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: 10292925
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292925
• 关键词: Acute; Address; Adverse effects; Chronic; Chronic Obstructive Pulmonary Disease; Disease; Event; Fibroblasts; Genetic; Grant; Growth Factor; Health; Homeostasis; Individual; Inflammasome; Inflammation; Inflammatory; Influenza; Injury; Lung; Mediating; Mitochondria; Mus; Outcome; Outer Mitochondrial Membrane; PINK1 gene; PTEN gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phosphotransferases; Play; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Pathology; Regulation; Reporting; Role; Signal Transduction; Signaling Molecule; Smoke; Smooth Muscle Actin Staining Method; Stains; Stress Fibers; Therapeutic; Tissues; Viral Respiratory Tract Infection; Virus; Virus Diseases; Zidovudine; aggregation pathway; base; cigarette smoke; cigarette smoke-induced; exposure to cigarette smoke; fibrotic lung; flu; improved; influenzavirus; insight; lung injury; macrophage; novel; null mutation; 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.

病毒感染在暴露于香烟烟雾（CS）的个体中具有更严重的后果 比没有接触过CS的人要多。COPD急性加重导致肺功能快速下降。 令人惊讶的是，暴露于CS的个体中夸大的病毒诱导反应的机制 没有得到充分的解决。我们的研究表明，病毒会导致 炎症、组织破坏和肺纤维化。我们首先报道了CS的不良反应 通过线粒体抗病毒信号分子（MAVS）的无效突变消除了暴露，MAVS是一种关键的适配器， 与线粒体外膜结合并对抗病毒信号传导至关重要的分子。以进一步限定 这些反应的机制，在CS引起MAVS介导的信号改变的前提下，我们 已经集中在CS暴露的MAVS介导的信号转导及其调节机制的失调， 和CS +病毒暴露的小鼠。 我们的研究突出了以下新的见解：（1）CS暴露导致持续的巨噬细胞 流感病毒（Flu）感染后炎症和肺纤维化改变增加;（2）肺巨噬细胞显示 MAVS水平增加，与过度炎症、损伤和纤维化反应相关， CS+Flu;（3）来自CS+Flu的离体肺源性成纤维细胞的增殖、α-IFN-γ表达增加， 平滑肌肌动蛋白染色应力纤维，促纤维化和促增殖生长因子表达 （4）MAVS的朊病毒样多聚体聚集，这是MAVS介导的转录组学特征的关键事件。 抗病毒信号在暴露于CS+Flu的小鼠肺中显著增强;（5）来自COPD患者的肺 具有增加的MAVS聚集;（6）炎性体活化、炎症和组织损伤反应 在CS+Flu肺中被夸大并涉及MAVS;和（7）磷酸酶和张力蛋白同源物（PTEN）- 诱导的推定激酶1（PINK 1）是线粒体健康的重要调节因子，在线粒体健康中起着关键的抑制作用 调节MAVS介导的炎性小体和病理学。 基于这些观察，我们假设CS诱导的MAVS稳态失调， 线粒体在肺部炎症和组织损伤中具有关键的功能作用， 在病毒感染期间在肺部观察到的反应。在目标1中，我们将描述 MAVS对线粒体的稳态调节、MAVS朊病毒样聚集以及MAVS-和PINK 1- 在CS和流感病毒共暴露后介导的信号传导。在目标2中，我们将定义 PINK 1介导的MAVS聚集对吸烟加重的病理性肺结局的调节 流感病理学和PINK 1增强作为可能的治疗方法。在目标3中，我们将描述 吸烟暴露和呼吸道病毒感染患者的MAVS聚集途径 这些拟议的研究将为MAVS如何调节巨噬细胞成纤维细胞提供新的见解 CS暴露和病毒感染肺部的相互作用，希望开发新的，基于发病机制的 改善疾病（如COPD急性加重）患者结局的治疗。