Caspase-1-inhibitor ac-YVAD-cmk reduces LPS-lethality in rats without affecting haematology or cytokine responses.
The effect of acetyl - tyrosyl-valyl-alanyl-aspartyl - chloromethylketone (ac-YVAD-cmk), an irreversible caspase-1 (IL-1beta converting enzyme, ICE) inhibitor on mortality, leukocyte and platelet counts and cytokine levels was investigated in a double-blind rat model of endotoxaemia. Intravenous (i.v.) bolus administration of lipopolysaccharide (LPS) (25-75 mg kg(-1), n=12 per group) to anaesthetized rats induced a dose dependent increase in mortality over 8 h (LD(50)=48 mg kg(-1)). During this period, animals became leukopenic and thrombocytopenic. Serum levels of IL-beta, IL-6, and TNF-alpha were highly elevated. Pretreatment of rats with ac-YVAD-cmk at a dose of 12.5 micromol kg(-1) significantly reduced mortality from 83 to 33% using Log Rank analysis. However, ac-YVAD-cmk did not modify blood cell counts or cytokine profiles as compared with the LPS-drug vehicle group. These data lay credence to the potential importance of caspase-1-inhibition in modifying the inflammatory response to endotoxin. Further investigations are warranted in understanding the relationship between caspase-1 inhibition, cytokine production and animal survival in different experimental paradigms of sepsis.
Mathiak
G
G
I. Department of Surgery, University of Cologne, Cologne, Germany. guenther.mathiak@uni-koeln.de
Grass
G
G
Herzmann
T
T
Luebke
T
T
Zetina
C C
CC
Boehm
S A
SA
Bohlen
H
H
Neville
L F
LF
Hoelscher
A H
AH
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D007970:Leukopenia / Q000209:etiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000209:etiology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone