Mechanisms of Recovery from Viral Pneumonia

病毒性肺炎的康复机制

• 批准号: 10696954
• 负责人: KAREN M RIDGE
• 金额: $ 275.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696954
• 关键词: 2019-nCoV; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Aging; Alveolar; Alveolar Macrophages; Antiviral Agents; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19 pandemic; Cell model; Cells; Cessation of life; Clinical; Complex; DNA; DNA Modification Methylases; Data Set; Development; Disease; Distal; Electron Transport; Epithelial Cells; Epithelium; Failure; Functional disorder; Genetic; Human; Hypermethylation; Immune; Immune response; Immunologics; Impairment; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Infrastructure; Intervention; Knowledge; Link; Lower respiratory tract structure; Lung; Lymphocyte; Macrophage Activation; Mechanical ventilation; Mediating; Mitochondria; Morbidity - disease rate; Mutant Strains Mice; NF-kappa B; Organ; Outcome; Pathway interactions; Patients; Phase; Phenotype; Play; Pneumonia; Population; Preparation; Primary Infection; Process; Production; Productivity; Pulmonary Inflammation; Recovery; Regulatory T-Lymphocyte; Research Personnel; Resolution; Respiratory Failure; Risk; Role; Sampling; Science; Scientist; Secondary to; Signal Transduction; Structure of parenchyma of lung; Supportive care; Technology; Testing; Tidal Volume; Time; Tissues; Vimentin; Viral; Viral Pneumonia; Virus; Work; experimental study; individualized medicine; innovation; lung injury; lung repair; monocyte; mortality; mouse model; multiple omics; neutrophil; participant enrollment; pathogen; pharmacologic; prevent; prospective; recruit; repair function; repaired; resilience; respiratory; response; seasonal influenza; tissue repair; ventilation

PROJECT SUMMARY_OVERALL Recovery from viral pneumonia is a clinically important yet understudied process. Severe influenza A virus and severe acute respiratory syndrome coronavirus 2 cause severe viral pneumonia, which damages the lower respiratory tract to induce acute respiratory distress syndrome (ARDS). Most ARDS deaths occur days-to-weeks after ARDS onset—a time when patients are recovering from the inciting insult, yet studies in murine models typically focus on the early development of acute lung injury and death from overwhelming infection. Other than avoidance of additional lung injury, via low tidal volume ventilation and a handful of other supportive therapies, there are no specific therapies for patients with viral pneumonia induced ARDS. A central hypothesis of this PPG is that the persistence of respiratory failure and the development of multiple organ dysfunction in patients with ARDS is a consequence of the failure of normal mechanisms of inflammation resolution and lung tissue repair. This hypothesis is clinically supported by a recent analysis of patients enrolled in the ARDSnet where a “hyperinflammatory” endotype of ARDS patients was associated with worse clinical outcomes, including death. We propose to investigate the process of recovery from viral pneumonia with a focus on mechanisms that promote resolution of lung inflammation and healthy repair of lung damage. The PPG investigators will test this central hypothesis through a highly integrated and innovative set of experiments by focusing on four Specific Aims: Specific Aim 1. To determine whether vimentin regulates persistent inflammation during recovery from severe influenza A virus–induced pneumonia by promoting a pro-inflammatory phenotype in monocyte-derived alveolar macrophages and by limiting the pro-repair capacity of regulatory T cells. Specific Aim 2. To determine whether mitochondrial electron transport chain complex I or III, and lactate production, drives persistent NLRP3 inflammasome-dependent inflammation during recovery from severe influenza A virus–induced pneumonia. Specific Aim 3. To determine whether persistent activation of LUBAC-mediated NF-kB signaling in the lung epithelium drives macrophage activation and inhibits lung repair following viral pneumonia. Specific Aim 4. To determine whether DNA methyltransferase activity and UHRF1 induce DNA hypermethylation in Treg cells during aging to impair Treg cell reparative function following severe viral pneumonia in older hosts.

项目概要_总体 病毒性肺炎的恢复是一个临床上重要但尚未得到充分研究的过程。严重甲型流感病毒和 严重急性呼吸综合征冠状病毒2引起严重病毒性肺炎，损害下呼吸道 呼吸道诱发急性呼吸窘迫综合征（ARDS）。大多数 ARDS 死亡发生在数天至数周内 ARDS 发作后——患者正从刺激性侮辱中恢复的时期，但在小鼠模型中进行的研究 通常关注急性肺损伤的早期发展和压倒性感染导致的死亡。以外 通过低潮气量通气和一些其他支持疗法避免额外的肺损伤， 目前尚无针对病毒性肺炎引起的 ARDS 患者的具体治疗方法。这个问题的一个中心假设 PPG是指患者持续存在呼吸衰竭并发展为多器官功能障碍 ARDS 是炎症消退和肺组织正常机制失败的结果 维修。最近对加入 ARDSnet 的患者进行的一项分析在临床上支持了这一假设，其中 ARDS 患者的“高炎症”内型与较差的临床结果（包括死亡）相关。 我们建议研究病毒性肺炎的恢复过程，重点关注机制 促进肺部炎症的解决和肺部损伤的健康修复。 PPG调查员 将通过一组高度集成和创新的实验来测试这一中心假设，重点关注四个 具体目标： 具体目标 1. 确定波形蛋白是否在重症恢复过程中调节持续性炎症 甲型流感病毒通过促进单核细胞来源的肺泡促炎表型诱导肺炎 巨噬细胞并限制调节性 T 细胞的促修复能力。 具体目标 2. 确定线粒体电子传递链复合物 I 或 III 以及乳酸 产生，在从严重的恢复过程中驱动持续的 NLRP3 炎性体依赖性炎症 甲型流感病毒引起的肺炎。 具体目标 3. 确定肺中 LUBAC 介导的 NF-kB 信号传导是否持续激活 上皮细胞驱动巨噬细胞活化并抑制病毒性肺炎后的肺部修复。 具体目标 4. 确定 DNA 甲基转移酶活性和 UHRF1 是否诱导 DNA 衰老过程中 Treg 细胞的高甲基化会损害严重病毒感染后 Treg 细胞的修复功能 老年宿主肺炎。