Impact of smoking and its cessation on systemic and airway immune activation

项目总结 吸烟率过高及其对艾滋病毒发病率和死亡率的重大贡献- 尽管抗逆转录病毒疗法有效，但吸烟仍是艾滋病毒感染人群中的一个主要健康风险。 吸烟对艾滋病毒引起的免疫功能障碍产生协同作用的机制仍然存在。 不清楚。我们的中心假设是，持续的艾滋病毒诱导的免疫功能障碍离开了肺 极易受到吸烟的进一步侮辱。吸烟进一步推动免疫调节途径，如 氧化应激和炎症增加，导致局部组织进一步破坏。肺部病理可以 导致肺部潜伏感染的肺泡巨噬细胞激活，产生低水平的艾滋病毒病毒血症，以及 使这种有利于炎症的环境永久化。此外，慢性氧化失衡会导致 仅局部组织损伤，但细胞DNA损伤，导致上皮基因表达改变。目标 1试图在一项对接受抗逆转录病毒药物治疗的艾滋病毒吸烟者的横断面研究中确定吸烟对慢性免疫系统的影响 通过评估细胞因子谱、免疫细胞表型和细胞ROS产生的差异 从从不吸烟的HIV感染者的呼吸道和血液中分离出来。这些地方和地方的关系 呼吸道上皮基因转录组的系统性免疫紊乱和残留病毒血症的证据 进行评估，以确定吸烟与艾滋病毒免疫功能障碍相互作用的生物学途径。在AIM 2为了进一步验证这一假设，我们提出了一项概念验证戒烟临床研究，以评估 实现戒烟的HIV吸烟者肺损伤的可逆性程度和性质 与那些继续吸烟的人相比。在这个单一地点的研究中，我们将采用密集吸烟 帮助从一家大型城市艾滋病毒感染门诊招募的参与者的戒烟计划 在有独特的综合临床研究基础设施的地方，实现戒烟。纵向的 将从那些能够达到10周的人身上收集戒烟前和戒烟后的样本 从肺和血中止血。我们将评估炎症水平、免疫激活和 氧化应激，并确定这些免疫中介途径是否与艾滋病毒残留的变化有关 病毒血症和肺上皮细胞基因表达。最后，利用现有资源，我们将比较 从我们的合作者已经收集的银行样本中发现了那些未受感染的吸烟者。这 艾滋病毒感染患者的戒烟研究将是此类研究中的第一项，并将提供纵向样本 从肺室和血室收集，并利用翻译方法通过 与病毒学、免疫学、基因转录和健康差异研究方面的专家合作。 了解吸烟与免疫激活相互作用的相对贡献和途径 慢性HIV疾病的炎症特征将有助于指导治疗干预措施的发展 阻止或逆转这些病理过程和随后的临床疾病。

PROJECT SUMMARY The exceedingly high rate of smoking and its substantial contribution to morbidity and mortality in the HIV- infected population despite effective ART makes smoking a major health risk in the HIV-infected population. The mechanism by which smoking exerts synergistic effects on HIV-induced immune dysfunction remains unclear. Our central hypothesis is that the persistent HIV-induced immune dysfunction leaves the lung exceeding vulnerable to further insults by smoking. Smoking further drives immune-mediate pathways, such as increase in oxidative stress and inflammation, to cause further local tissue destruction. The lung pathology can result in activation of latently infected alveolar macrophages in the lung to produce low level HIV viremia, and perpetuates this pro-inflammatory environment. Additionally, the chronic oxidative imbalance can cause not only local tissue damage but cellular DNA damage, which results in epithelial gene expression alterations. Aim 1 seeks to identify in a cross-sectional study of ART-treated HIV smokers chronic immune effects of smoking by evaluating for differences in cytokine profile and immune cell phenotype and ROS production of cells isolated in the airways and blood from HIV-infected never smokers. The relationships of these local and systemic immune perturbations with airway epithelial gene transcriptome and evidence of residual viremia will be evaluated to identify biological pathways by which smoking interacts with HIV immune dysfunction. In Aim 2 to further test the hypothesis we propose a proof-of-concept smoking cessation clinical study to assess the degree and nature of reversibility of lung damage among HIV smokers who achieve smoking cessation compared to those who continue to smoke. In this single site study, we will employ an intensive smoking cessation program to help study participants who are recruited from a large urban HIV-infected outpatient clinic where a unique integrated clinical research infrastructure is in place, achieve smoking cessation. Longitudinally samples will be collected pre-cessation and post-cessation from those who are able to achieve 10-week cessation from the lung and blood. We will evaluate the change in level of inflammation, immune activation and oxidative stress, and determine if these immune-mediate pathways are related to changes in HIV residual viremia and epithelial gene expression in the lung. Lastly, leveraging existing resources, we will compare these finding to those in uninfected smokers from banked samples collected already by our collaborator. This smoking cessation study in HIV-infected patients will be the first of its kind, with longitudinal specimen collection from both the lung and blood compartments, and utilizing translational approaches through collaborations with experts in virology, immunology, gene transcription and health disparity research. Understanding the relative contribution and pathways by which smoking interacts with immune activation and inflammation characteristic of chronic HIV disease will help guide development of therapeutic interventions to halt or reverse these pathological processes and ensuing clinical disease.