MECHANISMS OF COCAINE INDUCED EXACCERBATION OF VIRAL MYO

可卡因导致病毒性心肌炎恶化的机制

• 批准号: 6634280
• 负责人: JAMES P MORGAN
• 金额: $ 35.24万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634280
• 关键词: T lymphocyte; adrenergic receptor; apoptosis; catecholamines; cocaine; comorbidity; disease /disorder etiology; disease /disorder proneness /risk; drug abuse; encephalomyocarditis virus; host organism interaction; immunoglobulin M; laboratory mouse; myocarditis; necrosis; pathologic process; virus infection mechanism

Clinical evidence suggests that cocaine abusers have an increased incidence of Human Immunodeficiency Virus (HIV) infection and HIV-related myocarditis. These data indicate a causal relationship between cocaine use and myocarditic viral pathogenicity, which we plan to investigate in this proposal by studying a readily reproducible murine model of viral myocarditis using Encephalomyocarditis (EMC) Virus as a surrogate for HIV. Our central, unifying hypothesis is that cocaine-induced exacerbation of viral myocarditis is an indirect effect mediated by drug-induced enhancement of catecholamine concentrations in the heart. When catecholamines from the systemic circulation and local release at cardiac sympathetic nerve endings reach toxic concentrations, they may compromise cellular integrity and specific cellular and humoral body defenses, making the myocardium more susceptible to infection. We will test this hypothesis by means of seven specific aims that employ techniques currently available in the laboratories of the collaborating Investigators. I. We will determine whether chronic cocaine treatment alone can induce myocarditis, necrosis or apoptosis. II. We will test the hypothesis that exposure to cocaine can enhance the susceptibility of mice to myocarditis after virus exposure. III. We will determine whether cocaine can enhance persistence of the viral genome. IV. We will determine whether cocaine can impair specific body defenses against viral infection by measuring T cell function and IgM levels. V. We will determine whether the adrenergic or local anesthetic properties of cocaine are responsible for increased viral myocarditic pathogenicity. VI. We will test the hypothesis that catecholamine-mediated stimulation of the adrenergic receptors on myocytes is responsible for increased viral myocarditic pathogenicity by use of sympatholytic agents. VII. We will demonstrate that the enhancement of viral myocarditic pathogenicity produced by cocaine is synergistic with other drugs, foods and activities that increase catecholamine levels. Taken together, these results will provide new mechanistic information about the etiology of viral myocarditis in cocaine abusers, should allow us to identify distinct risk factors for developing myocarditis in the general population, and may provide a rational basis for predicting who may place themselves at increased additional risk by the use of cocaine, particularly among the HIV-exposed population.

临床证据表明，可卡因滥用者有人类免疫缺陷病毒（HIV）感染和HIV相关心肌炎的发病率增加。这些数据表明可卡因使用与心肌病毒致病性之间存在因果关系，我们计划在本提案中通过研究一种容易复制的病毒性心肌炎小鼠模型来研究这一点，该模型使用脑心肌炎（EMC）病毒作为HIV的替代品。我们的中心统一假设是，可卡因引起的病毒性心肌炎恶化是一种间接效应，由药物引起的心脏中儿茶酚胺浓度的增强介导。当体循环中的儿茶酚胺和心脏交感神经末梢的局部释放达到毒性浓度时，它们可能破坏细胞完整性和特定的细胞和体液体防御，使心肌更容易受到感染。我们将通过七个具体目标来检验这一假设，这些目标采用了合作研究者实验室中目前可用的技术。我们将确定单独慢性可卡因治疗是否会引起心肌炎、坏死或细胞凋亡。2。我们将验证暴露于可卡因可以增强病毒暴露后小鼠对心肌炎的易感性的假设。3。我们将确定可卡因是否能增强病毒基因组的持久性。我们将通过测量T细胞功能和IgM水平来确定可卡因是否会损害人体对病毒感染的特异性防御。V.我们将确定可卡因的肾上腺素能或局部麻醉特性是否与病毒性心肌致病性增加有关。我们将通过使用交感神经溶解剂来验证儿茶酚胺介导的对肌细胞肾上腺素能受体的刺激是增加病毒性心肌病致病性的原因。7。我们将证明，可卡因对病毒性心肌致病性的增强与其他药物、食物和增加儿茶酚胺水平的活动具有协同作用。总之，这些结果将为可卡因滥用者病毒性心肌炎的病因提供新的机制信息，使我们能够确定普通人群中发生心肌炎的不同危险因素，并可能为预测谁可能因使用可卡因而使自己处于增加的额外风险中提供合理的基础，特别是在艾滋病毒暴露人群中。

项目成果

Cocaine enhances myocarditis induced by encephalomyocarditis virus in murine model.

可卡因增强小鼠模型中脑心肌炎病毒诱导的心肌炎。

• DOI: 10.1152/ajpheart.00648.2001
• 发表时间: 2002
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Wang,Ju-Feng;Zhang,Jielin;Min,Jiang-Yong;Sullivan,MatthewF;Crumpacker,ClydeS;Abelmann,WalterH;Morgan,JamesP
• 通讯作者: Morgan,JamesP

Propranolol ameliorates and epinephrine exacerbates progression of acute and chronic viral myocarditis.

• DOI: 10.1152/ajpheart.00258.2005
• 发表时间: 2005-10
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Ju-Feng Wang;A. Meissner;Sohail Malek;Yu Chen;Q. Ke;Jielin Zhang;V. Chu;T. Hampton;C. Crumpacker;W. Abelmann;I. Amende;J. Morgan