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.

项目总结

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