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

National Institute On Alcohol Abuse And Alcoholism

Investigators

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Abstract

Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury and inflammation. Cannabinoid receptor 2 (CB2R), primarily expressed in inflammatory cells, is an attractive target for various diseases associated with tissue injury and inflammation. However, there are no specific antibodies against this receptor and most of the ligands used in preclinical studies are neither selective nor specific. Furthermore, despite numerous CB2R agonists entering clinical development, the mode of actions of CB2R agonists is very poorly understood. Consequently, the target validation is extremely difficult, which is slowing down the clinical development of this class of drugs. In a recent study by using several CBR ligands and endocannabinoids we explored the mechanisms of the molecular activation of CB2R. This study delineated the molecular mechanism of CB2R activation by selective agonists and highlighted the role of lipophilicity in CB2R engagement. The study may also have important implications for GPCR drug design and sheds light on their activation by endogenous ligands. In this study we also described the development of a new selective and specific CB2R agonist. Our ongoing collaborative studies with numerous academic institutions and industry have also been focused on development and characterization of improved CB2R ligands and on understanding the role of CB2Rs in brain, kidney, and liver inflammation. 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 understanding the mechanisms of the activation of the endocannabinoid system during tissue injury and on the further elucidation of the role of the endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes (e.g., MAGL, DAGLs and CB2R in collaboration with Drs. Greather, Van der Stelt, Cinar and Kunos) in various models of liver disease, cardiomyopathies, and alcohol related pathologies. Role of oxidative/nitrosative stress, inflammation, metabolic dysregulation in tissue injury Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways which promote cell survival and suppress inflammation through adenosine receptors including the A2BR. In collaboration with Dr. Hasko we have recently demonstrated that the CD39-CD73-A2BR axis plays a pivotal role in protecting against T/HS-induced multiple organ failure. Our ongoing collaboration with Dr. Steven N Ebert has explored the effects of maternal binge alcohol consumption on cardiac pathology and gene expression. This study identified Wnt7a and a short list of potential other candidate genes and pathways for further study, which could provide mechanistic insights into how maternal binge alcohol consumption produces congenital cardiac malformations. In a prior collaborative study with Drs. Lohoff and Koob we discovered that inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9 serine protease), an important regulation of cholesterol metabolism, with a therapeutically approved monoclonal antibody may represent a novel therapeutic approach for alcohol-induced liver disease by attenuating hepatic inflammation and steatosis. Our ongoing studies are also directed to evaluate the potential beneficial effect of the PCSK9 inhibition on alcohol-induced neuroinflammation in rats. Additionally, in a small-scale clinical study, we plan to explore the translatability of this approach and plan to include numerous cardiovascular endpoints. Our recent studies are also focused on understanding the role of PCSK9 in cardiovascular and liver aging and on understanding the cardiovascular effects of chronic alcohol consumption in the presence of cardiovascular risk factors. In collaboration with Dr. Panagiotis Koutakis, we also plan to explore the mechanisms of the exacerbation of peripheral artery disease in minority patients with alcohol use disorder. Our future collaborative studies with Drs. Kunos, Gao, Koob, Cinar and Lohoff 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 disorder.