Blockade of neutrophil elastase attenuates severe liver injury in hepatitis B transgenic mice
Blockade of neutrophil elastase attenuates severe liver injury in hepatitis B transgenic mice
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DOI：
10.1128/jvi.79.24.15142-15150.2005
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发表时间：
2005-12-01
影响因子：
5.4
通讯作者：
Moriwaki, H
中科院分区：
文献类型：
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作者：
Takai, S;Kimura, K;Moriwaki, H
多形核中性粒细胞产生的丝氨酸蛋白酶在炎症部位中性粒细胞介导的组织损伤中起重要作用。尽管中性粒细胞向肝脏募集已被证明参与肝脏炎症的加剧，但中性粒细胞弹性蛋白酶（NE）在肝损伤中的功能尚不清楚。本研究发现，在将抗原特异性细胞毒性T淋巴细胞（ctl）注射到乙肝病毒转基因小鼠体内后8至24小时，给予NE抑制剂（NEI）可降低血清丙氨酸转氨酶（sALT）活性和肝脏炎症细胞浸润。此外，NEI治疗降低了肝脏中炎症细胞因子和趋化因子的表达以及巨噬细胞产生的肿瘤坏死因子α。此外，NEI处理在CTL注射后8 h抑制肝脏中性粒细胞CC趋化因子配体3 （CCL-3）、CCL-4和巨噬细胞炎症蛋白2 (MIP-2) mRNA表达。为了支持这些结果，我们证实了抗ccl -3、抗ccl -4和抗mip -2单克隆抗体抑制了sALT活性和白细胞向肝脏的迁移。总之，目前的研究结果表明，NEIs有助于急性病毒性肝炎炎症级联的早期步骤，并且NEIs可能有潜力作为治疗急性重型病毒性肝炎的药物。
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.