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Ann Thorac Surg 2005;80:611-617
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

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

Departments of Cardiovascular Surgery and Cardiology, Institute of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

Accepted for publication February 9, 2005.

^_* Address reprint requests to Dr Hiramatsu, Department of Cardiovascular Surgery, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan (Email: yuji3{at}md.tsukuba.ac.jp).

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

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