title: ONO-6818, a novel, potent neutrophil elastase inhibitor, reduces inflammatory mediators during simulated extracorporeal circulation.
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.
authors.affiliation: Department of Cardiovascular Surgery, Institute of Clinical Medicine, University of Tsukuba, Tennodai, Tsukuba, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Homma
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Enomoto
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Jikuya
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Sakakibara
mesh_terms: D000199:Actins / Q000097:blood; D039481:CD11b Antigen / Q000097:blood; D002315:Cardiopulmonary Bypass; D015938:Complement Membrane Attack Complex / Q000032:analysis; D005112:Extracorporeal Circulation; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000097:blood; D019041:L-Selectin / Q000097:blood; D019272:Leukocyte Elastase / Q000097:blood; D008954:Models, Biological; D010069:Oxadiazoles / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*
chemical_list: D000199:Actins; D039481:CD11b Antigen; D015938:Complement Membrane Attack Complex; D016209:Interleukin-8; C419152:ONO 6818; D010069:Oxadiazoles; D011744:Pyrimidinones; D019041:L-Selectin; D019272:Leukocyte Elastase