Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection
Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection
In the presented project, the role of heme oxygenase 1 and 2 in the procesess associated with
 fibroproduction in the chronic HCV infection will be studied. Heme oxygenase expression will
 be evaluated by the techniques of molecular genetics and immunohistochemistry, both in the
 liver tissue and in peripheral blood mononuclear cells. These parameters will be correlated
 with basic virological and clinical characteristics of the chronic HCV infection. The
 investigators' expected results may help in understanding the mechanisms of fibroproduction
 in chronic HVC infection and, therefore, contribute to explain individual differences in the
 development of chronic HCV infection.
Hepatitis C virus (HCV) is a single stranded positive RNA virus belonging to the Flaviviridae
 family. HCV is a major cause of chronic hepatitis and progressive liver fibrosis leading to
 cirrhosis. Currently, the mechanisms responsible for hepatocellular injury are not fully
 understood. Oxidative damage has been hypothesized to play a role in HCV-induced liver
 disease, with reactive oxygen species (ROS), generated from HCV-infected hepatocytes and
 infiltrating immune cells. Persistence of recurrent hepatocellular injury leads to
 wound-healing process in which oxidative stress, inflammatory response mediated by immune
 cells and/or cytokines, and activation of hepatic stellate cells (HSCs) contribute to cascade
 of fibrogenesis. HCV can infect peripheral blood mononuclear cells (PBMC) of patients with
 chronic HCV infection . PBMC play key roles both in innate and adaptive antigen-specific
 immunity and they constitute critical components of the immune response.Heme oxygenase (HO)
 is the rate-limiting enzyme in the heme catabolic pathway. It cleaves pro-oxidant heme into
 equimolar amounts of carbon monoxide (CO), free iron, and biliverdin, which is rapidly
 metabolized to bilirubin by biliverdin reductase.The human HO-1 gene is located at chromosome
 22q12 and a variable number of tandem repeat polymorphism (VNTR) was identified in the
 proximal promoter region. It is suggested that these highly polymorphic (GT)n repeats could
 alter the transcriptional activity. In recent years, enhanced HO enzymatic activity has been
 reported - probably through its formation of bioactive products - to possess antioxidant,
 cytoprotective, and neurotransmitter activity and to play a role in anti-inflammatory
 functions . AIMS: AIM 1.To characterize HO expression in liver biopsies in patients with
 chronic hepatitis C comparing to expression in patients with other types of hepatitis (esp.
 autoimmune) and to normal liver tissue. To investigate the relationship between HO expression
 and hepatitis C virus concentration, duration of infection, level of fibrosis and
 inflammation, ALT, AST activities, bilirubin levels, response to the standard treatment and a
 level of apoptosis. AIM 2. To characterize HO expression in PBMC in patients with chronic
 hepatitis C before, in the week 12 and after the standard treatment (PEG-IFN+RBV). To
 correlate HO expression in PBMC with viral concentration in sera and a response to the
 standard treatment.AIM 3. To investigate HO polymorphisms in patients with chronic hepatitis
 C. AIM 4. To investigate UGT1A1 28 polymorphism which is responsible for benign
 hyperbilirubinemia. Expected results: 1. This study could elucidate a relationship between
 development of liver fibrosis and inflammation and HO expression. 2. This project may, for
 the first time, show the relationship between chronic HCV infection and regulation of HO
 expression in PBMC. 3.This project will answer the question whether genetic predisposition,
 length polymorphism in HO promoter responsible for its lower transcriptional activity, could
 be a risk factor for fibrosis/cirrhosis development in patients infected with hepatitis C
 virus. UGT1A1 28 polymorphism is connected with low prevalence of diseases in which the
 oxidative stress is increased. We suggest that HCV infected persons might have low prevalence
 of this polymorphism or this polymorphism might be connected to low efficacy of antiviral
 treatment in these persons.
Inclusion Criteria:

 -  chronic HCV infection

 -  must undergo liver biopsy

 -  must undergo antiviral treatment

 Exclusion Criteria:

 -  liver sample not obtained

 -  blood samples for HCV testing not obtained in specified time points during antiviral
 therapy