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

Joel G R Weaver, Mark S. Rouse, James M. Steckelberg, Andrew David Badley

Research output: Contribution to journalArticle

63 Citations (Scopus)

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%; 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-α (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.

Original languageEnglish (US)
Pages (from-to)1185-1191
Number of pages7
JournalFASEB Journal
Volume18
Issue number11
DOIs
StatePublished - Aug 2004

Fingerprint

Lymphocytes
proteinase inhibitors
Protease Inhibitors
Sepsis
lymphocytes
apoptosis
Apoptosis
cytokines
Cytokines
mice
Anti-Retroviral Agents
therapeutics
interleukin-10
pathophysiology
interleukin-6
Interleukin-10
Ligation
Interleukin-6
Blood
blood

Keywords

  • CLP
  • Cytokine
  • Lymphocyte
  • Protease inhibitor
  • SIRS

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis. / Weaver, Joel G R; Rouse, Mark S.; Steckelberg, James M.; Badley, Andrew David.

In: FASEB Journal, Vol. 18, No. 11, 08.2004, p. 1185-1191.

Research output: Contribution to journalArticle

Weaver, Joel G R ; Rouse, Mark S. ; Steckelberg, James M. ; Badley, Andrew David. / Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis. In: FASEB Journal. 2004 ; Vol. 18, No. 11. pp. 1185-1191.
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