Understanding and targeting fibroblast activation in influenza-triggered lung inflammation and post-viral disease

了解和靶向流感引发的肺部炎症和病毒后疾病中的成纤维细胞激活

基本信息

批准号：
10717809
负责人：
David Fielding Boyd
金额：
$ 63.76万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717809
关键词：
ADAMTS Acute Acute Respiratory Distress Syndrome Address Alveolar Alveolar Cell Apoptosis Automobile Driving Cell Death Cells Cellular biology Cessation of life Chronic Chronic Obstructive Pulmonary Disease Coculture Techniques Data Disease Epithelium Failure Fibroblasts Flow Cytometry Hospitals Immune Immunology Impairment Infection Inflammation Inflammation Mediators Inflammatory Influenza Influenza A virus Intervention Label Length of Stay Link Long-Term Effects Lung Lung diseases Mediating Mediator Modeling Molecular Nature Pathogenesis Pathology Pathway interactions Patients Peptide Hydrolases Phase Prevention Production Pulmonary Inflammation Pulmonary Pathology Recovery Research Respiratory Signs and Symptoms Role Severity of illness Signal Transduction Source Stromal Cells Structure of parenchyma of lung Survivors System Testing Therapeutic Tissues Viral Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Work acute infection alveolar epithelium cell type chronic respiratory disease clinically relevant comorbidity dark matter disabling symptom epithelial repair experience healing high dimensionality idiopathic pulmonary fibrosis immune cell infiltrate immune modulating agents immunopathology improved in vivo influenza infection influenza virus strain inhibitor lung injury lung repair mouse model novel therapeutics pharmacologic prevent progenitor pulmonary function repaired respiratory restoration small molecule targeted treatment therapeutic target therapeutically effective transcriptomics

项目摘要

PROJECT SUMMARY Influenza virus infection triggers lung inflammation and pathology and is a leading cause of acute respiratory distress syndrome. Following viral clearance, lung inflammation and pathology can persist preventing recovery from severe cases of infection. Such persistent lung inflammation and pathology, also referred to as Post-viral Lung Disease (PVLD), is an underappreciated aspect of influenza virus infections, even though many patients suffer extended hospital stays, and 25 – 50% of patients continue to experience respiratory symptoms for at least 2 months after hospital discharge. Severe influenza virus infections also exacerbate other chronic respiratory diseases, including COPD and idiopathic pulmonary fibrosis. Currently, there are no approved pharmacologic interventions to improve recovery after viral clearance and to prevent or reverse PVLD and its long-term effects. PVLD is characterized by the persistence of inflammatory immune cells in the lung tissue and the failure of effective alveolar epithelial repair capable of restoring tissue function. The cellular and/or molecular mechanisms driving the persistence of inflammatory immune cells and preventing effective alveolar repair in the absence of ongoing viral replication are not known. We recently identified lung fibroblasts as drivers of inflammation and influenza disease severity. We showed that a lineage of lung fibroblasts, which we term inflammatory fibroblasts (iFibs), are especially important for driving pathogenesis, and not only promote hyperinflammation, but also prevent restoration of normal alveolar function during acute infections. Our preliminary data now demonstrate that these iFibs do not die during the acute phase of the infection, but instead persist into post-viral stages of influenza disease. Together, these data allow us to hypothesize that a subset of lung fibroblasts survives regulated cell death during acute IAV infection, differentiate into activated iFibs, persist in damaged lung tissue well after viral clearance, and drive PVLD by continued production of inflammatory mediators. We will test this hypothesis by addressing the following three key questions: (1) From which cells, and when, do PVLD-driving inflammatory fibroblasts arise? (2) Do inflammatory fibroblasts persist because they do not undergo regulated cell death, and (3) What is the therapeutic potential of inhibiting persistent inflammatory fibroblast activity in PVLD? Successful completion of this project will identify a distinct lineage of inflammatory lung fibroblasts as the cell type that initiates and drives PVLD and the mechanism of their persistence following infection. This research will identify novel therapeutic entry points to prevent or reduce PVLD before it develops to the point that it becomes irreversible.

项目概要流感病毒感染引发肺部炎症和病理，是急性呼吸道疾病的主要原因病毒清除后，肺部炎症和病理状况可能持续存在，阻碍康复。来自严重感染病例的持续性肺部炎症和病理，也称为病毒后。肺部疾病 (PVLD) 是流感病毒感染的一个未被充分认识的方面，尽管许多患者住院时间延长，25-50% 的患者持续出现呼吸道症状至少出院后至少 2 个月，严重的流感病毒感染也会使其他慢性病恶化。呼吸系统疾病，包括慢性阻塞性肺病和特发性肺纤维化，目前尚无批准。药物干预以改善病毒清除后的恢复并预防或逆转 PVLD 及其 PVLD 的特点是肺组织中炎症免疫细胞的持续存在。以及无法恢复组织功能的有效肺泡上皮修复。驱动炎症免疫细胞持续存在并阻止有效肺泡形成的分子机制我们最近发现肺成纤维细胞在没有持续病毒复制的情况下进行修复尚不清楚。我们展示了肺成纤维细胞的谱系，这是炎症和流感疾病严重程度的驱动因素。术语炎症成纤维细胞 (iFib) 对于驱动发病机制尤其重要，并且不仅促进过度炎症，但也会阻止急性感染期间正常肺泡功能的恢复。现在初步数据表明，这些 iFib 在感染急性期不会死亡，但相反，流感病毒会持续到病毒后阶段，这些数据使我们能够捕捉到这一点。肺成纤维细胞亚群在急性 IAV 感染期间的受调节细胞死亡中幸存下来，分化为活化的 iFib 在病毒清除后仍存留在受损的肺组织中，并通过持续产生我们将通过解决以下三个关键问题来检验这一假设：（1）来自哪些细胞以及何时产生 PVLD 驱动的炎症成纤维细胞 (2) 炎症成纤维细胞会持续存在吗？因为它们不会经历受调节的细胞死亡，以及（3）抑制的治疗潜力是什么？ PVLD 中持续的炎症成纤维细胞活性？成功完成该项目将确定一个独特的炎症性肺成纤维细胞谱系作为启动和驱动 PVLD 的细胞类型及其机制这项研究将确定新的治疗切入点来预防或治疗。在 PVLD 发展到不可逆转之前减少它。