Studies of Cigarette Smoke Exposure in an Animal Model of HIV-1 Infection

HIV-1 感染动物模型中香烟烟雾暴露的研究

• 批准号: 8624954
• 负责人: WALTER ROYAL
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624954
• 关键词: Adult; Animal Model; Animals; Basal Ganglia; Behavioral; Blood - brain barrier anatomy; Brain; Cells; Chemicals; Cigarette; Cigarette Smoker; Clinical; Cognitive; Complication; Control Groups; Development; Exposure to; General Population; Generations; Glycoproteins; Grant; HIV; HIV Infections; HIV-1; Health; Human; Immune; Immune Cell Activation; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Injury; Lead; Leukocytosis; Link; Medial; Mediating; Mediator of activation protein; Modeling; Neurocognitive; Neuroglia; Neurons; Neuropsychological Tests; Nicotine; Oxidative Stress; Pathway interactions; Performance; Permeability; Plasma; Poison; Prefrontal Cortex; Prevalence; Property; Proteins; Rattus; Recording of previous events; Relative (related person); Risk; Role; Smoker; Smoking; Suggestion; Testing; Transgenic Organisms; Viral Load result; Woman; antiretroviral therapy; behavior test; biological adaptation to stress; chemokine; cigarette smoking; cigarette smoking; cohort; cytokine; gp160; immune activation; improved; mortality; neurotoxic; oxidative damage; public health relevance; response; smoking prevalence

DESCRIPTION (provided by applicant): Neurocognitive impairment (NCI), often a devastating complication of HIV infection, is on the rise as infected individuals survive longer with the introduction of effective antiretroviral therapy. Factors that underlie the occurrence of NCI include the release of neurotoxic factors in brains of such individuals as a result of enhanced activation of immune cells and glia, release of cytokines, chemokines and other soluble mediators of infection. In addition, HIV proteins, particularly HIV glycoprotein and tat, have been demonstrated to be directly toxic to neurons. In this grant we will develop a model that will allow for the examination of effects of cigarette smoke (CS) exposure as another potential co-factor in increasing the risk of NCI in HIV infected individuals. Our hypothesis is that CS exposure can increase such risk by inducing inflammation and oxidative stress response in brain. We also hypothesize that these responses can override potentially beneficial effects that have been demonstrated from nicotine in suppressing inflammation and enhancing cognitive abilities. It is estimated that over 40% of HIV+ individuals are cigarette smokers, a number that is twice the estimated prevalence of smoking among adults in the general population. There are greater than 4,000 chemicals and toxic substances in CS and a number have been shown to potentially cause serious and permanent negative health consequences due to the induction of inflammatory and oxidative damage. Cigarette smoking has been shown to alter a number of innate and adaptive immune mechanisms and can elicit cellular oxidative stress responses that can promote injury. In smokers, CS causes a leukocytosis and smoking is associated with higher plasma HIV viral loads and an increased mortality. Nicotine promotes cigarette smoking through its addictive properties. However, in individuals with HIV infection, nicotine may improve cognitive performance. Nicotine has been also shown to suppress immune activation and proinflammatory responses. Therefore, it has been speculated that nicotine or its metabolites may be useful for treating NCI. In previous studies in adult Lewis rats, we demonstrated that CS exposure can result in marked inflammatory and oxidative stress responses in the brains of the exposed animals. Therefore, in the proposed studies we will examine the effects of nicotine delivered in CS on behavioral function in the HIV-1 transgenic rat model as compare to nicotine alone and to CS that contains minimal amounts of nicotine. We will also examine the relative effects of such exposures on the generation of inflammation and oxidative stress in the brains of the animals. These studies should provide clues regarding mechanisms that might contribute to the occurrence and progression of abnormalities that have been linked to the development and progression of NCI in HIV infected individuals.

描述（由申请人提供）：神经认知障碍（NCI）通常是艾滋病毒感染的毁灭性并发症，随着受感染的个体的生存更长的时间，随着引入有效的抗逆转录病毒疗法的生存更长的时间。 NCI发生的基础的因素包括由于免疫细胞和神经胶质的激活，细胞因子的释放，趋化因子和其他可溶性感染介质的释放而释放了此类个体的神经毒性因子。此外，HIV蛋白，尤其是HIV糖蛋白和TAT已是 证明对神经元有毒。在这笔赠款中，我们将开发一个模型，该模型将允许 为了检查香烟烟雾（CS）暴露的作用，作为增加HIV感染个体NCI风险的另一个潜在的共同因素。我们的假设是，CS暴露可以通过诱发脑部炎症和大脑中的氧化应激反应来增加这种风险。我们还假设这些反应可以覆盖尼古丁在抑制炎症和增强认知能力方面所证明的潜在有益作用。据估计，超过40％的艾滋病毒+个体是吸烟者，这是一般人群中成年人吸烟率估计的两倍。 CS中有超过4,000种化学物质和有毒物质，并且由于诱导炎症和氧化损伤，已显示出许多可能造成严重和永久性的健康后果。吸烟已被证明会改变许多先天和适应性免疫机制，并可能引起可以促进损伤的细胞氧化应激反应。在吸烟者中，CS引起白细胞增多和吸烟与较高的血浆HIV病毒载量和死亡率增加有关。尼古丁通过其上瘾的特性促进吸烟。但是，在患有艾滋病毒感染的个体中，尼古丁可以改善认知能力。尼古丁也已被证明可以抑制免疫激活和促炎反应。因此，已经推测尼古丁或其代谢物可能对治疗NCI有用。在成年刘易斯大鼠的先前研究中，我们证明了CS暴露会导致暴露动物的大脑中明显的炎症和氧化应激反应。因此，在拟议的研究中，我们将研究CS中尼古丁对HIV-1转基因大鼠模型中行为功能的影响，与单独的尼古丁相比，与含有最小量尼古丁的CS相比。我们还将检查这种暴露对动物大脑中炎症和氧化应激产生的相对影响。这些研究应提供有关可能有助于与HIV感染个体NCI的发展和进展有关的异常发生和进展的机制的线索。