Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice.
Caspase-9 is believed to play an essential role in sepsis-induced lymphocyte apoptosis. The aim of this study was therefore to evaluate its contribution within the caspase-dependent apoptosis pathway in a murine model of polymicrobial sepsis. Local injections of Z-LEHD-fmk, a specific caspase-9 inhibitor, into thymi of septic mice led to the complete inhibition of caspase-9, decreased apoptosis of resident tissue cells, and, in addition, reduced further downstream caspase-3 activity. In contrast to its systemic administration, only local injections improved the overall survival of septic mice. However, local injections of a pancaspase inhibitor (Z-VAD-fmk) did not improve survival, although caspase-3 activity was reduced to a similar degree as by the administration of Z-LEHD-fmk. These results indicate that local apoptosis of lymphatic tissue in polymicrobial sepsis is processed dependent of caspase-9 and suggests alternative caspase-dependent beneficial effects, which may determine a positive outcome.
Oberholzer
Caroline
C
Department of Trauma and Reconstructive Surgery, CHARITE-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
Tschoeke
Sven K
SK
Moldawer
Lyle L
LL
Oberholzer
Andreas
A
D000590:Amino Acid Chloromethyl Ketones; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality*; D015996:Survival Rate; D013950:Thymus Gland / Q000187:drug effects / Q000201:enzymology*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D009842:Oligopeptides; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053453:Caspase 9