Targeting tissue inhibitor of metalloproteinase 1/2 using a shRNA lentiviral system offers a novel treatment strategy against hepatic fibrosis

Hepatic fibrosis is a result of constant wound-healing response caused by repeated injury in liver. Up to now, there is still no standard treatment for this disease. Tissue inhibitors of metalloproteinase (TIMP) 1/2 have been described to be highly expressed in liver with hepatic fibrosis. However, whether the down-regulation of these two proteins would show protective or curative effect against hepatic fibrosis remains to be defined. In this study, using a shRNA lentiviral system, we investigated the effect of TIMP1/2 down-regulation against hepatic fibrosis on a rat model. Our results showed that specifically knock-down of TIMP1 or TIMP2 could significantly alleviate the severity of hepatic fibrosis. Further study also showed that matrix metalloproteinase (MMP)-1 and MMP-13 were significantly increased in rats with TIMP1/2 knock-down. Signaling pathway analysis by RT-PCR and western blot further revealed that the altered expression of TGF-β1-Smad signaling pathway proteins including TGF-β1, Smad3 and Smad7 was modulated back to normal levels in TIMP1/2 knock-down rats. Taken together, our study revealed that specifically knocking-down of TIMP1 or TIMP2 by shRNA lentiviral particles could increase the expression of MMP-1 and MMP-13 and alleviate the severity of hepatic fibrosis, probably via TGF-β1-Smad signaling pathway. The findings in this study imply a novel treatment strategy against hepatic fibrosis.