Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis.
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%; P<0.0005) compared with controls (17%) and a significant (P<0.05) reduction in lymphocyte apoptosis. Even mice receiving therapy beginning 4 h after perforation demonstrated improved survival (50%; P<0.05) compared with controls. PI therapy is also associated with an increase in the Th1 cytokine TNF-alpha (P<0.05) early in sepsis and a reduction in the Th2 cytokines IL-6 and IL-10 (P<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
Joel G R
JG
Division of General Surgery, University of Ottawa, Ottawa, Ontario, Canada.
Rouse
Mark S
MS
Steckelberg
James M
JM
Badley
Andrew D
AD
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002432:Cecum / Q000293:injuries; D016207:Cytokines / Q000097:blood; D004353:Drug Evaluation, Preclinical; D016983:Enterococcus / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D016654:Genes, RAG-1; D005856:Germ-Free Life; D007416:Intestinal Perforation / Q000150:complications; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008826:Microbial Sensitivity Tests; D019888:Nelfinavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016985:Streptococcus bovis / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology
D016207:Cytokines; D011480:Protease Inhibitors; D019888:Nelfinavir; D019438:Ritonavir