HIV-associated Chronic Obstructive Pulmonary Disease

HIV 相关的慢性阻塞性肺疾病

基本信息

批准号：
9302513
负责人：
Neerad Mishra
金额：
$ 53.89万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302513
关键词：
Acetylcholine Acquired Immunodeficiency Syndrome Address Age Alveolar Animals Anti-Retroviral Agents Applications Grants Architecture Asthma Biological Assay Breathing Bronchoalveolar Lavage Fluid CXCR4 gene Cause of Death Cell Culture Techniques Cell Line Cells Characteristics Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Chronic lung disease Cigarette Smoker Combined Modality Therapy 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 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 Nicotine 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 experimental study gamma-Aminobutyric Acid immunoreactivity improved morphometry mortality novel pathogen public health relevance receptor response simian human immunodeficiency virus synergism

项目摘要

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（由应用提供）：在进行抗逆转录病毒疗法（ART）之前，包括高活性艺术（HAART），肺部疾病是艾滋病患者死亡的主要原因。尽管ART极大地改善了感染HIV的受试者的发病率和死亡率，但慢性肺部疾病（如慢性阻塞性肺部疾病（COPD），慢性支气管炎和哮喘）的发生在该人群中仍然很高。吸烟在HIV感染的患者中非常普遍，吸烟是人类COPD和慢性支气管炎的主要原因。但是，由于吸烟史类似，COPD比未感染的吸烟者更为普遍，并且在感染HIV的年龄年龄较小。最近的报告表明，艾滋病毒是开发COPD的独立风险因素。 COPD是一种进行性阻塞性肺疾病，没有已知的治愈方法。 COPD，哮喘和慢性支气管炎的一个共同特征是气道粘液过量生产。虽然气道粘液在遗传病原体和成分的粘膜钙清除率中很重要，但过量的粘液有助于气道异议，并且是许多病原体生长的绝佳培养基，这可能会加速该疾病并引起COPD加剧。我们最近的结果表明，尽管有ART，SIV和HIV感染的肺含有大量粘液和GP120免疫反应性。此外，细胞培养研究表明，正常人支气管上皮（NHBE）细胞的原发性培养表达CD4和CXCR4，但不表达CCR5，并被X4HIV-1产生有效的感染。此外，在NHBE细胞中，少于10 ng/ml = 8 x 10-11m x4-HIV GP120，诱导粘液产生和粘液细胞增生/化生。由HIV-1 GP120诱导的粘液产生受CXCR4，烟碱乙酰胆碱受体和γ-氨基丁基酸性受体的调节。在啮齿动物模型中，越来越多的证据表明，在COPD的发展中，香烟烟雾与某些病毒感染之间存在协同作用。基于这些研究，我们假设HIV-1和香烟烟雾合成以加速COPD的发展，而HIV-GP120通过肺部过量的粘液产生来促进COPD加剧。实际上，最近的证据将SHIV感染与气道猴子的阻塞性变化联系起来。在此赠款应用中，我们建议使用cernomolgus猕猴，SHIV感染和Haart（Tenofovir，Emtricabine和Elvitegravir的组合）来确定HIV的独立和/或香烟在COPD开发中的烟雾以及COPD开发中的烟雾（AIM 1）（AIM 1），以及促进HIV-GP120的组成部分。我们认为，这是了解COPD开发中吸烟，艾滋病毒感染和艺术之间相互作用的第一项研究，并将提供信息，有助于减少COPD在受HIV感染的受试者中的事件。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HIF-1α Plays a Critical Role in the Gestational Sidestream Smoke-Induced Bronchopulmonary Dysplasia in Mice.

DOI：
10.1371/journal.pone.0137757
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Singh SP;Chand HS;Gundavarapu S;Saeed AI;Langley RJ;Tesfaigzi Y;Mishra NC;Sopori ML
通讯作者：
Sopori ML