Mechanisms of Recovery from Viral Pneumonia

病毒性肺炎的康复机制

基本信息

批准号：
10269670
负责人：
KAREN M RIDGE
金额：
$ 284.87万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10269670
关键词：
2019-nCoV Acute Lung Injury Address Adult Respiratory Distress Syndrome 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 Enrollment Epithelial Epithelial Cells 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 Lung Inflammation Lymphocyte Macrophage Activation Mechanical ventilation Mediating Mitochondria Morbidity - disease rate Mutant Strains Mice NF-kappa B Organ Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Phenotype Play Pneumonia Population Preparation Primary Infection Process Production Productivity 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 pathogen prevent prospective recruit repair function repaired resilience respiratory response seasonal influenza tissue repair ventilation

项目摘要

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summary_overall 从病毒性肺炎中恢复是一个临床上重要但知识的过程。严重的影响病毒和严重的急性呼吸道综合征冠状病毒2引起严重的病毒性肺炎，损害较低呼吸道诱导急性呼吸窘迫综合征（ARDS）。大多数ARDS死亡发生了几天 ARDS发作后 - 患者从煽动注射中恢复过来的时候，但在鼠模型中进行了研究通常着重于急性肺损伤和压倒性感染死亡的早期发展。以外避免通过低潮汐通风和少数其他支持疗法避免额外的肺损伤，对于病毒肺炎诱导的ARDS没有特定的疗法。一个中心假设 ppg是呼吸衰竭的持续性和患者多个器官功能障碍的发展 ARDS是炎症和肺组织正常机制失败的结果维修。该假设在临床上通过对Ardsnet的患者的最新分析在临床上得到支持 ARDS患者的“高炎性”内型与临床结果较差有关，包括死亡。我们建议研究从病毒肺炎恢复的过程，重点是机制促进肺部感染的分辨率和肺部损伤的健康修复。 PPG调查人员将通过四个具体目的：具体目标1。确定波形蛋白是否调节严重恢复期间的持续注射通过促进单核细胞衍生的促炎表型，流感病毒诱导的肺炎巨噬细胞并通过限制调节T细胞的支持能力。特定目标2。确定线粒体电子传输链复合物I还是III和乳酸生产，驱动持续的NLRP3炎症体依赖性炎症，从严重流感一种病毒诱导的肺炎。特定目的3。确定肺中Lubac介导的NF-KB信号的持续激活是否持续激活上皮驱动巨噬细胞激活并抑制病毒性肺炎后的肺修复。具体目标4。确定DNA甲基转移酶活性和UHRF1是否影响DNA 衰老过程中Treg细胞中的高甲基化，以损害严重病毒后Treg细胞的修复功能年长宿主的肺炎。