Mechanism of oxidative/nitrosative stress and inflammation-induced tissue injury

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury and inflammation. Accumulating evidence suggests that there are important interactions between various organ systems, which may promote cardiovascular disease and/or development of various severe cardiovascular complications in certain diseases (e.g. chronic liver and kidney diseases). We have been very interested in understanding the interactions of liver with the cardiovascular system and kidneys during chronic hepatic inflammation, fibrosis, and injury. Chronic liver diseases are among the top contributors to mortality worldwide and patients with severe acute and chronic liver disease often develop different cardiovascular complications including portal hypertension, peripheral splanchnic vasodilation resistant to vasoconstrictors, vasculopathies, hepatopulmonary syndrome, encephalopathy, and cirrhotic cardiomyopathy, which largely contribute to the increased mortality observed in this patient group. In addition to affecting cardiovascular function, liver disease may also profoundly interact with other organ systems. Hepatorenal syndrome (HRS) is a very frequent and potentially lethal complication of acute and chronic liver failure (e.g. induced by alcoholic steatohepatitis, cirrhosis, etc.) and is an important predictor of short-term mortality with poor prognosis. Recently, using a well-established model of liver inflammation and fibrosis induced by bile duct ligation (BDL) in mice we aimed to investigate the potential interplay of chronic liver disease with cardiovascular and renal systems. We found that development of liver inflammation, impaired microcirculation and fibrosis following BDL in mice was paralleled with time-dependent development of cardiomyopathy and kidney dysfunction/injury. These studies demonstrated that BDL-induced advanced liver fibrosis is a suitable mouse model to study the pathophysiology of hepatic/cirrhotic cardiomyopathy and hepatorenal syndrome at a preclinical level. Using these newly established animal models and multiple molecular biology, genomics, lipidomic and proteomics approaches in our ongoing and future studies we aim to understand the role of oxidative stress, inflammation, lipid (.e.g. endocannabinoid and eicosanoid) and cell death signaling in mediating these important organ to organ interactions. Our ongoing collaborative studies with industry and numerous academic institutions has also been focused on understanding the role of cannabinoid 2 receptors (CB2R) in kidney and liver inflammation and fibrosis, development and characterization of improved CB2R ligands and tools to detect these receptors in various tissues and cell types. Our collaborative studies with Dr. Yuri Persidsky have also been exploring the role of CB2R in AIDS using humanized mouse models of the disease. Our impending studies will also focus on the understanding the mechanisms of the activation of the endocannabinoid system during tissue injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes and CB2R in collaboration with Drs. Cravatt, Van der Stelt, Mechoulam, Cinar and Kunos) in various models of liver disease, cardiomyopathy and nephropathy. Role of oxidative/nitrosative stress, inflammation, metabolic dysregulation in tissue injury In collaboration with Drs. Lohoff and Koob we discovered that inhibition of PCSK9 in rats with a therapeutically approved monoclonal antibody for the treatment of atherosclerosis may represent a novel therapeutic approach for alcoholic liver disease by attenuating hepatic inflammation and steatosis. In a small-scale clinical study, we plan to explore the translatability of this approach and plan to include numerous cardiovascular endpoints. In a recent collaborative study with Dr. Gao we also found that PCSK9 inhibition in mouse model of NASH attenuated the liver injury and inflammation. This study also identified an important role of neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer as a potential therapeutic target for NASH. Another, recent interesting collaborative study with Dr. Gao established an important role of bile acid-activated macrophages in promoting biliary epithelial cell proliferation through integrin v6 signaling following liver injury. Our future collaborative studies with Drs. Kunos, Gao, Koob, Cinar and Falk will also explore the role of oxidative/nitrosative stress, inflammation, lipid endocannabinoid signaling and cell death in various new rat and mouse models of alcohol use disorders. Our ongoing collaborative studies with Dr. Hasko have also been exploring the role of adenosine and adenosine receptors in tissue injury and inflammation.