Mechanisms of Recovery from Viral Pneumonia

项目概要_总体 从病毒性肺炎中恢复是一个临床上重要但尚未充分研究的过程。严重的甲型流感病毒和 严重急性呼吸系统综合征冠状病毒2型引起严重的病毒性肺炎， 急性呼吸窘迫综合征（ARDS）。大多数ARDS死亡发生在几天到几周内 在ARDS发作后，患者从刺激性损伤中恢复，但在小鼠模型中的研究 通常集中在急性肺损伤的早期发展和由压倒性感染引起的死亡。除了 避免额外的肺损伤，通过低潮气量通气和一些其他支持疗法， 对于病毒性肺炎引起的ARDS患者没有特异性治疗。一个核心假设是 PPG是指呼吸衰竭持续存在并发展为多器官功能障碍的患者 急性呼吸窘迫综合征是炎症消退和肺组织正常机制失败的结果。 修复.这一假设在临床上得到了最近对ARDSnet中招募的患者的分析的支持， ARDS患者的“高炎症”内型与更差的临床结局相关，包括死亡。 我们建议研究从病毒性肺炎中恢复的过程，重点是机制 促进肺部炎症的消退和肺损伤的健康修复。PPG研究人员 我将通过一系列高度综合和创新的实验来检验这一中心假设，重点是四个 具体目标： 具体目标1。为了确定波形蛋白是否在严重创伤后恢复期间调节持续性炎症， 甲型流感病毒通过促进单核细胞源性肺泡巨噬细胞中促炎表型诱导肺炎 巨噬细胞和通过限制调节性T细胞的促修复能力。 具体目标2。为了确定线粒体电子传递链复合物I或III， 在从严重炎症恢复期间，NLRP 3的产生驱动持续的NLRP 3炎性体依赖性炎症 甲型流感病毒引起的肺炎。 具体目标3。为了确定是否持续激活LUBAC介导的NF-κ B信号在肺 上皮驱动巨噬细胞活化并抑制病毒性肺炎后的肺修复。 具体目标4。为了确定DNA甲基转移酶活性和UHRF 1是否诱导DNA 衰老过程中Treg细胞的高甲基化损害严重病毒感染后Treg细胞的修复功能 老年人的肺炎

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.