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The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury.
Transplantation. 2010 May 15; 89(9):1050-6.T

Abstract

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.

Authors+Show Affiliations

Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20160675

Citation

Uchida, Yoichiro, et al. "The Protective Function of Neutrophil Elastase Inhibitor in Liver Ischemia/reperfusion Injury." Transplantation, vol. 89, no. 9, 2010, pp. 1050-6.
Uchida Y, Freitas MC, Zhao D, et al. The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. Transplantation. 2010;89(9):1050-6.
Uchida, Y., Freitas, M. C., Zhao, D., Busuttil, R. W., & Kupiec-Weglinski, J. W. (2010). The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. Transplantation, 89(9), 1050-6. https://doi.org/10.1097/TP.0b013e3181d45a98
Uchida Y, et al. The Protective Function of Neutrophil Elastase Inhibitor in Liver Ischemia/reperfusion Injury. Transplantation. 2010 May 15;89(9):1050-6. PubMed PMID: 20160675.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. AU - Uchida,Yoichiro, AU - Freitas,Maria Cecilia S, AU - Zhao,Danyun, AU - Busuttil,Ronald W, AU - Kupiec-Weglinski,Jerzy W, PY - 2010/2/18/entrez PY - 2010/2/18/pubmed PY - 2010/5/29/medline SP - 1050 EP - 6 JF - Transplantation JO - Transplantation VL - 89 IS - 9 N2 - 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. SN - 1534-6080 UR - https://www.unboundmedicine.com/medline/citation/20160675/The_protective_function_of_neutrophil_elastase_inhibitor_in_liver_ischemia/reperfusion_injury_ L2 - http://dx.doi.org/10.1097/TP.0b013e3181d45a98 DB - PRIME DP - Unbound Medicine ER -