Kimura K, Ando K, Ohnishi H, Ishikawa T, Kakumu S, Takemura M, Muto Y, Moriwaki H
First Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan.
Int Immunol. 1999 Sep;11(9):1491-500. doi: 10.1093/intimm/11.9.1491.
Liver fibrosis is commonly observed in chronic liver disease. However, the immunological mechanisms underlying hepatic fibrosis due to chronic inflammation are not well defined, mainly because suitable experimental models have not been established. We have found that weekly i.v. administration of concanavalin A (Con A) in BALB/c mice brought about a striking alanine aminotransferase increase, resulting in piecemeal necrosis with bridging fibrosis in the parenchyma. Using this fibrosis model, we demonstrated the kinetics of cytokine mRNA expression in liver. Transforming growth factor (TGF)-beta1, TGF-alpha, basic fibroblast growth factor (bFGF) and hepatocyte growth factor mRNAs were up-regulated after each Con A administration. Furthermore, either anti-IFN-gamma, anti-tumor necrosis factor (TNF)-alpha or anti-TGF-beta mAb given together with Con A markedly inhibited the development of hepatic fibrosis. Treatment with either anti-IFN-gamma or anti-TNF-alpha mAb also completely prevented hepatic injury; in contrast, treatment with anti-TGF-beta mAb did not. The treatment with anti-TGF-beta mAb did not affect the levels of hepatic mRNAs for either IFN-gamma or TNF-alpha after Con A injection. Treatment with either anti-IFN-gamma or anti-TNF-alpha did not affect the expression levels of TGF-beta in the liver. In conclusion, the continuous presence of both severe liver damage and up-regulation of TGF-beta synthesis is necessary to induce hepatic fibrosis in this model.
肝纤维化在慢性肝病中较为常见。然而，由于慢性炎症导致的肝纤维化的免疫机制尚未完全明确，主要是因为尚未建立合适的实验模型。我们发现，每周一次向BALB/c小鼠静脉注射伴刀豆球蛋白A（Con A）会导致显著的丙氨酸转氨酶升高，进而导致实质内出现碎片状坏死并伴有桥接纤维化。利用这个纤维化模型，我们展示了肝脏中细胞因子mRNA表达的动力学。每次注射Con A后，转化生长因子（TGF）-β1、TGF-α、碱性成纤维细胞生长因子（bFGF）和肝细胞生长因子的mRNA均上调。此外，与Con A一起给予抗干扰素-γ、抗肿瘤坏死因子（TNF）-α或抗TGF-β单克隆抗体（mAb）可显著抑制肝纤维化的发展。用抗干扰素-γ或抗TNF-α mAb治疗也完全预防了肝损伤；相比之下，用抗TGF-β mAb治疗则没有。注射Con A后，用抗TGF-β mAb治疗不影响肝脏中干扰素-γ或TNF-α的mRNA水平。用抗干扰素-γ或抗TNF-α治疗不影响肝脏中TGF-β的表达水平。总之，在该模型中，严重肝损伤和TGF-β合成上调的持续存在是诱导肝纤维化所必需的。
