Cocaine Smoking Effects on Lung Immunity & Host Defense

描述（由申请人提供）：在过去的8年中，我们已经确定了与快克可卡因相关的几种新的和潜在的严重健康后果。我们的研究已经检查了两个一般领域：1）快克可卡因对肺部炎症，损伤和生理学的影响; 2）可卡因对免疫和宿主防御的影响。这第二条调查线，可卡因对免疫和宿主防御的影响，已成为这次竞争性更新的主要焦点。在这方面，我们已经证明，肺泡巨噬细胞回收的裂缝用户的肺表现出明显的缺陷，在他们的能力上调诱导型一氧化氮合酶，产生一氧化氮，并限制金黄色葡萄球菌的生长。当在小鼠模型中测试时，可卡因不利地调节T辅助细胞因子（Thl/Th 2）平衡，导致TGF-β和IL-10的过度表达，抑制T细胞功能，并允许植入的肺肿瘤细胞不受控制地生长。新的实验已经确定σ受体可能参与体外和体内的这些效应。我们还开发了一个重要的新模型，用于研究可卡因与艾滋病毒之间的相互作用。可卡因给药严重联合免疫缺陷（SCID）小鼠重建与人外周血白细胞（huPBL/SCID），并感染HIV，导致病毒复制，下调CD 4计数和CD 4/CD 8比值，并在HIV共受体的表达的变化显着增加。最近，我们在从滥用可卡因的受试者身上采集的血液中发现了免疫功能的改变。基于这些发现，我们提出了3个具体目标：1）确定可卡因在huPBL/SCID和SCID-hu模型中增强体内HIV复制和感染的机制。2)确定可卡因抑制小鼠抗肿瘤免疫模型中免疫应答的途径（对T细胞、树突状细胞、细胞因子的影响），并描述σ受体信号传导在此过程中的作用。3)证明可卡因相关的HIV辅助因子和免疫功能改变的类型和程度，因为它们发生在一个良好描述的快克可卡因使用者队列。还将在多中心艾滋病队列研究（MACS）建立的数据库中寻找快克使用史与艾滋病毒相关疾病的发展和进展之间的相关性。通过完成这些研究，我们将获得相关的动物数据和人类临床相关性，将吸入性可卡因滥用与免疫功能和宿主防御的调节以及对HIV发病机制和进展重要的风险因素的调节联系起来。

DESCRIPTION (provided by applicant): Over the past 8 years we have identified several novel and potentially serious health consequences associated with crack cocaine. Our research has examined two general areas: 1) the effects of crack cocaine on lung inflammation, injury and physiology and 2) the impact of cocaine on immunity and host defense. This second line of investigation, the impact of cocaine on immunity and host defense, has become the primary focus for this competitive renewal. In this respect, we have demonstrated that alveolar macrophages recovered from the lungs of crack users exhibit a marked deficiency in their ability to upregulate inducible nitric oxide synthase, produce nitric oxide, and limit the growth of Staphylococcus aureus. When tested in a mouse model, cocaine adversely regulated T-helper cytokine (Thl/Th2) balance leading to over-expression of TGF-beta and IL-10, suppressed T cell function, and allowed the uncontrolled growth of implanted lung tumor cells. Novel experiments have identified sigma receptors as likely to be involved in these effects both in vitro and in vivo. We have also developed an important new model for studying the interaction between cocaine and HIV. Administration of cocaine to severe-combined immunodeficiency (SCID) mice reconstituted with human peripheral blood leukocytes (huPBL/SCID), and infected with HIV, results in dramatic increases in viral replication, down-regulation of CD4 counts and CD4/CD8 ratios, and changes in expression of HIV co-receptors. More recently, we have identified altered immune function in blood collected from crack-abusing subjects. Building on these findings, we propose 3 specific aims' 1) To define the mechanisms by which cocaine enhances HIV replication and infection in vivo in the huPBL/SCID and SCID-hu models. 2) To determine the pathway(s) by which cocaine suppresses immune responses in a murine model of anti-tumor immunity (effects on T cells, dendritic cells, cytokines) and delineate the role of the sigma-receptor signaling in this process. 3) To demonstrate the type and magnitude of cocaine-related alterations in HIV co-factors and immune function as they occur in a well-described cohort of crack cocaine users. Correlations will also be sought between a history of crack use and the development and progression of HIV-related diseases in an established database from the Multicenter AIDS Cohort Study (MACS). By the completion of these studies we will have relevant animal data and human clinical correlates linking inhaled cocaine abuse to the regulation of immune function and host defense, and the modulation of risk factors important to the pathogenesis and progression of HIV.