Loss of Endothelial S1PR1 Drives Post-Influenza Pulmonary Fibrosis

内皮 S1PR1 的缺失导致流感后肺纤维化

• 批准号: 10634045
• 负责人: Rachel S Knipe
• 金额: $ 73.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634045
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Affect; Alveolar; Architecture; Attenuated; Automobile Driving; Back; Bleomycin; Blood Vessels; Bronchoalveolar Lavage Fluid; COVID-19; COVID-19 pandemic; Cell Communication; Cell surface; Cells; Chronic; Clinical Trials; Coculture Techniques; Collagen; Complication; Contracts; Coronavirus; Coughing; Coupled; Deposition; Development; Down-Regulation; Effector Cell; Endothelial Cells; Endothelium; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Gene Expression Profile; Genetic; Genetic Transcription; Human; Influenza; Influenza A virus; Injury; Interleukin-1 alpha; Interruption; Intervention; Lead; Lung; Mechanical ventilation; Mediating; Mediator; Messenger RNA; Modeling; Molecular; Mus; Outcome; Pathologic; Phase; Phosphorylation; Physiological; Play; Process; Production; Pulmonary Fibrosis; Recombinants; Recycling; Respiration Disorders; Respiratory Failure; Role; Severities; Shortness of Breath; Signal Induction; Signal Transduction; Sphingosine-1-Phosphate Receptor; Sterility; Surface; Survivors; System; Testing; Therapeutic; Tissues; Transgenic Mice; Vascular Permeabilities; Viral; Viral Respiratory Tract Infection; Virus Diseases; clinically relevant; disability; disabling symptom; efficacy validation; endothelial dysfunction; epidemic virus; exercise intolerance; gain of function; in vivo; influenzavirus; loss of function; lung injury; lung repair; mortality; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; prevent; protein expression; receptor; repaired; response; sphingosine 1-phosphate; tissue repair; transcriptomics

Project Summary Respiratory viral infections such as influenza and coronaviruses are frequent causes of acute respiratory distress syndrome (ARDS), a disabling condition with a mortality up to 46%. While supportive interventions have reduced the overall mortality of ARDS, severe cases requiring prolonged mechanical ventilation remain common, and many cases are complicated by the development of fibrosis in the lung. Post-viral pulmonary fibrosis can lead to chronic disability due to respiratory dysfunction, exercise intolerance and disabling symptoms such as shortness of breath and cough. Endothelial injury and dysfunction contribute to the severity of ARDS, persistence of lung injury, and dysregulated tissue repair. Currently there are no therapies to prevent the development of post-viral pulmonary fibrosis, and in fact supportive mechanical ventilation may further perpetuate pathological endothelial injury and worsen fibrotic outcomes. The sphingosine-1-phosphate (S1P)-S1P receptor 1 (S1PR1) signaling axis on endothelial cells (EC) is a key modulator of endothelial function, including a regulatory role in vascular permeability. However, the role of S1PR1 during the fibroproliferative phase of pulmonary viral infection induced ARDS has not been well explored. Specifically, cross talk between EC and lung fibroblasts, key effector cells in the development of pulmonary fibrosis because of their production of extracellular matrix and their ability to contract and distort tissue architecture, has not been defined. Reversing endothelial dysfunction and restoring pulmonary vascular integrity via augmentation of EC S1PR1 after viral infection could have great therapeutic value by preventing the development of post-viral pulmonary fibrosis. Our preliminary results demonstrate that persistent loss of endothelial S1PR1 is deleterious during influenza A virus (IAV) infection, resulting in increased vascular permeability and increased pulmonary fibrosis. We hypothesize that IAV infection induced lung injury induces loss of EC S1PR1, leading to altered EC-fibroblast cross talk which drives fibrosis. Furthermore, we propose that augmenting EC S1PR1 expression in the context of IAV infection will lead to the development of a novel anti-fibrotic strategy. We will use endothelial specific gain- of-function and loss-of-function mice in an IAV infection model to determine how IAV infection drives sustained reduction of EC S1PR1 (Aim 1), how EC S1PR1 affects transcriptomic signatures and cross talk with fibroblasts after IAV infection (Aim 2), and how augmentation of EC S1PR1 can be used in a therapeutic manner to prevent post-IAV pulmonary fibrosis (Aim 3). A better understanding of the molecular mechanisms and sequelae of EC dysfunction after IAV and the effects on subsequent fibroproliferation will lead to novel therapeutics to prevent this debilitating complication of pulmonary viral infections.

项目概要 流感和冠状病毒等呼吸道病毒感染是急性呼吸窘迫的常见原因 综合征 (ARDS)，一种致残性疾病，死亡率高达 46%。虽然支持性干预措施减少了 ARDS 的总体死亡率，需要长时间机械通气的严重病例仍然很常见，并且 许多病例因肺部纤维化的发展而变得复杂。病毒后肺纤维化可导致 由于呼吸功能障碍、运动不耐症和身材矮小等残疾症状而导致的慢性残疾 呼吸和咳嗽。内皮损伤和功能障碍导致 ARDS 的严重程度和肺损伤的持续存在 损伤和失调的组织修复。目前尚无治疗方法可以预防病毒后感染的发生 肺纤维化，事实上支持性机械通气可能会进一步延续病理性内皮细胞 损伤并恶化纤维化结果。 内皮细胞 (EC) 上的 1-磷酸鞘氨醇 (S1P)-S1P 受体 1 (S1PR1) 信号轴是关键 内皮功能调节剂，包括血管通透性的调节作用。然而，角色 S1PR1 在肺部病毒感染引起的 ARDS 的纤维增殖期尚未得到充分研究。 具体来说，EC 和肺成纤维细胞（肺成纤维细胞发育中的关键效应细胞）之间的交互作用 由于它们产生细胞外基质以及收缩和扭曲组织的能力而导致纤维化 架构，尚未定义。逆转内皮功能障碍并恢复肺血管完整性 通过在病毒感染后增强 EC S1PR1 可以通过预防病毒感染而具有巨大的治疗价值。 病毒后肺纤维化的发展。 我们的初步结果表明，甲型流感期间内皮 S1PR1 的持续缺失是有害的 病毒（IAV）感染，导致血管通透性增加和肺纤维化加剧。我们 假设 IAV 感染引起的肺损伤导致 EC S1PR1 丢失，导致 EC 成纤维细胞改变 串扰会导致纤维化。此外，我们建议增强 EC S1PR1 的表达 IAV 感染的研究将导致新型抗纤维化策略的开发。我们将使用内皮特异性增益- IAV 感染模型中的功能和功能丧失小鼠，以确定 IAV 感染如何驱动持续 EC S1PR1 的减少（目标 1）、EC S1PR1 如何影响转录组特征以及与成纤维细胞的交互作用 IAV 感染后（目标 2），以及如何以治疗方式使用 EC S1PR1 增强来预防 IAV 后肺纤维化（目标 3）。更好地了解 EC 的分子机制和后遗症 IAV 后的功能障碍以及对随后的纤维增殖的影响将导致新的治疗方法来预防 肺部病毒感染的这种使人衰弱的并发症。