Role of NLRX1 in cigarette smoke-induced pulmonary inflammation and remodeling

NLRX1 在香烟烟雾诱导的肺部炎症和重塑中的作用

• 批准号: 9175689
• 负责人: Min-Jong Kang
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175689
• 关键词: Address; Air; Alveolar Macrophages; Apoptotic; Attenuated; Binding; CASP1 gene; Cell Death; Cells; Characteristics; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Research; DNA Damage; Development; Disease; Disease Progression; Disease model; Ensure; Excision; Gene Delivery; Goals; Grant; Health; Human; Inflammatory; Interleukin-18; Intervention; Leucine-Rich Repeat; Lung; Mediating; Medical; Metalloproteases; Mitochondria; Mitochondrial Proteins; Modality; Monitor; Mus; Mutant Strains Mice; Nucleotides; Organelles; PTEN gene; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmacologic Substance; Phenotype; Phosphotransferases; Play; Population; Proteins; Pulmonary Emphysema; Pulmonary Inflammation; Quality Control; Reactive Oxygen Species; Research; Role; Severities; Smoking; Stress; Structure of parenchyma of lung; Syndrome; Testing; Therapeutic; Transgenic Organisms; Wild Type Mouse; base; cigarette smoke-induced; cigarette smoking; cohort; environmental tobacco smoke exposure; in vivo; inhibitor/antagonist; macrophage; non-smoker; novel; novel therapeutics; overexpression; response; restoration

Project Summary Chronic obstructive pulmonary disease (COPD) encompasses several clinical syndromes, most notably emphysema and chronic bronchitis. It is a major unmet medical need in human health and is strongly associated with cigarette smoke (CS) exposure. Most of the current treatments, however, fail to attenuate severity and progression of the disease, thereby requiring better mechanistic understandings of pathogenesis to develop disease-modifying therapeutics. We recently demonstrated that the nucleotide-binding domain and leucine-rich-repeat-containing protein X1 (NLRX1), a novel mitochondrial molecule, plays an important inhibitory role in the pathogenesis of COPD. The importance of NLXR1 was also evident in clinical studies. From three independent human COPD cohorts, the expression of NLRX1 was suppressed in lungs from patients with COPD and this suppression showed strong correlation with the degree of airflow limitation, a hallmark of COPD. The current proposal aims to define the underlying mechanism(s) by which the suppression of NLRX1 contributes to the pathogenesis of COPD and to determine the therapeutic potential of NLRX1 restoration in vivo as a disease modifier of COPD. Preliminary studies revealed that (i) pulmonary macrophages were the cell population where the expression of NLRX1 was most prominent in lungs from both non-smokers and no-smoking (NS) control mice; (ii) the expression of NLRX1 was significantly suppressed in pulmonary macrophages from mice exposed to CS; and (iii) importantly, the expression of markers of CS- induced activated macrophages (interleukin (IL)-18, mitochondrial reactive oxygen species (mtROS), metalloproteases (MMPs)) were markedly enhanced in macrophages from NLRX1-/- mice compared to those from WT mice after CS exposure. These results highlight NLRX1 as a critical regulator of CS-induced activation of pulmonary macrophages, a cell population that plays a major role in COPD pathogenesis. Furthermore, we identified that NLRX1 interacts with PTEN-induced kinase 1 (PINK1), a molecule known to have an important role in mitochondrial quality control (MQC). Based on these observations, we hypothesize that NLRX1 plays as a critical inhibitor of CS-induced activation of pulmonary macrophages via PINK1- mediated MQC. To test the hypothesis, we will utilize newly generated mice that harbor macrophage-specific conditional NLRX1-/- (MΦ-NLRX1-/-) and macrophage-specific NLRX1 transgenic overexpression (MΦ-NLRX1 Tg). Proposed aims are as follows: #1. Characterize the effects of CS on the expression of NLRX1 in mice, the alteration of the expression of NLRX1 in patients with COPD, and define the role(s) of macrophage-specific NLRX1 in CS-induced pulmonary inflammation and remodeling responses; #2. Define the alteration of functional characteristics of CS-exposed pulmonary macrophages and the underlying mechanism(s) by which NLRX1 determines these alterations; #3. Determine if restoring the expression of NLRX1 in vivo ameliorates CS-induced pulmonary inflammatory and remodeling responses.

项目摘要 慢性阻塞性肺疾病(COPD)包括几种临床症状，最值得注意的是 肺气肿和慢性支气管炎。它是人类健康中一个主要的未得到满足的医疗需求，并强烈 与香烟烟雾(CS)暴露有关。然而，目前的大多数治疗方法都不能减弱 疾病的严重性和进展，因此需要对发病机制有更好的理解 开发治疗疾病的疗法。我们最近证明了核苷酸结合域和 富含亮氨酸重复序列的蛋白X1(NLRX1)是一种新的线粒体分子，在线粒体中起着重要的作用。 抑制作用在COPD发病机制中的作用。NLXR1的重要性在临床研究中也是显而易见的。 从三个独立的COPD队列中，NLRX1在肺中的表达受到抑制 COPD患者的这种抑制与气流受限的程度有很强的相关性， 这是慢性阻塞性肺病的标志。目前的建议旨在定义压制的潜在机制(S) NLRX1在COPD发病机制中的作用及NLRX1的治疗潜力 体内修复作为慢性阻塞性肺疾病的疾病修饰物。初步研究显示：(I)肺脏 巨噬细胞是NLRX1在两种动物的肺中表达最显著的细胞群。 非吸烟者和不吸烟(NS)对照组小鼠；(Ii)NLRX1的表达在 CS暴露小鼠肺巨噬细胞；以及(Iii)重要的是，CS标志物的表达- 诱导活化的巨噬细胞(白介素18、线粒体活性氧)、 NLRX1-/-小鼠巨噬细胞中金属蛋白酶(MMPs)的表达显著增强 从CS暴露后的WT小鼠中提取。这些结果强调了NLRX1是CS诱导的关键调节因子 肺巨噬细胞的激活，这是一种在COPD发病机制中发挥主要作用的细胞群。 此外，我们还发现NLRX1与PTEN诱导的激酶1(PINK1)相互作用，PINK1是一种已知的 在线粒体质量控制(MQC)中起着重要作用。基于这些观察结果，我们假设 NLRX1是CS通过PINK1-1诱导肺巨噬细胞活化的关键抑制因子 中介MQC。为了验证这一假设，我们将利用新生的携带巨噬细胞特异性的小鼠 条件性NLRX1-/-(MΦ-NLRX1-/-)和巨噬细胞特异性NLRX1转基因过表达(MΦ-NLRX1 Tg)。提出的目标如下：1.表征CS对小鼠NLRX1表达的影响， 慢性阻塞性肺疾病患者外周血中NLRX1的表达变化及巨噬细胞特异性表达的作用(S) NLRX1在CS诱导的肺部炎症和重塑反应中的作用；#2.定义 CS染毒肺巨噬细胞的功能特征及其作用机制(S) NLRX1决定了这些改变；#3.确定在体内恢复NLRX1的表达是否会改善 CS诱导的肺炎症和重塑反应。