Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

✍ Scribed by 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; Paul Ng; Peggy Lum; Claudia Hirth-Dietrich; Adrian Tomkinson; David A. Brenner

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 373 KB
• Volume: 40
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.20425

✦ Synopsis

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 ␣-actin (␣-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 ␣-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. (HEPATOLOGY 2004;40:1106 -1115.