Prevention of leukocyte activation by the neutrophil elastase inhibitor, sivelestat, in the hepatic microcirculation after ischemia-reperfusion.
BACKGROUND
Liver ischemia-reperfusion (I/R) injury is one of the most serious complications of hepatic surgery. However, no effective treatment is yet clinically available. Although neutrophil elastase inhibitor (NEI) has been used clinically in acute lung injury, the effect of NEI on leukocyte dynamics in the liver microcirculation after hepatic I/R remained unclear. The purpose of this study was to use intravital microscopy (IVM) to evaluate the effect of NEI on leukocyte dynamics in the liver microcirculation after hepatic I/R.


METHODS
Hepatic ischemia was induced in male Sprague-Dawley (SD) rats. Sivelestat, a specific NEI, or normal saline (NS) was given as a continuous intravenous infusion before ischemia. The number of adherent leukocytes and the disturbances of sinusoidal perfusion in hepatic microcirculation were observed up to 120 min after reperfusion. Samples of liver tissue and blood were taken for histological examination and measurement of liver enzymes and tissue malondialdehyde (MDA).


RESULTS
Compared with NS, sivelestat significantly decreased the number of adherent leukocytes and prevented perfusion disturbance. In addition, sivelestat obviously improved liver injury as assessed by histological findings and liver enzymes, and prevented the increase of MDA.


CONCLUSIONS
Administration of sivelestat before ischemia effectively suppressed the activation of leukocytes and lipid peroxide, and it consequently prevented hepatic I/R injury.
Nakano
Yoritaka
Y
Department of Surgery, Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Kondo
Tadashi
T
Matsuo
Ryota
R
Murata
Soichiro
S
Fukunaga
Kiyoshi
K
Ohkohchi
Nobuhiro
N
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007962:Leukocytes / Q000187:drug effects* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D023421:Models, Animal; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010196:Pancreatic Elastase; D005998:Glycine