The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury.
BACKGROUND.: A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia/reperfusion injury, a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver ischemia/reperfusion injury. METHODS.: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 hr of reperfusion. The mice were given Sivelestat (100 mg/kg, subcutaneous) at 10 min before ischemia, 10 min before reperfusion, and at 1 and 3 hr of reperfusion thereafter. RESULTS.: Sivelestat treatment significantly reduced serum alanine aminotransferase levels and NE activity, when compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), chemokines (CXCL-1, CXCL-2, and CXCL-10), and toll-like receptor 4 was significantly reduced in the treatment group, along with diminished apoptosis through caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of proinflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate toll-like receptor 4 signaling. CONCLUSION.: Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states.
Uchida
Yoichiro
Y
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Freitas
Maria Cecilia S
MC
Zhao
Danyun
D
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics; D017931:DNA Primers; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000517:prevention & control; D015850:Interleukin-6 / Q000235:genetics; D019272:Leukocyte Elastase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000097:blood; D016133:Polymerase Chain Reaction; D053491:Proteinase Inhibitory Proteins, Secretory / Q000627:therapeutic use*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D015427:Reperfusion Injury / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D017931:DNA Primers; D015850:Interleukin-6; D053491:Proteinase Inhibitory Proteins, Secretory; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; C069195:sivelestat; D009195:Peroxidase; D019272:Leukocyte Elastase; D005998:Glycine