Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte.
Sepsis induces lymphocyte apoptosis and prevention of lymphocyte death may improve the chances of surviving this disorder. We compared the efficacy of a selective caspase-3 inhibitor to a polycaspase inhibitor and to caspase-3-/- mice. Both inhibitors prevented lymphocyte apoptosis and improved survival. Caspase-3-/- mice shared a decreased, but not total, block of apoptosis. The polycaspase inhibitor caused a very substantial decrease in bacteremia. Caspase inhibitors did not benefit RAG-1-/- mice, which had a > tenfold increase in bacteremia compared to controls. Adoptive transfer of T cells that overexpressed the anti-apoptotic protein Bcl-2 increased survival. T cells stimulated with anti-CD3 and anti-CD28 produced increased interleukin 2 and interferon gamma by 6 h. Thus, caspase inhibitors enhance immunity by preventing lymphocyte apoptosis and lymphocytes act rapidly, within 24 h, to control infection.
Hotchkiss
R S
RS
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. hotch@morpheus.wustl.edu
Chang
K C
KC
Swanson
P E
PE
Tinsley
K W
KW
Hui
J J
JJ
Klender
P
P
Xanthoudakis
S
S
Roy
S
S
Black
C
C
Grimm
E
E
Aspiotis
R
R
Han
Y
Y
Nicholson
D W
DW
Karl
I E
IE
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D015169:Colony Count, Microbial; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018398:Homeodomain Proteins; D007376:Interleukin-2; C064658:RAG-1 protein; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases