Liver Fibrosis in HCV Monoinfected and HIV/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs) and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors

Abstract

An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to liver fibrosis in patients with hepatitis C (HCV) infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated the potential for anti-HCV therapy to modulate MMP and TIMP levels in HCV subjects. We analyzed 83 plasma samples from 16 HCV monoinfected patients undergoing dual or triple anti-HCV therapy, 15 HIV/HCV coinfected patients with undetectable HIV load, and 10 healthy donors (HD). Levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, TIMP-1, and TIMP-2 were measured by a SearchLight Multiplex Immunoassay Kit. MMP-2 and MMP-9 were the highest expressed MMPs among all the analyzed samples and their levels significantly increased in HCV monoinfected and HIV/HCV coinfected subjects compared to HD. TIMP-1 levels were significantly higher in HCV and HIV/HCV subjects compared to HD and were correlated with liver stiffness. These findings raise the possibility of using circulating TIMP-1 as a non-invasive marker of liver fibrosis in HCV infection. A longitudinal study demonstrated that MMP-9 levels significantly decreased (40% reduction from baseline) in patients receiving dual as well as triple direct-acting antivirals (DAA) anti-HCV therapy, which had no effect on MMP-2, TIMP-1, and TIMP-2. As the dysregulation of MMP-2 and MMP-9 may reflect inflammatory processes in the liver, the decrease of MMP-9 following HCV protease inhibitor treatment suggests a positive effect on the reduction of liver inflammation.

Metalloproteinases in liver fibrosis: current insights

“…53,54 Thus, MMP-2-deficient mice show enhanced fibrosis after CCL 4 treatment and MMP-2 could be therefore critical for inhibiting type I collagen synthesis by activated HSCs, which strongly express this MMP. 55,56 MMP-9 and MMP-2 are elevated in serum and livers of patients with chronic hepatitis type B and C. [57][58][59] Elevated expression of MMPs in the mentioned fibrotic conditions was shown both in liver parenchyma 60 and portal macrophages. 57,61 Especially, MMP-9 seems to be involved in ongoing liver inflammation, 62 and its level drops after antiviral treatment.…”

“…55,56 MMP-9 and MMP-2 are elevated in serum and livers of patients with chronic hepatitis type B and C. [57][58][59] Elevated expression of MMPs in the mentioned fibrotic conditions was shown both in liver parenchyma 60 and portal macrophages. 57,61 Especially, MMP-9 seems to be involved in ongoing liver inflammation, 62 and its level drops after antiviral treatment. 57,63 Induction of MMP-2 is significantly stimulated in the liver of HCV-infected patients.…”

“…57,61 Especially, MMP-9 seems to be involved in ongoing liver inflammation, 62 and its level drops after antiviral treatment. 57,63 Induction of MMP-2 is significantly stimulated in the liver of HCV-infected patients. 64 Although it appears that MMP-9 and MMP-2 induction in fibrosis is the most prominent among MMPs, there are also other MMPs that are able to cleave collagen-IV and other basement membrane components.…”

“…9 Probably, loss of this hepatoprotective function in TIMP-1 knockout results in exacerbated fibrosis. Still, expression of TIMP-1 and TIMP-2 is elevated in HCV patients, 57 and some studies examined blockage of TIMP-1 as potential therapeutic treatment for patients with cirrhosis. In one case, TIMP-1 expression was reduced by adenoviral delivery of siRNA.…”

(–)-Catechin-7-O-β-d-Apiofuranoside Inhibits Hepatic Stellate Cell Activation by Suppressing the STAT3 Signaling Pathway

“…They are expressed during HSC activation after liver injury. They are considered the putative target of STAT3, and high expressions were observed in hepatic fibrosis patients, liver fibrosis animal models, and activated HSCs [61]. This study demonstrated that MMP-2 and MMP-9 were increased in TGF-β1-activated HSCs, and C7A significantly inhibited its expression, which imply that C7A potentially reduces cell migration and proliferation of activated HSCs.…”