HIV-associated Chronic Obstructive Pulmonary Disease

HIV 相关的慢性阻塞性肺疾病

• 批准号: 9100911
• 负责人: Neerad Mishra
• 金额: $ 61.43万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100911
• 关键词: Acetylcholine; Acquired Immunodeficiency Syndrome; Address; Age; Alveolar; Animals; Anti-Retroviral Agents; Applications Grants; Architecture; Asthma; Biological Assay; Breathing; Bronchoalveolar Lavage Fluid; CCR5 gene; CXCR4 gene; Cause of Death; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette Smoker; Culture Media; Data; Development; Diffuse; Disease; Epidemiology; Epithelial; Epithelial Cells; Fibrosis; Forced expiratory volume function; Goblet Cells; Growth; Growth Factor Receptors; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; HIV-1; Health; Hematoxylin and Eosin Staining Method; Highly Active Antiretroviral Therapy; Human; Hyperplasia; Incidence; Infection; Kinetics; Link; Longevity; Lung; Lung Compliance; Lung diseases; MUC5AC gene; Macaca; Macaca fascicularis; Metalloproteases; Metaplasia; Monkeys; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Nicotinic Receptors; Obstructive Lung Diseases; Particulate; Pathway interactions; Patients; Population; Production; Pulmonary Emphysema; Pulmonary Fibrosis; Reporting; Respiratory Signs and Symptoms; Respiratory physiology; Risk Factors; Rodent Model; Role; SIV; Smoke; Smoker; Smoking; Smoking History; Staining method; Stains; Tenofovir; Testing; Trichrome stain; Viral Respiratory Tract Infection; Virus Diseases; airway obstruction; antiretroviral therapy; base; chemokine; cigarette smoking; cytokine; early onset; gamma-Aminobutyric Acid; immunoreactivity; improved; morphometry; mortality; novel; pathogen; receptor; research study; response; simian human immunodeficiency virus; synergism

 DESCRIPTION (provided by applicant): Prior to antiretroviral therapy (ART) including highly active ART (HAART), lung diseases were the major cause of death in AIDS patients. While ART has dramatically improved the morbidity and mortality in HIV-infected subjects, the incidence of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, and asthma remain high in this population. Smoking is highly prevalent in HIV-infected patients and smoking is the leading cause of COPD and chronic bronchitis in humans; however, with a similar smoking history COPD is more common and appears at younger age in HIV-infected than uninfected smokers. Recent reports suggest HIV as possible independent risk factors for the development of COPD. COPD is a progressive obstructive lung disease with no known cure. A common feature of COPD, asthma, and chronic bronchitis is overproduction of airway mucus. While airway mucus is important in the mucociliary clearance of inhaled pathogens and particulates, excessive mucus contributes to airway obstruction and is an excellent medium for the growth of many pathogens, which may accelerate the disease and cause COPD exacerbations. Our recent results indicate that, in spite of ART, SIV- and HIV-infected lungs contain substantial amounts of mucus and gp120 immunoreactivity. Moreover, cell culture studies indicated that primary cultures of normal human bronchial epithelial (NHBE) cells express CD4 and CXCR4 but not CCR5 and are productively infected by X4HIV-1. Moreover, as little as 10 ng/ml ≡ 8 x 10-11M X4-HIV gp120, induces mucus production and mucous cell hyperplasia/metaplasia in NHBE cells. Mucus production induced by HIV-1 gp120 is regulated by CXCR4, nicotinic acetylcholine receptors, and γ-aminobutyric acidA receptors. In rodent models, increasing evidence shows a synergy between cigarette smoke and some viral infections in the development of COPD. Based on these studies, we hypothesize that HIV-1 and cigarette smoke synergizes to accelerate the development of COPD, and HIV-gp120 promotes COPD exacerbation through excessive mucus production in the lung. Indeed, recent evidence links SHIV infection to airway obstructive changes in cynomolgus monkeys. In this grant application we propose to use cynomolgus macaques, SHIV infection, and HAART (combination of tenofovir, emtrictabine, and elvitegravir) to ascertain independent and/or synergistic roles of HIV, and cigarette smoke in the development of COPD (aim 1), and delineate the mechanism by which HIV-gp120 promotes mucus formation in NHBE cells (aim 2). We believe that this is the first study to understand the interaction between smoking, HIV infection, and ART in the development of COPD and will provide information that will help to reduce the incidence of COPD in HIV-infected subjects.

 描述（由申请人提供）：在抗逆转录病毒治疗（ART）（包括高效ART（HAART））之前，肺部疾病是艾滋病患者的主要死因。虽然ART显著改善了HIV感染受试者的发病率和死亡率，但慢性肺病如慢性阻塞性肺病（COPD）、慢性支气管炎和哮喘的发病率在这一人群中仍然很高。吸烟在HIV感染患者中非常普遍，吸烟是人类COPD和慢性支气管炎的主要原因;然而，吸烟史相似的COPD更常见，并且在HIV感染者中出现的年龄比未感染的吸烟者小。最近的报告表明，HIV可能是COPD发展的独立危险因素。COPD是一种进行性阻塞性肺病，目前尚无治愈方法。COPD、哮喘和慢性支气管炎的共同特征是气道粘液过度产生。虽然气道粘液在吸入的病原体和颗粒的粘膜纤毛清除中是重要的，但过多的粘液有助于气道阻塞，并且是许多病原体生长的极好介质，这可能加速疾病并导致COPD恶化。我们最近的研究结果表明，尽管ART，SIV和HIV感染的肺含有大量的粘液和gp 120免疫反应性。此外，细胞培养研究表明，正常人支气管上皮（NHBE）细胞的原代培养物表达CD 4和CXCR 4，但不表达CCR 5，并被X4 HIV-1有效感染。此外，低至10 ng/ml × 10- 11 M X4-HIV gp 120可诱导NHBE细胞中的粘液产生和粘液细胞增生/化生。HIV-1 gp 120诱导的粘液产生受CXCR 4、烟碱乙酰胆碱受体和γ-氨基丁酸A受体调节。在啮齿动物模型中，越来越多的证据表明香烟烟雾和一些病毒感染在COPD的发展中具有协同作用。基于这些研究，我们假设HIV-1和香烟烟雾协同作用加速COPD的发展，HIV-gp 120通过肺中过多的粘液产生促进COPD恶化。事实上，最近的证据将SHIV感染与食蟹猴的气道阻塞性变化联系起来。在该资助申请中，我们提出使用食蟹猴、SHIV感染和HAART（替诺福韦、恩曲他滨和埃替拉韦的组合）来确定HIV和香烟烟雾在COPD发展中的独立和/或协同作用（目的1），并描述HIV-gp 120促进NHBE细胞中粘液形成的机制（目的2）。我们认为，这是第一项了解吸烟、HIV感染和ART在COPD发展中相互作用的研究，并将提供有助于降低HIV感染受试者COPD发病率的信息。