MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD

香烟烟雾暴露和流感病毒感染以及 COPD 期间 MAVS 介导的肺部炎症和损伤反应

• 批准号: 10515290
• 负责人: Charles S Dela Cruz
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515290
• 关键词: Actins; Acute; Address; Adverse effects; Binding; Chronic; Chronic Obstructive Pulmonary Disease; Disease; Event; Fibroblasts; Genetic; Grant; Growth Factor; Health; Homeostasis; Individual; Inflammasome; Inflammation; Inflammatory; Influenza; Injury; Lung; Macrophage; Mediating; Mitochondria; Mus; Outcome; Outer Mitochondrial Membrane; PTEN gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphotransferases; Play; Proliferating; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Pathology; Regulation; Reporting; Role; Signal Transduction; Signaling Molecule; Smoke; Smooth Muscle; Stains; Stress Fibers; Therapeutic; Tissues; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Zidovudine; aggregation pathway; cigarette smoke; cigarette smoke-induced; exposure to cigarette smoke; fibrotic lung; improved; influenzavirus; insight; lung injury; novel; null mutation; pharmacologic; prion-like; pulmonary function decline; response; response to injury; smoke-induced lung disease; smoking exposure; transcriptomics

Viral infections have more severe consequences in individuals who have been exposed to cigarette smoke (CS) than in those not exposed to CS. Acute exacerbations of COPD contributes toward rapid lung function decline. Surprisingly, the mechanisms that underlie the exaggerated virus-induced responses in CS-exposed individuals have not been adequately addressed. Our studies demonstrated that viruses cause increased levels of inflammation, tissue destruction and lung fibrosis in CS exposed mice. We first reported adverse effects of CS exposure were eliminated by null mutations of mitochondrial antiviral signaling molecule (MAVS), a key adapter molecule that is bound to the mitochondrial outer membrane and essential for antiviral signaling. To further define the mechanisms of these responses, on the premise that CS causes alteration of MAVS-mediated signaling, we have focused on the dysregulation of MAVS-mediated signaling and its regulatory mechanisms in CS-exposed and CS + virus exposed mice. Our studies highlight the following novel insights: (1) CS exposure leads to persistent macrophage inflammation and increased fibrotic lung changes after influenza virus (Flu); (2) Lung macrophages show increased MAVS levels which were associated with excessive inflammatory, injury and fibrotic responses during CS+Flu; (3) Ex vivo lung-derived fibroblasts from CS+Flu have increased proliferation, expression of alpha- smooth muscle actin stained stress fibers, growth factor expression with pro-fibrotic and pro-proliferative transcriptomic signature; (4) The prion-like multimeric aggregation of MAVS, a key event in MAVS-mediated antiviral signaling, is markedly enhanced in mouse lungs exposed to CS+Flu; (5) Lungs from COPD patients have increased MAVS aggregation; (6) Inflammasomes activation, inflammatory and tissue damage responses are exaggerated in CS+Flu lungs and involves MAVS; and (7) Phosphatase and tensin homologue (PTEN)- induced putative kinase 1 (PINK1), an important regulator of mitochondrial health, plays a critical inhibitory role in regulating MAVS-mediated inflammasomes and pathology. Based on these observations, we hypothesize that CS-induced dysregulation of MAVS homeostasis on mitochondria has a critical functional role in the exaggerated pulmonary inflammation and tissue damage responses observed in the lungs during viral infection. In Aim 1, we will characterize the dysregulation of homeostatic regulation of MAVS on mitochondria, the MAVS prion-like aggregation and MAVS- and PINK1- mediated signaling after CS and influenza virus co-exposure. In Aim 2, we will define the consequences of PINK1-mediated regulation of MAVS aggregation on pathological pulmonary outcomes in smoke exacerbated influenza pathology and PINK1 augmentation as a possible therapeutic approach. In Aim 3, we will characterize MAVS aggregation pathway in patients with smoking exposure and respiratory viral infection. These proposed studies will provide new insights into how MAVS regulates macrophage-fibroblast interactions in CS exposure and virus infected lungs with the hope of developing novel, pathogenesis-based therapies to improve patient outcomes in diseases such as acute exacerbations of COPD.

病毒感染对暴露于香烟烟雾（CS）的个体会产生更严重的后果 而不是不暴露于CS的人。 COPD的急性加重有助于肺功能快速下降。 令人惊讶的是，CS暴露的个体中夸大的病毒诱导反应的基础的机制 尚未得到充分解决。我们的研究表明，病毒导致 CS暴露小鼠的炎症，组织破坏和肺纤维化。我们首先报道了CS的不良影响 线粒体抗病毒信号分子（MAVS）的无效突变（一种关键适配器）消除了暴露 与线粒体外膜结合的分子，对于抗病毒信号所必需。进一步定义 这些响应的机制，即CS导致MAVS介导的信号传导改变的前提，我们 已关注MAVS介导的信号传导的失调及其在CS暴露中的调节机制 和CS +病毒暴露的小鼠。 我们的研究强调了以下新见解：（1）CS暴露导致持续的巨噬细胞 流感病毒后炎症和纤维化肺的变化增加（流感）； （2）肺巨噬细胞显示 增加了与过度炎症，损伤和纤维化反应有关的MAV水平 CS+流感； （3）来自CS+流感的体内肺衍生成纤维细胞的增殖增加，α-表达 平滑肌肌动蛋白染色应激纤维，促纤维化和促增殖的生长因子表达 转录组签名； （4）MAV的Prion样多聚体聚集，这是MAVS介导的关键事件 暴露于CS+流感的小鼠肺中，抗病毒信号传导显着增强。 （5）COPD患者的肺 MAV的聚集增加了； （6）炎症激活，炎症和组织损伤反应 在CS+流感肺中被夸大，涉及MAV； （7）磷酸酶和Tensin同源物（PTEN） - 诱导的假定激酶1（PINK1）是线粒体健康的重要调节剂，起着关键的抑制作用 在调节MAVS介导的炎症和病理学方面。 基于这些观察结果，我们假设CS诱导的MAV稳态失调 线粒体在夸张的肺部炎症和组织损伤中具有关键的功能作用 病毒感染期间肺中观察到的反应。在AIM 1中，我们将表征的失调 MAV在线粒体上的稳态调节，Mavs prion样聚集以及MAVS和PINK1- CS和流感病毒共同暴露后介导的信号传导。在AIM 2中，我们将定义 pink1介导的MAV汇总对烟气中病理肺预后结局的调节加剧了 流感病理学和PINK1增强是一种可能的治疗方法。在AIM 3中，我们将描述 吸烟和呼吸道病毒感染患者的MAVS聚集途径。 这些提出的研究将提供有关MAV如何调节巨噬细胞纤维细胞的新见解 CS暴露和病毒感染的肺相互作用，希望发展基于发病机理的新型， 改善疾病中患者结局的疗法，例如COPD急性加重。