Cocaine Smoking Effects on Lung Immunity & Host Defense

描述(由申请人提供)：在过去的8年里，我们已经确定了几个与强效可卡因有关的新的和潜在的严重健康后果。我们的研究主要考察了两个方面：1)强效可卡因对肺部炎症、损伤和生理的影响；2)可卡因对免疫和宿主防御的影响。这第二条线，可卡因对免疫和宿主防御的影响，已成为这场竞争更新的主要焦点。在这方面，我们已经证明，从吸毒者的肺中回收的肺泡巨噬细胞在上调诱导型一氧化氮合酶、产生一氧化氮和限制金黄色葡萄球菌生长的能力方面存在明显不足。当在小鼠模型中进行测试时，可卡因对T辅助细胞因子(Th1/Th2)的平衡产生不利影响，导致转化生长因子-β和IL-10的过度表达，抑制T细胞功能，并允许移植的肺肿瘤细胞失控生长。新的实验已经确定，在体外和体内，Sigma受体都可能参与这些效应。我们还开发了一个重要的新模型来研究可卡因和艾滋病毒之间的相互作用。给感染了HIV的人外周血白细胞重组的严重联合免疫缺陷(SCID)小鼠注射可卡因后，病毒复制显著增加，CD4计数和CD4/CD8比值下调，HIV辅助受体的表达发生变化。最近，我们在从吸食毒品的受试者身上采集的血液中发现了免疫功能的改变。在这些发现的基础上，我们提出了3个具体目标：1)在HuPBL/SCID和SCID-Hu模型中，确定可卡因促进HIV复制和体内感染的机制。2)确定可卡因抑制小鼠抗肿瘤免疫反应(对T细胞、树突状细胞、细胞因子的影响)的途径(S)，并阐明Sigma受体信号在此过程中的作用。3)展示与可卡因相关的艾滋病毒辅助因素和免疫功能变化的类型和程度，因为它们发生在一个著名的强效可卡因使用者队列中。还将在多中心艾滋病队列研究(MACS)建立的数据库中寻找吸毒史与艾滋病毒相关疾病的发展和进展之间的相关性。通过这些研究的完成，我们将获得相关的动物数据和人类临床相关数据，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艾滋病毒发生和发展至关重要的危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.