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‐1β 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‐β, IL‐6, and TNF‐α were highly elevated. Pretreatment of rats with ac‐YVAD‐cmk at a dose of 12.5 μmol 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. British Journal of Pharmacology (2000) 131 , 383–386; doi: 10.1038/sj.bjp.0703629