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

氧化/亚硝化应激与炎症引起的组织损伤的机制

基本信息

批准号：
8746473
负责人：
PAL PACHER
金额：
$ 120.75万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8746473
关键词：
2-arachidonylglycerol 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Acute Adenosine Adenosine A2B Receptor Affect Aging Alcoholic Cardiomyopathy Alcoholic beverage heavy drinker Alcohols Animal Disease Models Animals Apoptosis Apoptotic Arachidonic Acids Atherosclerosis Behavior Blood Vessels Blood flow CNR2 gene Cannabinoids Cardiac Myocytes Cardiogenic Shock Cardiomyopathies Cardiovascular Models Cardiovascular Physiology Cardiovascular system Cell Death Chronic Collaborations Development Diabetic Retinopathy Dimerization Disease Disease model Dose Eicosanoids Endocannabinoids Endotoxins Enzymes Ethanol Fibrosis Functional disorder Future Glucocorticoid Receptor Goals Heart Heart failure Heavy Drinking Hemorrhagic Shock Homeostasis Human Hypertension In Vitro Inflammation Inflammatory Injury Interleukin-10 Ischemia Kidney Kidney Diseases Lead Link Lipids Liver Liver diseases Mediating Metabolic Diseases Metabolism Modeling Molecular Monoacylglycerol Lipases Mus Muscle Fibers Myocardial Myocardial Infarction Myocardial Ischemia NADP Nitrates Operative Surgical Procedures Organ Transplantation Oxidants Oxidative Stress Pathologic Processes Pathology Pathway interactions Patients Peroxonitrite Play Prevention Prostaglandin Production Receptor Activation Receptor, Angiotensin, Type 1 Recovery Reperfusion Injury Reperfusion Therapy Reporting Research Resveratrol Risk Factors Rodent Role STAT3 gene Septic Shock Signal Pathway Signal Transduction Skeletal muscle injury Stress Stroke System Thrombosis Tissue Sample Tissues Trauma Universities Vascular Smooth Muscle Wine cardiovascular injury clinically relevant computerized data processing conditioning coronary angioplasty diabetic cardiomyopathy drinking in vivo Model inhibitor/antagonist interest liver injury liver ischemia lung injury macrophage neointima formation new therapeutic target nitrosative stress problem drinker receptor restenosis therapeutic target vascular smooth muscle cell proliferation

项目摘要

Overwhelming evidence suggests that oxidative-nitrosative/nitrative stress and inflammation are involved in essentially all major pathological processes affecting humans, including those induced by excessive alcohol consumption. The research focus of SOSTI is to understand the cellular and molecular mechanisms underlying oxidative/nitrosative/nitrative stress, inflammation, and their downstream effector pathways using clinically relevant animal models of disease (e.g. ischemia reperfusion injury, cardiomyopathy/heart failure), and to identify novel therapeutic targets against these pathologies. Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury. Recently we have been exploring the interplay of oxidative/nitrative stress, inflammation with the ES; an emerging very promising therapeutic target against various inflammatory and other diseases. Our previous studies provided evidence that the activation of cannabinoid 1 receptors (CB1) by pathologically dysregulated endocannabinoid system contributed to cardiovascular and renal inflammation and cell death in models of cardiovascular and kidney injury, diabetic retinopathy and diabetic cardiomyopathy. These studies also revealed important interactions of cardiovascular CB1 with angiotensin II receptor type 1 AT1R and its downstream signaling via p47(phox)/ROS-generating NADPH. Our prior in vitro studies have also established that CB1 plays an important role in vascular smooth muscle signaling and proliferation. Our recent collaborative studies with Dr. Sabine Steffens showed that CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation in an in vivo model of restenosis, raising a possibility that CB1 antagonists would be beneficial in the management or prevention of vascular restenosis complicating coronary angioplasty and vascular surgeries. In collaboration with Dr. Zoltan Benyo we found an important role of CB1 in cerebrocortical blood flow autoregulation. In earlier studies using models of hepatic ischemia/reperfusion injury we demonstrated that oxidative/nitrosative/nitrative stress is involved in the marked activation of the ES during reperfusion injury. In a recent study we explored the role of endocannabinoids and their metabolism during acute liver injury. We revealed very interesting interactions of endocannabinoid and eicosanoid lipid signaling pathways in controlling acute liver injury induced by various triggers. We demonstrated a key role for monoacylglycerol lipase (MAGL), one of the main endocannabinoid degrading enzymes, linking these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We showed that MAGL inhibition decreases hepatic injury via dual control over endocannabinoid-CB2 receptor and eicosanoid signaling pathways, suggesting that MAGL inhibitors might be developed to treat conditions that expose the liver to acute oxidative stress and inflammatory damage. Our upcoming studies will also be directed towards the understanding of the mechanisms of the activation of the endocannabinoid system during reperfusion injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes in collaboration with Drs. Cravatt, Nomura and Kunos) in various models of cardiomyopathy and nephropathy. Our future collaborative studies with Drs. George Kunos, Bin Gao and Byoung-Joon Song will also explore the role of oxidative/nitrosative stress and ES in various other models of liver and metabolic disorders and fibrosis. The above mentioned studies may identify new pharmacological targets in various forms of tissue injury associated with increased inflammation, oxidative stress, and fibrosis. Our collaborative studies with Dr. Gyorgy Hasko revealed that adenosine augmented IL-10-induced STAT3 signaling in M2c macrophages and that stimulation of A2B adenosine receptors protected against trauma-hemorrhagic shock-induced lung injury. In collaboration with Dr. Esther Sternberg we have demonstrated that glucocorticoid receptor dimerization was required for proper recovery from endotoxin-induced inflammation, sickness behavior and metabolism in mice. With Dr. Lucas Liaudet we recently demonstrated that the potent oxidant and nitrating species peroxynitrite may be responsible for the protection observed during ischemic post-conditioning in the heart, suggesting that reactive oxidants may modulate very specific signaling processes to exert context-dependent effects, including activation of various endogenous protective mechanisms. Role of oxidative-nitrative stress, inflammation and apoptosis in ethanol-induced tissue-damage. Moderate and heavy drinking may significantly influence cardiovascular function in different ways. During the course of the last decade, several research groups have reported that, in models of myocardial ischemia/reperfusion injury using young rodents, low dose ethanol or non-ethanolic components of wine (e.g. resveratrol) may exert acute cardioprotective effect independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. However, chronic drinking may also lead to the development of cardiomyopathy and potent immunomodulatory effects. Alcohol-mediated apoptosis of cardiomyocytes has been documented in experimental animals, and there is also evidence of skeletal muscle cell apoptosis in chronic heavy drinkers. The extent of apoptotic damage in the heart is similar in heavy drinkers and in patients with long-standing hypertension and is related to structural damage. Our recent ongoing studies are also focused on the understanding of the mechanisms of ethanol-induced oxidative/nitrative stress, inflammation and cell death in the cardiovascular system and also in the liver during pathological processes (e.g. associated with aging). Through collaboration with Drs. Emanuel Rubin and Gyorgy Hajnoczky at Dept. of Pathology, Thomas Jefferson University, we will also assess tissue samples from alcoholics to investigate the role of oxidative stress and inflammatory signaling in alcohol-induced myocardial and skeletal muscle injury.

压倒性的证据表明，氧化氮/硝化应激和炎症基本上都参与影响人类的所有主要病理过程，包括过量饮酒引起的那些。 Sosti的研究重点是了解使用临床相关疾病的动物模型（例如缺血性再灌注损伤，心脏疾病/心脏失败/心脏失败），以识别这些病理学的靶标，使用临床相关的疾病模型（例如，缺血性再灌注损伤，脑融合再灌注损伤），使用临床相关的动物模型，并识别这些病理学的靶标。氧化/硝化应激的相互作用，在组织损伤中与内源性大麻素系统（ES）的炎症。最近，我们一直在探索氧化/硝化应激的相互作用，即与ES的炎症。出现的非常有前途的治疗靶标针对各种炎症和其他疾病。我们先前的研究提供了证据表明，在心血管和肾脏损伤，糖尿病性视网膜病变和糖尿病性心肌病模型中，通过病理失调的内源性内源性内源性内源性内源性失调的大麻素1受体（CB1）有助于心血管和肾脏炎症以及细胞死亡。这些研究还揭示了心血管CB1与血管紧张素II受体1型AT1R及其通过P47（PHOX）/ROS-ROS-生成NADPH的下游信号传导的重要相互作用。我们先前的体外研究还确定，CB1在血管平滑肌信号传导和增殖中起着重要作用。我们最近与Sabine Steffens博士的合作研究表明，CB1激活在重新狭窄的体内模型中促进血管平滑肌肉细胞的增殖和新内膜形成，这提出了CB1拮抗剂有可能有益于使血管造成的冠状动脉血管成形菌和血管性表情的治疗或预防。与Zoltan Benyo博士合作，我们发现CB1在脑皮质流动自动调节中的重要作用。在使用肝缺血/再灌注损伤模型的早期研究中，我们证明了氧化/亚硝化/硝化应激与再灌注损伤期间ES的显着激活有关。在最近的一项研究中，我们探讨了内源性大麻素及其在急性肝损伤中的新陈代谢的作用。我们揭示了内源性大麻素和类花生素脂质信号通路的非常有趣的相互作用，以控制各种触发因素引起的急性肝损伤。我们证明了单酰基甘油脂肪酶（MAGL）的关键作用，这是主要的内源性大麻素降解酶之一，将这些途径连接起来，水解了内源性大麻素2-芳基二烯丙基甘油，以生成蛛网膜酸前体的生产。我们表明，MAGL抑制通过对内源性大麻素CB2受体和eicosanoid信号通路的双重控制减少肝损伤，这表明可能开发出MAGL抑制剂来治疗使肝脏暴露于急性氧化应激和炎性损害的疾病。我们即将进行的研究还将针对理解再灌注损伤期间内刺素系统激活的机制，并进一步阐明内源性大麻素系统的作用（尤其是针对内源性大麻素代谢酶在与Drs and andura and kunyos的合作中的内源性代谢化酶）in Cardiopath and cardiopath and cardiopath and cardiopath in soparath and ofdiys ins in drysath。我们与Drs的未来合作研究。 George Kunos，Bin Gao和Byoung-Joon Song还将探索氧化/亚硝化应激和ES在其他各种肝脏和代谢性疾病和纤维化模型中的作用。上述研究可以确定与炎症增加，氧化应激和纤维化有关的各种形式的组织损伤的新药理靶标。我们与Gyorgy Hasko博士的合作研究表明，腺苷增强了IL-10诱导的M2C巨噬细胞中的STAT3信号传导，并刺激了受保护的A2B腺苷受体免受创伤性 - 突破性休克诱导的肺损伤的刺激。与Esther Sternberg博士合作，我们已经证明，要从内毒素诱导的炎症，疾病行为和代谢中适当恢复糖皮质激素受体二聚化。使用Lucas Liaudet博士，我们最近证明，有效的氧化剂和硝化物质过氧硝酸盐可能负责心脏缺血后调节期间观察到的保护，这表明反应性氧化剂可能会调节非常具体的信号传导过程，以施加上下文依赖性依赖性效应，包括各种内在保护机制的激活。氧化量子应激，炎症和凋亡在乙醇诱导的组织破坏中的作用。中度和大量饮酒可能会以不同的方式显着影响心血管功能。在过去十年的过程中，几个研究小组报告说，在心肌缺血/再灌注模型中，使用年轻啮齿动物，低剂量的乙醇或葡萄酒的非甲醇成分（例如白藜芦醇）可能会施加急性心脏保护作用，使其独立于血管造成的经典危险因素，与血管造成的抗血管抗体和触发因素无关。但是，长期饮酒也可能导致心肌病和有效的免疫调节作用的发展。酒精介导的心肌细胞的凋亡已在实验动物中有记录，并且还有证据表明慢性重饮酒者的骨骼肌细胞凋亡。在重饮酒和长期高血压患者中，心脏凋亡损伤的程度相似，并且与结构性损害有关。我们最近正在进行的研究还集中在对乙醇诱导的氧化/硝化应激，心血管系统中以及病理过程中肝脏中的机制的理解（例如，与衰老有关）。通过与Drs的合作。托马斯·杰斐逊大学（Thomas Jefferson University）病理学系的伊曼纽尔·鲁宾（Emanuel Rubin）和gyorgy hajnoczky，我们还将评估酒精中毒的组织样本，以研究氧化应激和炎症信号传导在酒精诱导的心肌和骨骼肌损伤中的作用。