both the innate and adaptive immune system. During sepsis there is an extensive apoptosis induced loss of lymphocytes that has highly negative consequences on the host's immune competence. Apoptosis of lymphocytes not only results in depletion of key helper and effector lymphocytes but also results in an impaired innate immune response because of the intimate feedback or 'cross-talk' between the innate and adaptive immune systems. [unreadable] Furthermore, apoptotic lymphocytes are engulfed by macrophages and dendritic cells and this process results in immune suppression or apoptosis in these scavenger cells as well. Given the above, it is not surprising that numerous laboratories have demonstrated using a variety of strategies that prevention of lymphocyte death can improve sepsis survival. This is the focus of the current application. [unreadable] An important finding in research investigating the life and death of lymphocytes is the critical role of accessory stimuli in determining cell fate. Once a B or T cell has been activated, many factors are involved in the cell's decision to undergo proliferation or apoptosis. In this proposal, selected molecules that have anti-apoptotic activity in lymphocytes will be administered to determine if sepsis induced lymphocyte apoptosis can be ameliorated. Effects of anti-apoptotic therapy on cytokine profiles and survival in a clinically relevant murine sepsis model will be evaluated. [unreadable] [unreadable]