The Protective Function of Neutrophil Elastase Inhibitor in Liver Ischemia/Reperfusion Injury

• DOI: 10.1097/tp.0b013e3181d45a98
• Publication Date: 2010-03-18T09:40:39Z
• Authors: Yoichiro Uchida; Maria Cecilia S. ...; Danyun Zhao; Ronald W. Busuttil; Jerzy W. Kupiec-W...
• Keywords: Proinflammatory cytokine; Neutrophil elastase

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 liver inflammatory states. We recently documented importance NE pathophysiology ischemia/reperfusion injury, a local Ag-independent response. This study was designed to explore putative cytoprotective functions clinically available Sivelestat injury. METHODS.: Partial warm ischemia produced left and middle hepatic lobes C57BL/6 mice 90 min, followed by 6 or 24 hr reperfusion. The were given (100 mg/kg, subcutaneous) at 10 min before ischemia, reperfusion, 1 3 reperfusion thereafter. RESULTS.: significantly reduced serum alanine aminotransferase levels activity, when compared controls. Histological examination revealed that unlike controls, ameliorated hepatocellular damage decreased activity infiltration. expression proinflammatory cytokines (tumor necrosis factor-alpha interleukin-6), chemokines (CXCL-1, CXCL-2, CXCL-10), toll-like receptor 4 group, along diminished apoptosis through caspase-3 pathway. Moreover, vitro studies confirmed downregulation cytokine chemokine programs mouse macrophage cell cultures, depression innate signaling. CONCLUSION.: Sivelestat-mediated inhibition may represent an effective therapeutic option transplantation other disease