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.

Tiziana Latronico,Miriam Lichtner,Ilaria Pati,Grazia Liuzzi,Vincenzo Vullo,Claudio Mastroianni,Tiziana Tieghi,Valeria Belvisi,Raffaella Marocco,Paola Zuccala,Claudia Mascia,Fabio Mengoni

doi:10.3390/ijms17040455

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.

Highlights

Chronic infection with hepatitis C virus (HCV) is characterized by progressive damage to liver tissue leading to progressive fibrosis and evolving to cirrhosis, liver failure, and hepatocellular carcinoma [1]
Among the studied matrix metalloproteinases (MMPs) we focused our attention on MMP-2 and MMP-9 for two different reasons: (i) they were the highest expressed MMPs among those analyzed; (ii) in the family of MMPs, MMP-2 and MMP-9 are important for the development of liver fibrosis since they degrade type IV collagen and are involved in the early steps of tissue remodeling that characterizes chronic liver disease [21,22]
We found that MMP-9 plasma concentrations significantly increased in HIV/HCV coinfected subjects compared to HCV monoinfected subjects, despite the fact that HIV/HCV coinfected subjects were treated with antiretroviral therapies, which are known to inhibit MMP-9 levels [23,24]

Summary

Introduction

Chronic infection with hepatitis C virus (HCV) is characterized by progressive damage to liver tissue leading to progressive fibrosis and evolving to cirrhosis, liver failure, and hepatocellular carcinoma [1]. Liver fibrosis is a dynamic pathologic process characterized by an accumulation of the extracellular matrix, which is a consequence of an imbalance between the enhanced matrix synthesis and reduced breakdown of connective tissue proteins reflecting dysregulation of several pathways, including matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) [2] MMPs are a large family of zinc-dependent endopeptidases that degrade the components of extracellular matrix and basement membrane [3]. The activity of these enzymes is controlled by TIMPs, which form stable, non-covalent complexes with active MMPs [5]. Changes in the fine balance between MMPs and TIMPs drives the turnover of the extracellular matrix and may be crucial for inflammation in infection as well as other pathological conditions. With regard to HCV, several data in literature indicated that hepatic fibroproliferation has been associated with alterations in the expression of circulating and hepatic MMPs and TIMPs [6,7,8], but results obtained are controversial and the information is fragmentary as most studies are limited to the analysis of individual MMPs and/or TIMPs

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Results

Conclusion