Caspase-1-inhibitor ac-YVAD-cmk reduces LPS-lethality in rats without affecting haematology or cytokine responses

Abstract

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.

Figure 1

Mortality profile of ac-YVAD-cmk treated rats in a model of endotoxaemia. Rats were pretreated with the various doses of ac-YVAD-cmk 30 min prior to an i.v. administration of LPS (65 mg kg⁻¹).

Figure 2

Leukocyte (a) and Platelet (b) counts in ac-YVAD-cmk-treated and non-treated rats. Thirty minutes prior to an i.v. bolus administration of LPS (65 mg kg⁻¹). Data are means±s.d.

Figure 3

Effect of various doses of ac-YVAD-cmk on serum cytokine levels in a rat model of endotoxaemia (a) IL-1β, (b) IL-6, (c) TNF-α. Data are means±s.d.