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Journal of Virology, December 2005, p. 15142-15150, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15142-15150.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Blockade of Neutrophil Elastase Attenuates Severe Liver Injury in Hepatitis B Transgenic Mice

Shinji Takai,¹ Kiminori Kimura,^1, Masahito Nagaki,¹ Shinichi Satake,¹ Kazuhiro Kakimi,² and Hisataka Moriwaki^1*

First Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu-shi, Gifu 501-1194, Japan,¹ Department of Immunotherapeutics (Medinet), Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan²

Received 28 March 2005/ Accepted 15 September 2005

Serine proteinases produced by polymorphonuclear neutrophils play important roles in neutrophil-mediated tissue injury at inflammatory sites. Although neutrophil recruitment to the liver has been shown to be involved in the exacerbation of liver inflammation, the function of neutrophil elastase (NE) in liver injury remains unclear. Here, we found that administration of an NE inhibitor (NEI) reduced serum alanine aminotransferase (sALT) activity and inflammatory cell infiltration into the liver from 8 to 24 h after injection of antigen-specific cytotoxic T lymphocytes (CTLs) into hepatitis B virus transgenic mice. Furthermore, the NEI treatment reduced the expressions of inflammatory cytokines and chemokines in the liver and tumor necrosis factor alpha production by macrophages. In addition, the NEI treatment suppressed the mRNA expressions of CC chemokine ligand 3 (CCL-3), CCL-4, and macrophage inflammatory protein 2 (MIP-2) in neutrophils in the liver at 8 h after the CTL injection. In support of these results, we confirmed that administration of anti-CCL-3, anti-CCL-4, and anti-MIP-2 monoclonal antibodies suppressed sALT activity and leukocyte migration into the liver. In conclusion, the present results suggest that NE contributes to the early step of the inflammatory cascade in acute viral hepatitis and that NEIs may have potential as therapeutic drugs against acute severe viral hepatitis.

Present address: Center for Emerging Infectious Diseases, Gifu University, Gifu 501-1194, Japan.

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