Sivelestat reduces inflammatory mediators and preserves neutrophil deformability during simulated extracorporeal circulation.
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 micromol/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.
Matsuzaki
Kanji
K
Department of Cardiovascular Surgery, Institute of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Hiramatsu
Yuji
Y
Homma
Satoshi
S
Sato
Shoko
S
Shigeta
Osamu
O
Sakakibara
Yuzuru
Y
D000199:Actins / Q000096:biosynthesis / Q000097:blood; D039481:CD11b Antigen / Q000096:biosynthesis / Q000097:blood; D015815:Cell Adhesion Molecules / Q000187:drug effects; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000097:blood; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005112:Extracorporeal Circulation; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000097:blood; D019041:L-Selectin / Q000096:biosynthesis / Q000097:blood; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008955:Models, Cardiovascular; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D000199:Actins; D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; D002630:Chemotactic Factors; D018836:Inflammation Mediators; D016209:Interleukin-8; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D019041:L-Selectin; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine