Blockade of neutrophil elastase attenuates severe liver injury in hepatitis B transgenic mice.
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.
Takai
Shinji
S
First Department of Internal Medicine, Gifu University School of Medicine, Gifu-shi, Gifu 501-1194, Japan. hmori@cc.gifu-u.ac.jp.
Kimura
Kiminori
K
Nagaki
Masahito
M
Satake
Shinichi
S
Kakimi
Kazuhiro
K
Moriwaki
Hisataka
H
D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006470:Hemorrhage / Q000150:complications*; D006509:Hepatitis B / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000473:pathology* / Q000821:virology; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D018925:Chemokines; D004791:Enzyme Inhibitors; D019272:Leukocyte Elastase