The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen alpha1(I), TIMP-1 and MMP-2.
BACKGROUND
Pirfenidone (5 methyl-1-phenyl-2(1H)-pyridone) is a novel anti-fibrotic agent, which has been shown to decrease collagen deposition in a variety of animal models in vivo, and recently in hepatic fibrosis also. At cellular level, we have recently demonstrated that pirfenidone is able to inhibit proliferation of hepatic stellate cells induced by platelet-derived growth factor, as well as collagen type I accumulation and alpha1(I) procollagen mRNA expression.


OBJECTIVE
To evaluate if pirfenidone maintains its anti-fibrotic properties also when administered after the induction of hepatic damage and to further investigate the molecular mechanisms leading to the anti-fibrotic effect of pirfenidone.


RESULTS
Rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks received a liquid diet containing 0.5% pirfenidone starting from the third week. Pirfenidone treatment reduced the degree of liver injury, as determined by alanine aminotransferase values and necro-inflammatory score, which was associated with reduced hepatic stellate cells proliferation and collagen deposition. Treatment with dimethylnitrosamine increased transcripts levels for transforming growth factorbeta1, procollagen alpha1(I), tissue inhibitors of metalloproteinase-1 and matrix metalloproteinase-2 by 7-, 7-, 4- and 15-fold, respectively. Pirfenidone administration downregulated elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition.


CONCLUSIONS
(1) Pirfenidone is effective also if administered after the induction of the hepatic damage; (2) the anti-fibrotic effect of pirfenidone is mainly due to the reduced expression of profibrogenic procollagen alpha1(I) and TIMP-1, most likely through the downregulation of transforming growth factorbeta1 mRNA, and of matrix metalloproteinase-2, which is mainly implicated in the degradation of the normal extracellular matrix.
Di Sario
A
A
Gastrointestinal Unit, University of Ancona, Polo Didattico, III Piano, Via Tronto 10, 60020 Torrette, Ancona, Italy. a.disario@univpm.it
Bendia
E
E
Macarri
G
G
Candelaresi
C
C
Taffetani
S
S
Marzioni
M
M
Omenetti
A
A
De Minicis
S
S
Trozzi
L
L
Benedetti
A
A
D000818:Animals; D024042:Collagen Type I / Q000502:physiology*; D015536:Down-Regulation; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D011728:Pyridones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*
D024042:Collagen Type I; D011728:Pyridones; D019715:Tissue Inhibitor of Metalloproteinase-1; C093844:pirfenidone; D020778:Matrix Metalloproteinase 2