ONO-6818, a novel, potent neutrophil elastase inhibitor, reduces inflammatory mediators during simulated extracorporeal circulation.

Article Details

Citation

Copy to clipboard

Yoshimura Y, Hiramatsu Y, Sato Y, Homma S, Enomoto Y, Jikuya T, Sakakibara Y

ONO-6818, a novel, potent neutrophil elastase inhibitor, reduces inflammatory mediators during simulated extracorporeal circulation.

Ann Thorac Surg. 2003 Oct;76(4):1234-9.

PubMed ID

14530017 [ View in PubMed

]

Abstract

BACKGROUND: Among the serine proteases, neutrophil elastase is a powerful cytotoxic enzyme and plays a pivotal role in the inflammatory response associated with cardiopulmonary bypass. This study assesses the effects of the specific inhibition of neutrophil elastase by a novel, potent, low-molecular-weight neutrophil elastase inhibitor, ONO-6818. We hypothesized that ONO-6818 reduces inflammatory mediators and modulates adhesion molecules and the deformability of neutrophils during simulated extracorporeal circulation. METHODS: Simulated extracorporeal circulation was established by recirculating fresh heparinized (3.75 U/mL) human blood for 120 minutes in a membrane oxygenator and a roller pump with and without 1.0 micromol/L of ONO-6818 (n = 9 for control group, n = 7 for ONO-6818 group). The neutrophil adhesion molecules, CD11b and L-selectin, and the cytoplasmic F-actin of neutrophils were measured by flow cytometry. Neutrophil deformability was evaluated using simulated silicon microcapillaries. Neutrophil elastase, interleukin 8, and C5b-9 were measured using enzyme immunoassay. RESULTS: Neutrophil elastase levels were significantly lower in the ONO-6818 group. ONO-6818 significantly reduced interleukin 8 and C5b-9 production. ONO-6818 did not modulate changes of CD11b and L-selectin during recirculation. Cytoplasmic F-actin content and changes of neutrophil deformability did not significantly differ between the groups. CONCLUSIONS: Inhibition of neutrophil elastase activity with ONO-6818 reduces further interleukin 8 production and the formation of the complement membrane attack complex, and this results in a reduction of neutrophil elastase levels during simulated extracorporeal circulation. This study suggests that specific neutrophil elastase inhibition with ONO-6818 is a feasible therapeutic option to attenuate the exaggerated inflammatory response associated with cardiopulmonary bypass.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Freselestat	Neutrophil elastase	Protein	Humans	Unknown	Inhibitor	Details