纤维化
肝星状细胞
细胞外基质
羟脯氨酸
四氯化碳
抗体
基质金属蛋白酶
四氯化碳
化学
金属蛋白酶组织抑制剂
金属蛋白酶
炎症
肝纤维化
酶谱
中和抗体
病理
内分泌学
医学
内科学
免疫学
生物化学
有机化学
作者
Christopher J. Parsons,Blair U. Bradford,Clark Q. Pan,Ellen Cheung,Michael Schauer,Andreas Knorr,Barbara Krebs,Sabine Kraft,Stefan Zahn,Bodo Brocks,Nikki Feirt,Baisong Mei,Myung-Sam Cho,Roopa Ramamoorthi,Greg Roldan,Phillip Ng,Peggy Lum,Claudia Hirth-Dietrich,Adrian Tomkinson,David A. Brenner
出处
期刊:Hepatology
[Wiley]
日期:2004-10-14
卷期号:40 (5): 1106-1115
被引量:172
摘要
Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which blocks matrix metalloproteinase (MMP) activity. TIMP-1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP-1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl(4)), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti-TIMP-1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl(4)-treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle alpha-actin (alpha-SMA). Compared to controls, rats administered anti-TIMP-1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti-TIMP-1 resulted in a marked decrease in alpha-SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP-2. In conclusion, administration of a TIMP-1 antibody attenuated CCl(4)-induced liver fibrosis and decreased HSC activation and MMP-2 activity.
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