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Antifibrotic effects of a tissue inhibitor of metalloproteinase‐1 antibody on established liver fibrosis in rats
Author(s) -
Parsons Christopher J.,
Bradford Blair U.,
Pan Clark Q.,
Cheung Ellen,
Schauer Michael,
Knorr Andreas,
Krebs Barbara,
Kraft Sabine,
Zahn Stefan,
Brocks Bodo,
Feirt Nikki,
Mei Baisong,
Cho MyungSam,
Ramamoorthi Roopa,
Roldan Greg,
Ng Paul,
Lum Peggy,
HirthDietrich Claudia,
Tomkinson Adrian,
Brenner David A.
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20425
Subject(s) - fibrosis , hepatic stellate cell , extracellular matrix , hydroxyproline , ccl4 , antibody , matrix metalloproteinase , carbon tetrachloride , chemistry , tissue inhibitor of metalloproteinase , metalloproteinase , inflammation , hepatic fibrosis , zymography , neutralizing antibody , pathology , endocrinology , medicine , immunology , biochemistry , organic chemistry
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 α‐actin (α‐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 α‐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. (H EPATOLOGY 2004.)