The Impact of Oxidative Stress on HIV-induced Lung Disease

描述(申请人提供)：肺部疾病是感染人类免疫缺陷病毒(HIV)患者发病和死亡的主要原因。目前，抗逆转录病毒疗法(ART)已经将艾滋病毒变成了一种慢性病。在抗逆转录病毒治疗之前的时代，肺部感染非常常见。然而，在ART患者中，肺部感染的发生率较低，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重要的致病原因。这些都是导致发病率和死亡率的重要原因，但造成艾滋病毒患者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有关，其特征是基质表达、沉积和降解的改变。有趣的是，HIV感染还与氧化应激有关，氧化应激是由硫醇二硫键对半胱氨酸(Cys)/半胱氨酸(Cyss)氧化还原电位(Eh)引起的，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维连接蛋白(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1b。它还刺激了 肺成纤维细胞的增殖和上皮间质转化，这些过程与组织重塑有关。这些数据表明，HIV相关的Eh Cys/Cyss氧化可能促进肺组织重塑。我们已经证明，氧化Eh Cys/Cyss刺激组织重塑的一个机制是通过激活烟碱型乙酰胆碱受体(NAChRs)。考虑到像gp120这样的HIV-1蛋白结合并增加脑内表达的nAChRs的表达和信号，这一点很有趣，这一机制已被认为与HIV相关性痴呆有关。我们假设HIV感染患者有Eh Cys/Cyss的氧化，它与gp120一起激活了nAChR介导的肺细胞信号转导，并导致他们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。这些因子的持续和夸大的产生激活了肺组织重塑，从而促进了艾滋病毒相关的肺部疾病。然而，疾病的类型(例如，慢性阻塞性肺病与肺动脉高压)既取决于受试者的基因构成，也取决于吸烟和感染等外部因素。考虑到饮食和其他干预措施已被证明影响Eh Cys/Cyss(9)，对这一假说进行检验是很重要的。如果被发现是原因，Eh Cys/Cyss和nAChRs可以作为干预的目标，希望减少艾滋病毒相关非传染性肺部疾病的发生率和/或严重程度。

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.