Mechanisms of Recovery from Viral Pneumonia

病毒性肺炎的康复机制

• 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
• 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

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.

项目汇总_总体 病毒性肺炎的康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 严重急性呼吸系统综合症冠状病毒2型导致严重病毒性肺炎，损害下层 呼吸道导致急性呼吸窘迫综合征(ARDS)。大多数ARDS死亡发生在几天到几周之间 ARDS发病后--患者正在从煽动性侮辱中恢复的时间，但对小鼠模型的研究 通常侧重于急性肺损伤的早期发展和压倒性感染造成的死亡。除 通过低潮气量通气量和其他几种支持性治疗避免额外的肺损伤， 目前还没有针对病毒性肺炎引起的ARDS患者的特效治疗方法。这方面的一个中心假说 PPG是指持续呼吸衰竭并发展为多器官功能障碍的患者 ARDS是正常的炎症消退机制和肺组织失败的结果 修理。最近一项对ARDSNet患者的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相关，包括死亡。 我们建议研究病毒性肺炎的康复过程，重点研究发病机制。 促进肺部炎症的消退和肺损伤的健康修复。PPG调查人员 我将通过一组高度集成和创新的实验来测试这一中心假设，重点是四个 具体目标： 具体目标1.确定波形蛋白是否调节重症恢复期的持续性炎症 甲型流感病毒通过促进单核细胞来源的肺泡炎性表型诱导肺炎 巨噬细胞和限制调节性T细胞的修复能力。 具体目的2.测定线粒体电子传递链复合体I或III和乳酸 生产，推动持续的NLRP3炎症依赖炎症从严重的恢复期间 甲型流感病毒引起的肺炎。 具体目的3.确定LUBAC介导的肺组织中NF-kB信号的持续激活 上皮细胞驱动巨噬细胞激活并抑制病毒性肺炎后的肺修复。 特定目的4.确定DNA甲基转移酶活性和uhrf1是否诱导DNA 重症病毒感染后Treg细胞老化过程中高甲基化损害Treg细胞修复功能 老年宿主中的肺炎。