elastin and Hepatitis-C

Major HCV infections lead to chronic hepatitis, which results in progressive liver disease including fibrosis, cirrhosis and eventually hepatocellular carcinoma (HCC). P2X4 and P2X7 are most widely distributed receptors on hepatocytes.. Full length P2X4 (1.7kb) (Rattus norvegicus) was sub cloned in mammalian expression vector pcDNA3.1+. Two stable cell lines 293T/P2X4 (experimental) and 293T/ NV or null vector (control) were established. Both cell lines were inoculated with high viral titers human HCV sera and control human sera. Successfully infected cells harvested on day 5 and day 9 of post infection were used for further studies.. The results revealed a significant increase in gene expression of P2X4 on day 5 and day 9 Post -infection in cells infected with HCV sera compared with cells inoculated with control sera. Quantitative real time PCR analysis revealed that HO-1 was significantly upregulated in presence of P2X4 in HCV infected cells (P2X4/HCV) when compared with control NV/HCV cells. A significant decrease was observed in expression of Cu/ZnSOD in presence of P2X4 in HCV infected cells compared to control NV/HCV cells. However, expression of both antioxidants was observed unaltered in cells harvested on day 9 post infection. Gene expression of angiotensin II significantly increased in HCV infected cells in presence of P2X4 on day 5 and day 9 of post infection when compared with control NV/HCV cells. A significant increase in gene expression of TNF-α and TGF-β was observed in HCV infected cells in presence of P2X4 on day 9 post infection in comparison with control (NV/HCV cells). However, gene expression of adipokine leptin was not affected in both experimental (P2X4/HCV) and control (NV/HCV) groups on day 5 and day 9 of post infection. Extracellular matrix proteins, laminin and elastin genes expression also significantly increased in presence of P2X4 (HCV/P2X4) on day 9 of post-infection compared to control group NV/HCV cells.. In conclusion, these findings constitute the evidence that P2X4 receptors in the presence of HCV play a significant role in the regulation of key antioxidant enzymes (HO-1, Cu/ZnSOD), in the induction of proinflammatory. cytokine (TNF-α), profibrotic cytokine (TGF-β) vasoactive cytokine (angiotensin II). P2X4 also increases the expression of extracellular matrix proteins (laminin and elastin) in the presence of HCV.

Topics: Angiotensin II; Animals; Antioxidants; Carcinoma, Hepatocellular; Cytokines; Elastin; Fibrosis; Hepacivirus; Hepatitis C; Humans; Laminin; Liver Neoplasms; Rats; Receptors, Purinergic P2X4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Combined antiretroviral therapy (cART) attenuates hepatic fibrosis in hepatitis C virus and HIV coinfected patients. However, the role of HIV or cART on hepatic fibrosis in HIV monoinfection is discussed controversially. During liver fibrosis, matrix metalloproteinases (MMPs) degrade extracellular matrix (ECM) proteins into small soluble fragments, which reflect hepatic remodeling processes. This study used these novel biomarkers to investigate the effect of HIV and cART on hepatic fibrosis remodeling.. In 249 patients with HIV monoinfection and 55 healthy controls, the serum levels of MMP-degraded collagen type III (C3M), biglycan (BGM), elastin (ELM), as well as the formation marker 7S (P4NP 7S), and MMP-degraded collagen type IV (C4M) were determined using specific ELISAs. Sixty-eight patients underwent a follow-up visit 3 years later including assessment of ECM markers and fibrosis using transient elastography (Fibroscan).. C3M, BGM, C4M and P4NP 7S were significantly elevated in HIV patients compared to controls and correlated to HIV viral loads and inversely to cART duration. C4M, P4NP 7S and ELM were lower in patients under cART therapy and in patients without HIV viremia, indicating that lowering of the HIV load by cART attenuates remodeling of ECM. The levels of C3M, C4M, P4NP 7S and ELM correlated significantly with the progression of fibrosis in these patients.. Specific therapy of patients with HIV monoinfection also beneficially influences liver fibrosis. These novel markers of liver fibrosis remodeling may help to monitor the hepatic effects by HIV therapy.

Topics: Adult; Antiviral Agents; Biglycan; Biomarkers; Coinfection; Collagen Type III; Cross-Sectional Studies; Disease Progression; Drug Therapy, Combination; Elasticity Imaging Techniques; Elastin; Extracellular Matrix; Female; Follow-Up Studies; Hepatitis C; HIV Infections; Humans; Liver Cirrhosis; Longitudinal Studies; Male; Middle Aged; Peptide Mapping

Topics: Animals; Collagen; Elastin; Hepatitis B; Hepatitis C; Humans; Liver Cirrhosis; Rats