The Impact of Oxidative Stress on HIV-induced Lung Disease

氧化应激对 HIV 引起的肺病的影响

• 批准号: 9116287
• 负责人: JESSE ROMAN
• 金额: $ 48.85万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116287
• 关键词: Address; Binding; Blood; Brain; Bronchoalveolar Lavage Fluid; Cause of Death; Cells; Chronic Disease; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical Research; Cysteine; Data; Data Analyses; Databases; Dementia; Deposition; Deterioration; Diet; Disease; Disulfides; Epidemiologic Studies; Epithelial; Fibroblasts; Fibronectins; Glycoproteins; Goals; Growth; HIV; HIV Envelope Protein gp120; HIV-1; Health; Immunologist; In Vitro; Incidence; Individual; Infection; Inflammatory; Interleukin-1 beta; Interleukins; Intervention; Lung; Lung Inflammation; Lung diseases; Malignant neoplasm of lung; Mediating; Mesenchymal; Morbidity - disease rate; Myofibroblast; Nicotinic Receptors; Oxidation-Reduction; Oxidative Stress; Patients; Peptide Hydrolases; Physicians; Process; Production; Proteins; Pulmonary Fibrosis; Pulmonary Hypertension; Research Personnel; Scientist; Severities; Signal Transduction; Smoking; Structure of parenchyma of lung; Sulfhydryl Compounds; Testing; Tissues; Transforming Growth Factors; Universities; Virus Diseases; antiretroviral therapy; base; clinical investigation; cytokine; design; env Gene Products; follow-up; genetic makeup; injury and repair; mortality; oxidant stress; oxidation; prevent; programs; pulmonary function; research and development; transdifferentiation

DESCRIPTION (provided by applicant): Lung diseases are major causes of morbidity and mortality in patients infected with the Human Immunodeficiency Virus (HIV). Currently antiretroviral therapy (ART) has changed HIV into a chronic disease. In the pre-ART era, pulmonary infections were very common. In patients with ART, however, pulmonary infections are less frequent and noninfectious lung disorders, such as COPD, pulmonary hypertension, lung cancer, and pulmonary fibrosis are emerging as important causes of illness. These are important cause of morbidity and mortality, yet the mechanisms responsible for these disorders in HIV patients are unknown. All pulmonary disorders mentioned above are associated with, among other things, lung inflammation and tissue remodeling characterized by alterations in matrix expression, deposition, and degradation. Interestingly, HIV infection is also associated with oxidant stress caused by oxidation of the thiol disulfide couple cysteine (Cys)/cysteine (CySS) redox potential (Eh); also termed Eh Cys/CySS. This is important because in vitro studies show that an oxidized Eh Cys/CySS stimulates lung cells to produce more fibronectin (a matrix glycoprotein implicated in tissue injury and repair), transforming growth factor b (a pro-fibrotic growth factor), and pro-inflammatory cytokines like interleukin-1b. It also stimulates the proliferation and epithelial- mesenchymal transformation of lung fibroblasts, processes implicated in tissue remodeling. These data suggest that HIV-related oxidation of Eh Cys/CySS may promote lung tissue remodeling. We have shown that one mechanism by which oxidation of Eh Cys/CySS stimulates tissue remodeling is through the activation of nicotinic acetylcholine receptors (nAChRs). This is intriguing considering that HIV-1 proteins like gp120 bind and increase the expression and signaling of nAChRs expressed in brain, and this mechanism has been implicated in HIV-related dementia. We hypothesize that patients with HIV infection have oxidation of the Eh Cys/CySS which, together with gp120, activates nAChR-mediated signaling in lung cells and leads to their expression of cellular products with pro-inflammatory and pro-fibrotic effects such as cytokines and growth factors, matrix glycoproteins, and tissue proteases. The persistent and exaggerated production of these factors activates lung tissue remodeling thereby promoting HIV-related lung disease. The type of disease developed (e.g., COPD versus pulmonary hypertension), however, is dependent on both the genetic makeup of the subject and external factors such as smoking and infection. It is important that this hypothesis be tested considering that diet and other interventions have been shown to influence Eh Cys/CySS (9). If found to be causal, Eh Cys/CySS and nAChRs can be targeted for intervention in the hope of reducing the incidence and/or severity of HIV-related non-infectious lung disease.

描述（由申请人提供）：肺部疾病是人类免疫缺陷病毒（HIV）感染患者发病和死亡的主要原因。目前，抗逆转录病毒疗法（ART）已将艾滋病毒变成一种慢性疾病。在抗逆转录病毒疗法出现之前，肺部感染非常常见。然而，在ART患者中，肺部感染不太常见，非感染性肺部疾病，如COPD，肺动脉高压，肺癌和肺纤维化正在成为疾病的重要原因。这些都是发病率和死亡率的重要原因，但在艾滋病毒患者中负责这些疾病的机制尚不清楚。上述所有肺部疾病都与肺部炎症和组织重塑相关，其特征在于基质表达、沉积和降解的改变。有趣的是，HIV感染还与由巯基二硫键偶半胱氨酸（Cys）/半胱氨酸（CySS）氧化还原电位（Eh）氧化引起的氧化应激相关;也称为Eh Cys/CySS。这一点很重要，因为体外研究表明，氧化的Eh Cys/CySS刺激肺细胞产生更多的纤连蛋白（一种与组织损伤和修复有关的基质糖蛋白）、转化生长因子B（一种促纤维化生长因子）和促炎细胞因子（如白细胞介素-1 B）。它还刺激了 肺成纤维细胞的增殖和上皮-间质转化，涉及组织重塑的过程。这些数据表明，HIV相关的Eh Cys/CySS氧化可能促进肺组织重塑。我们已经表明，Eh Cys/CySS氧化刺激组织重塑的一种机制是通过激活烟碱乙酰胆碱受体（nAChR）。考虑到HIV-1蛋白如gp 120结合并增加脑中表达的nAChR的表达和信号传导，这是有趣的，并且这种机制与HIV相关的痴呆有关。我们假设HIV感染患者具有Eh Cys/CySS的氧化，Eh Cys/CySS与gp 120一起激活肺细胞中nAChR介导的信号传导，并导致其表达具有促炎和促纤维化作用的细胞产物，如细胞因子和生长因子、基质糖蛋白和组织蛋白酶。这些因子的持续和过度产生激活肺组织重塑，从而促进HIV相关的肺部疾病。疾病的类型（例如，然而，COPD与肺动脉高压之间的差异取决于受试者的遗传组成和外部因素，如吸烟和感染。考虑到饮食和其他干预措施已被证明会影响Eh Cys/CySS（9），对这一假设进行检验是很重要的。如果发现是因果关系，Eh Cys/CySS和nAChR可以作为干预的目标，希望降低HIV相关非感染性肺部疾病的发病率和/或严重程度。