Sivelestat Reduces Inflammatory Mediators and Preserves Neutrophil Deformability During Simulated Extracorporeal Circulation

• Published in: The Annals of thoracic surgery Vol. 80; no. 2; pp. 611 - 617
• Main Authors: Matsuzaki, Kanji, Hiramatsu, Yuji, Homma, Satoshi, Sato, Shoko, Shigeta, Osamu, Sakakibara, Yuzuru
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.2005; Elsevier Science
• Subjects: Actins - biosynthesis; Actins - blood; Biological and medical sciences; CD11b Antigen - biosynthesis; CD11b Antigen - blood; Cell Adhesion Molecules - drug effects; Chemotactic Factors - biosynthesis; Chemotactic Factors - blood; Chemotaxis, Leukocyte - drug effects; Extracorporeal Circulation; Glycine - analogs & derivatives; Glycine - pharmacology; Humans; Inflammation Mediators - blood; Inflammation Mediators - immunology; Interleukin-8 - biosynthesis; Interleukin-8 - blood; L-Selectin - biosynthesis; L-Selectin - blood; Leukocyte Elastase - antagonists & inhibitors; Medical sciences; Models, Cardiovascular; Neutrophils - drug effects; Neutrophils - immunology; Serine Proteinase Inhibitors - pharmacology; Sulfonamides - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the respiratory system; Deformability; Sivelestat; Treatment; Respiratory disease; Surgery; Granulocyte; Inflammation; Mediator; Thorax; Neutrophil
• ISSN: 0003-4975; 1552-6259
• DOI: 10.1016/j.athoracsur.2005.02.038

Neutrophil is a major focus in efforts to ameliorate the systemic inflammatory response associated with cardiopulmonary bypass. Neutrophil elastase is a powerful proteolytic enzyme, and plays a pivotal role in the development of the inflammatory response. This study assesses the inhibitory effects of sivelestat, a highly specific neutrophil elastase inhibitor, on elastase levels, cytokine production, and the functional changes of neutrophils in a simulated extracorporeal circulation model. Simulated recirculation was established by recirculating heparinized (3.75 U/mL) human blood for 120 minutes in an oxygenator and a roller pump circuit with and without 100 μmol/L of sivelestat (n = 7 for each group). Neutrophil elastase and interleukin-8 were measured with an enzyme immunoassay. Neutrophil deformability was evaluated by simulated microcapillaries. The neutrophil F-actin and the expression of CD11b and L-selectin were measured by flow cytometry. Sivelestat reduced both neutrophil elastase levels ( p = 0.0006) and interleukin-8 production ( p < 0.0001) at 120 minutes of recirculation. Sivelestat also significantly preserved neutrophil deformability ( p = 0.017) and reduced F-actin expression ( p = 0.0037). The drug did not modulate the changes of CD11b or L-selectin. This study suggests that specific elastase inhibition with sivelestat could be a feasible therapeutic strategy for patients undergoing cardiopulmonary bypass to attenuate neutrophil-derived inflammatory response and organ injuries.