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

吸烟及其戒烟对全身和气道免疫激活的影响

• 批准号: 10187537
• 负责人: Nina H. Lin
• 金额: $ 79.86万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187537
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Alveolar Macrophages; Ambulatory Care Facilities; Attenuated; Automobile Driving; Bacterial Pneumonia; Biological; Blood; Cardiovascular Diseases; Cells; Cessation of life; Characteristics; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Collaborations; Cross-Sectional Studies; DNA Damage; DNA Sequence Alteration; Data; Development; Disease; Epithelial; Epithelial Cells; Functional disorder; Future; Gene Expression; Gene Expression Alteration; General Population; Genes; Genetic Transcription; HIV; HIV Infections; Health; High Prevalence; Immune; Immune System Diseases; Immunologics; Immunology; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interruption; Intervention; Intervention Studies; Lead; Link; Literature; Lung; Lung Inflammation; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Morbidity - disease rate; Nature; Oxidative Stress; Participant; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Patients; Persons; Phenotype; Play; Population; Production; Public Health; Pulmonary Emphysema; Pulmonary Pathology; Reactive Oxygen Species; Recovery; Research; Research Infrastructure; Residual state; Resources; Respiratory System; Risk; Risk Factors; Role; Sampling; Signal Transduction; Site; Smoke; Smoker; Smoking; Smoking Cessation Intervention; Smoking History; Testing; Therapeutic Intervention; Time; Tissues; Transcription Alteration; Viremia; age related; airway epithelium; antiretroviral therapy; arm; cell injury; cigarette smoking; cytokine; health disparity; immune activation; inflammatory milieu; lung development; lung injury; microbial; monocyte; mortality; never smoker; non-smoker; programs; public health priorities; recruit; response; sample collection; smoking cessation; smoking exposure; smoking prevalence; systemic inflammatory response; therapeutic development; therapeutic target; tissue injury; transcriptome; translational approach; virology

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.

项目摘要 吸烟率极高及其对HIV的发病率和死亡率的大量贡献 尽管有效的艺术，受感染的人口使吸烟在感染HIV的人群中成为主要的健康风险。 吸烟对HIV诱导的免疫功能障碍的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HIV诱导的免疫功能障碍离开肺 超越吸烟而容易受到进一步侮辱的影响。吸烟进一步驱动免疫媒介途径，例如 氧化应激和炎症的增加，导致进一步的局部组织破坏。肺病理可以 导致肺部受感染的潜在感染肺泡巨噬细胞的激活，以产生低水平的HIV病毒血症，并且 这种促炎环境永久存在。另外，慢性氧化失衡不会导致 只有局部组织损伤，而是细胞DNA损伤，这会导致上皮基因表达改变。目的 1试图在对ART治疗的HIV吸烟者的横断面研究中识别吸烟的慢性免疫作用 通过评估细胞因子谱和免疫细胞表型的差异和细胞的ROS产生 在呼吸道中孤立，并从艾滋病毒感染者的血液中孤立。这些本地和 气道上皮基因转录组和残留病毒血症的证据的全身免疫扰动将 进行评估以识别吸烟与HIV免疫功能障碍相互作用的生物学途径。目标 2为了进一步检验假设，我们提出了一项概念证明的戒烟临床研究，以评估 戒烟的艾滋病毒吸烟者中肺损害可逆性的程度和性质 与那些继续吸烟的人相比。在这项单一站点研究中，我们将采用大量吸烟 戒烟计划，以帮助研究来自大型城市HIV的门诊诊所的参与者 在建立独特的综合临床研究基础设施的地方，可以戒烟。纵向 将从能够实现10周的人那里收集样本前的筛选和接收后 肺和血液停止。我们将评估炎症水平的变化，免疫激活和 氧化应激，并确定这些免疫 - 中途径是否与HIV残留的变化有关 肺中的病毒血症和上皮基因表达。最后，利用现有资源，我们将比较这些 从我们的合作者收集的那些未感染的吸烟者中发现的那些未感染的吸烟者。这 在艾滋病毒感染患者中进行的戒烟研究将是同类患者中的第一个，纵向标本 从肺和血室收集，并利用翻译方法 与病毒学，免疫学，基因转录和健康差异研究专家的合作。 了解吸烟与免疫激活相互作用的相对贡献和途径 慢性艾滋病毒疾病的炎症特征将有助于指导治疗干预措施的发展 停止或扭转这些病理过程并随之而来的临床疾病。

项目成果

Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.

接触烟草烟雾会招募炎症性空腔单核细胞，为结核分枝杆菌建立允许的肺部生态位。

• DOI: 10.1126/scitranslmed.adg3451
• 发表时间: 2023
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Corleis,Björn;Tzouanas,ConstantineN;Wadsworth2nd,MarcH;Cho,JosalynL;Linder,AliceH;Schiff,AbigailE;Zessin,Björn;Stei,Fabian;Dorhoi,Anca;Dickey,AmyK;Medoff,BenjaminD;Shalek,AlexK;Kwon,DouglasS
• 通讯作者: Kwon,DouglasS