Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats.
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.
Parsons
Christopher J
CJ
Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, USA.
Bradford
Blair U
BU
Pan
Clark Q
CQ
Cheung
Ellen
E
Schauer
Michael
M
Knorr
Andreas
A
Krebs
Barbara
B
Kraft
Sabine
S
Zahn
Stefan
S
Brocks
Bodo
B
Feirt
Nikki
N
Mei
Baisong
B
Cho
Myung-Sam
MS
Ramamoorthi
Roopa
R
Roldan
Greg
G
Ng
Paul
P
Lum
Peggy
P
Hirth-Dietrich
Claudia
C
Tomkinson
Adrian
A
Brenner
David A
DA
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009130:Muscle, Smooth / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000276:immunology / Q000502:physiology*
D000199:Actins; D000906:Antibodies; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D002251:Carbon Tetrachloride