Mesenchymal inflammatory signaling in regulation of the immune response and tissue dysfunction during lipopolysaccharide-induced acute lung injury

间充质炎症信号在脂多糖诱导的急性肺损伤期间调节免疫反应和组织功能障碍

• 批准号: 10389796
• 负责人: Nancy Christine Allen
• 金额: $ 7.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389796
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Admission activity; Affect; Alveolar; Biological Assay; Biology; Blocking Antibodies; Blood capillaries; Bronchoalveolar Lavage; Cell Membrane Permeability; Cells; Chemotactic Factors; Chemotaxis; Clinical; Coculture Techniques; Cytokine Receptors; Data; Development; Disease; Environment; Epithelial Cells; Etiology; Family; Fibroblasts; Flow Cytometry; Functional disorder; Gases; Goals; Heterogeneity; Immune; Immune response; Immunohistochemistry; Immunology; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Knowledge; Ligands; Lipopolysaccharides; Lung; Lung Compliance; Maintenance; Measurement; Mechanical ventilation; Mediating; Mentors; Mesenchymal; Mesenchyme; Monitor; Mus; Natural regeneration; Nuclear; Organ; Pancreatitis; Pathogenesis; Pattern Recognition; Pattern recognition receptor; Phase; Phenotype; Physicians; Physiological; Platelet-Derived Growth Factor; Play; Pneumonia; Population; Positioning Attribute; Proteins; Pulmonary Inflammation; Pulmonary aspiration of gastric contents; Pulmonology; Pulse Oximetry; Regulation; Research; Research Personnel; Resolution; Respiratory Failure; Role; Scientist; Sepsis; Severities; Signal Transduction; Structure of parenchyma of lung; TLR4 gene; Testing; Therapeutic; Thick; Tissues; Training; Translating; Vascular Endothelium; Vascular Permeabilities; airway epithelium; alveolar epithelium; career; career development; cell type; chemokine; cytokine; epithelial injury; epithelial repair; epithelium regeneration; experience; experimental study; healing; high risk; immunoregulation; improved; in vivo; inflammatory milieu; insight; interest; lung injury; monocyte; mortality risk; mouse model; neutrophil; non cardiogenic pulmonary edema; novel therapeutics; prevent; recruit; response; skills; systemic inflammatory response; targeted treatment; tissue injury; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by severe pulmonary inflammation leading to alveolar injury, non-cardiogenic pulmonary edema, and impaired gas exchange often necessitating mechanical ventilation. ARDS can be caused by direct or indirect injury to the lungs, with the most common etiologies of injury being pneumonia, aspiration of gastric contents and sepsis. Despite significant interest in finding new therapies for ARDS, treatment has remained predominately supportive, highlighting the need for improved mechanistic understanding. The pulmonary mesenchyme resides in close proximity to the alveolar epithelium, vascular endothelium, and resident and recruited immune cells, placing the mesenchyme in an optimal position to synthesize and respond to signals from the microenvironment. In this proposal we aim to elucidate how the pulmonary mesenchyme incorporates inflammatory signals to modify the immune response and tissue injury in ARDS. The nuclear factor -B (NF-B) family of transcription factors are activated downstream of several pattern-recognition and cytokine receptors, and play an important role in mediating inflammatory responses. A20, encoded by Tnfaip3, is a negative regulator of NF-B, and has been found in both immune and epithelial cells to play a crucial role in limiting excessive inflammation and tissue injury. The intranasal delivery of bacterial lipopolysaccharide (LPS) is a well-accepted murine model for ARDS, and LPS is known to activate NF-B through the pattern-recognition receptor Toll-like receptor 4 (TLR4). Preliminary data from our lab shows that in response to LPS, lung fibroblasts in which Tnfaip3 has been deleted have increased expression of both chemokines and cytokines known to recruit immune cells and alter vascular permeability, both physiologically important aspects of ARDS pathogenesis. We hypothesize that impaired negative regulation of mesenchymal NF-B signaling in ARDS leads to increased pulmonary recruitment of immune cells and physiologic injury, and propose experiments to test this hypothesis. Answering these questions will lead to important insight into the role of the lung mesenchyme in mediating the pathophysiology of ARDS. We hope that the fundamental knowledge gained with these studies will eventually contribute to the development of more targeted therapeutics for this devastating disease. The above experimental proposal is part of a comprehensive training plan that I have built with my mentors to develop the skills and knowledge needed to become a successful independent investigator in the field of lung biology, with an emphasis on acute lung injury/ARDS. As a unique part of this plan I have assembled a Career Development Committee composed of physician-scientists from the fields of pulmonology and immunology who will serve as both scientific and career advisors. Upon completion of the proposed training plan with the support of my mentors, advisors, and within the strong research environment that UCSF provides, I will be well-positioned to make both a meaningful contribution to the understanding of ARDS and meet my training goals.

项目摘要/摘要 急性呼吸窘迫综合征（ARDS）是一种以严重肺部为特征的呼吸衰竭 炎症会导致肺泡损伤，非心脏病肺水肿和气体交换受损 需要机械通气。 ARDS可能是由肺直接或间接伤害引起的 损伤的最常见病因是肺炎，胃含量和败血症的抽吸。尽管 人们对寻找新的ARD疗法的浓厚兴趣，治疗仍然得到支持， 强调需要提高机械理解的需求。肺间隙近距离 靠近肺泡上皮，血管内皮以及居民和招募的免疫细胞，放置 在最佳位置合成和响应微环境的信号。在这个 提案我们旨在阐明肺间充质如何进口炎症信号来修改 ARDS中的免疫反应和组织损伤。转录因子的核因子-B（NF -B）家族是 激活了几种模式识别和细胞因子受体的下游，并在 介导炎症反应。由TNFAIP3编码的A20是NF-B的负调节剂，已经是 在免疫和上皮细胞中发现，在限制过量炎症和组织中起着至关重要的作用 受伤。细菌脂多糖（LPS）的鼻内递送是ARDS良好认可的鼠模型， 已知LPS通过模式识别受体Toll样受体4（TLR4）激活NF-B。 来自我们实验室的初步数据表明，为了响应LPS，肺成纤维细胞TNFAIP3已成为 删除的趋化因子和细胞因子已知可募集免疫细胞并改变的细胞因子的表达增加 血管渗透性，都是ARDS发病机理的物理上重要方面。我们假设这一点 ARDS中间充质NF-B信号的负调节受损导致肺部增加 免疫细胞和生理损伤的募集，以及检验该假设的建议实验。回答 这些问题将导致对肺间充质在介导的作用的重要见解 ARDS的病理生理学。我们希望这些研究获得的基本知识最终将 为这种毁灭性疾病的更具针对性的治疗做出贡献。以上 实验建议是我与导师制定的全面培训计划的一部分 成为肺部生物学领域成功的独立研究者所需的技能和知识，并与 强调急性肺损伤/ARDS。作为该计划的独特部分，我集会了职业发展 由肺科学和免疫学领域的身体科学家组成的委员会，将作为 科学和职业顾问。在我的支持下完成拟议的培训计划后 导师，顾问以及UCSF提供的强大研究环境中，我将有很好的位置 为对ARD的理解做出有意义的贡献，并实现我的培训目标。