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.

项目总结/摘要 急性呼吸窘迫综合征（acute respiratory distress syndrome，ARDS）是一种以严重的肺动脉高压为特征的呼吸衰竭。 导致肺泡损伤、非心源性肺水肿和气体交换受损的炎症通常 需要机械通气。ARDS可由肺的直接或间接损伤引起， 最常见的损伤病因是肺炎、胃内容物吸入和败血症。尽管 对寻找新的ARDS治疗方法的兴趣很大，治疗仍然主要是支持性的， 强调需要改进对机械的理解。肺间质位于靠近 接近肺泡上皮、血管内皮以及驻留和募集的免疫细胞， 间充质处于最佳位置以合成和响应来自微环境的信号。在这 我们的目标是阐明肺间质如何整合炎症信号，以改变肺间质的炎症反应。 免疫反应与组织损伤核转录因子B（NF-κ B B）家族是转录因子家族中的一员， 在几种模式识别和细胞因子受体的下游激活，并在以下方面发挥重要作用： 介导炎症反应。由Tnfaip 3编码的A20是NF-κ B B的负调节因子，并且已经被证实是NF-κ B的负调节因子。 在免疫细胞和上皮细胞中发现，在限制过度炎症和组织 损伤细菌脂多糖（LPS）的鼻内递送是公认的用于ARDS的鼠模型， 已知LPS通过模式识别受体Toll样受体4（TLR 4）激活NF-κ B B。 我们实验室的初步数据显示，在对LPS的反应中，其中Tnfaip 3已经表达的肺成纤维细胞， 删除的趋化因子和细胞因子的表达增加，已知这些趋化因子和细胞因子可以招募免疫细胞并改变免疫细胞的功能。 血管通透性，两者都是ARDS发病机制的生理学重要方面。我们假设 在ARDS中间充质NF-κ B B信号负调节受损导致肺内 招募免疫细胞和生理损伤，并提出实验来验证这一假设。回答 这些问题将使我们对肺间充质在介导肺纤维化中的作用有重要的认识。 ARDS的病理生理学我们希望通过这些研究获得的基本知识最终将 有助于开发针对这种毁灭性疾病的更有针对性的治疗方法。上述 实验提案是我与导师共同制定的全面培训计划的一部分， 成为肺生物学领域成功的独立研究者所需的技能和知识， 强调急性肺损伤/ARDS。作为这个计划的一个独特部分，我已经收集了一个职业发展 委员会由来自肺病学和免疫学领域的医生-科学家组成，他们将担任 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，在UCSF提供的强大的研究环境中，我将处于有利地位， 为理解ARDS做出了有意义的贡献，并达到了我的培训目标。