Chronic Hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. It can be a precursor to cirrhosis, hepatocellular carcinoma and end-stage liver disease. In the absence of a vaccine, the current FDA approved standard of care for chronic hepatitis C is a combination of pegylated interferon-alpha (IFN1) and ribavirin. Unfortunately, this regimen is only effective in about 50% of patients, emphasizing the need for studies defining the molecular mechanisms underlying resistance to IFN1. Clinical studies have identified several potential cofactors that may contribute to the failure of anti-HCV therapy, including obesity, diabetes, alcohol abuse, oxidative stress, cigarette smoking and environmental pollutants. Acrolein is a ubiquitous, highly reactive environmental and industrial pollutant, and is designated by the U.S. Environmental Protection Agency (EPA) as a high priority air and water pollutant. Notably, acrolein is also formed endogenously as a byproduct of lipid peroxidation (LPO) and is, itself, known to cause oxidative stress. Moreover, acrolein is a major component of cigarette smoke and recent studies suggest that smokers with chronic hepatitis C have a lower response rate to IFN1 compared to non-smokers. We have convincing preliminary data showing that non-toxic concentrations of acrolein significantly down-regulate IFN1 signaling and antiviral gene expression in vitro (cultured human hepatic cells) and in vivo (mice). Published literature and our own compelling data strongly support our hypothesis that acrolein adversely influences IFN1 therapy outcomes by inhibiting or disrupting IFN1 mediated signaling and antiviral gene expression in hepatocytes, and that high acrolein exposure (environmental and/or endogenous) will correlate with poor IFN1 response in HCV infected individuals. Our hypotheses will be tested by examining the effects of acrolein on early IFN1-mediated signaling (including components of the Jak/STAT pathway) and antiviral gene expression using well established in vitro and in vivo experimental systems, as well as an HCV replicon that directly reports on HCV viral replication. Additionally, the investigators will establish a clinical/translational aspect of our hypothesis by conducting a retrospective analysis using banked serum, urine and/or liver biopsy samples from healthy, uninfected individuals and HCV-infected patients (responders and non-responders). This analysis will explore a possible correlation between acrolein exposure and poor IFN1 response (lack of sustained virologic response, SVR). The investigators expect their studies will elucidate critical mechanisms underlying resistance to IFN1 treatment and will identify potential targets for novel therapeutic intervention. Public Health Relevance: Acrolein is one of the major reactive aldehydes ubiquitously present in foods, water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN1 therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism, and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence, based on available literature and the investigators'own compelling preliminary results, they have opted to use acrolein as the model compound for this study.
The aim of the study is to determine the contribution of acrolein to the mechanisms of IFN1 resistance. The investigators have preliminary evidence to demonstrate that acrolein, at nontoxic concentrations, significantly down-regulates IFN1 signaling and antiviral/anti-HCV gene expression.
Acrolein is one of the major reactive aldehydes ubiquitously present in foods, water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN? therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism, and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence, based on available literature and our own compelling preliminary results, we have opted to use acrolein as the model compound for this study. The aim of this study is to determine the contribution of acrolein to the mechanisms of IFN? resistance. We have preliminary evidence to demonstrate that acrolein, at nontoxic concentrations, significantly down-regulates IFN? signaling and antiviral/anti-HCV gene expression.
|Ghare, Smita S; Donde, Hridgandh; Chen, Wei-Yang et al. (2016) Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine. Toxicol In Vitro 35:66-76|
|Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan et al. (2015) Molecular mechanisms of acrolein toxicity: relevance to human disease. Toxicol Sci 143:242-55|
|Kirpich, Irina; Zhang, Jingwen; Gobejishvili, Leila et al. (2013) Binge ethanol-induced HDAC3 down-regulates Cpt1Î± expression leading to hepatic steatosis and injury. Alcohol Clin Exp Res 37:1920-9|
|Mohammad, Mohammad K; Avila, Diana; Zhang, Jingwen et al. (2012) Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicol Appl Pharmacol 265:73-82|
|Moghe, Akshata; Joshi-Barve, Swati; Ghare, Smita et al. (2011) Histone modifications and alcohol-induced liver disease: are altered nutrients the missing link? World J Gastroenterol 17:2465-72|
|Gobejishvili, Leila; Avila, Diana V; Barker, David F et al. (2011) S-adenosylmethionine decreases lipopolysaccharide-induced phosphodiesterase 4B2 and attenuates tumor necrosis factor expression via cAMP/protein kinase A pathway. J Pharmacol Exp Ther 337:433-43|
|Ghare, Smita; Patil, Madhuvanti; Hote, Prachi et al. (2011) Ethanol inhibits lipid raft-mediated TCR signaling and IL-2 expression: potential mechanism of alcohol-induced immune suppression. Alcohol Clin Exp Res 35:1435-44|
|Cave, Matt; Falkner, Keith Cameron; Ray, Mukunda et al. (2010) Toxicant-associated steatohepatitis in vinyl chloride workers. Hepatology 51:474-81|
|von Montfort, Claudia; Beier, Juliane I; Kaiser, J Phillip et al. (2010) PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: role of hepatocyte division. Am J Physiol Gastrointest Liver Physiol 298:G657-66|
|Joshi-Barve, Swati; Amancherla, Kiranmayi; Patil, Madhuvanti et al. (2009) Acrolein, a ubiquitous pollutant and lipid hydroperoxide product, inhibits antiviral activity of interferon-alpha: relevance to hepatitis C. Free Radic Biol Med 47:47-54|