Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis

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Abstract
The pathophysiology of sepsis involves excessive lymphocyte apoptosis, which correlates with adverse outcomes, and disordered cytokine production, which may promote host injury. As the protease inhibitor (PI) class of antiretroviral agents is known to prevent apoptosis in vitro, we evaluated their effect on survival, lymphocyte apoptosis, and consequent cytokine production in mice with sepsis induced by cecal ligation and perforation. Mice pretreated with PIs have improved survival (67%; PPPPP<0.05) late in sepsis; despite no intrinsic antibacterial effects, PI also reduced quantitative bacterial blood cultures. The beneficial effects of PI appear to be specific to lymphocyte apoptosis, as lymphocyte-deficient Rag1−/− mice did not experience benefit from treatment with PI. Thus, inhibition of lymphocyte apoptosis by PI is a candidate approach for the treatment of sepsis.—Weaver, J. G. R., Rouse, M. S., Steckelberg, J. M., Badley, A. D. Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis.
Funding Information
  • National Institutes of Health (R01 AI40384-06, R21 AI54187-01A1)