Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis.
Lymphocyte apoptosis plays a central role in the pathophysiology of sepsis. Lymphocyte apoptosis was examined in mice with defective death receptor pathways due to transgenic expression of a dominant negative mutant of Fas-associated death domain (FADD-DN) or Bid-/- and in mice with defective mitochondrial-mediated pathways due to loss of Bim-/-, Puma-/-, or Noxa-/-. FADD-DN transgenic and Bid-/- mice had significant albeit incomplete protection, and this protection was associated with increased survival. Surprisingly, splenic B cells were also protected in FADD-DN mice although transgene expression was confined to T cells, providing evidence for an indirect protective mechanism. Bim-/- provided virtually complete protection against lymphocyte apoptosis whereas Puma-/- and Noxa-/- mice had modest or no protection, respectively. Bim-/- mice had improved survival, and adoptive transfer of splenocytes from Bim-/- mice into Rag 1-/- mice demonstrated that this was a lymphocyte intrinsic effect. The improved survival was associated with decreased interleukin (IL) -10 and IL-6 cytokines. Collectively, these data indicate that numerous death stimuli are generated during sepsis, and it therefore appears unlikely that blocking a single "trigger" can inhibit apoptosis. If siRNA becomes practical therapeutically, proapoptotic proteins would be potential targets.
Chang
Katherine C
KC
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Unsinger
Jacqueline
J
Davis
Christopher G
CG
Schwulst
Steven J
SJ
Muenzer
Jared T
JT
Strasser
Andreas
A
Hotchkiss
Richard S
RS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D053218:Receptors, Death Domain / Q000502:physiology*; D018805:Sepsis / Q000473:pathology*
D016207:Cytokines; D053218:Receptors, Death Domain; D053181:Caspase 8