G-CSF and STAT3 link inflammation to alveolar epithelial regeneration

G-CSF 和 STAT3 将炎症与肺泡上皮再生联系起来

• 批准号: 9975015
• 负责人: Andrew James Paris
• 金额: $ 16.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-07-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975015
• 关键词: AGTR2 gene; Acids; Acute Lung Injury; Address; Adoptive Transfer; Adrenal Cortex Hormones; Adult Respiratory Distress Syndrome; Affect; Alveolar; Alveolar Cell; Alveolar Cell Type I; Anti-Inflammatory Agents; Architecture; Area; Biological Assay; Bone Marrow; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Clinical; Clinical Trials; Data; Defect; Development; Developmental Biology; Diffuse; Epithelial; Epithelium; Etiology; Event; Gases; Generations; Granulocyte Colony-Stimulating Factor; Granulocyte Colony-Stimulating Factor Receptors; Histologic; Homeostasis; Human; Impairment; In Situ; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Link; Liquid substance; Lung; Mediating; Mediator of activation protein; Medical; Mentors; Methodology; Modeling; Mus; Myelogenous; Natural Immunity; Natural regeneration; Neutropenia; Non-Steroidal Anti-Inflammatory Agents; Organoids; Paris, France; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphorylation; Physicians; Population; Positioning Attribute; Process; Production; Reagent; Recombinants; Recovery; Reporter; Research; Resolution; Role; Scientist; Signal Pathway; Signal Transduction; Source; Stat3 protein; Testing; Therapeutic; Tissues; Training; Translating; Uncertainty; United States; alveolar epithelium; alveolar type II cell; base; body system; career; cell injury; clinical care; cytokine; design; enhancing factor; epithelium regeneration; human disease; improved; in vivo; inflammatory lung disease; injury and repair; innovation; insight; lung injury; mortality; mouse model; neutrophil; novel; novel strategies; pneumocyte; progenitor; radioresistant; recruit; repaired; restoration; stem cells; tissue regeneration; tissue repair

Project Summary The acute respiratory distress syndrome (ARDS) is a diffuse inflammatory lung disease that has been associated with multiple direct and indirect pulmonary insults. In ARDS, these diverse etiologies share a common histologic pattern known as diffuse alveolar damage in which the alveolar cells are damaged and the alveoli themselves become filled with proteinaceous fluid. As a result, oxygenation is severely impaired. Despite advances in clinical care, mortality remains high and the development of ARDS pharmacotherapy remains a major unmet medical need. Historically, research has focused on the inflammatory processes that underlie ARDS. This led to several clinical trials of anti-inflammatory medications such as corticosteroids and non-steroidal anti-inflammatory drugs. This strategy sought to limit tissue damage but did not promote restoration of normal lung architecture per se. To date, no anti-inflammatory medication has shown a convincing mortality benefit in ARDS. In this proposal we postulate that one reason anti-inflammatory medications have not shown a convincing benefit may be because the inflammatory cells themselves promote the restoration of normal lung architecture following ARDS. In fact, preliminary data show a link between the inflammatory response and subsequent re- epithelialization. This project will enhance our insight into reparative mechanisms in the lung and bolster a therapeutic strategy that seeks to directly promote restoration of the alveolar epithelium as a treatment for ARDS. The scientific objective of this proposal is to determine how granulocyte-colony stimulating factor (G-CSF), a key regulator of neutrophil homeostasis, promotes alveolar regeneration in a murine model of acid-induced lung injury, which is similar to human ARDS. Preliminary data suggest that these mice recruit fewer neutrophils to the alveoli following lung injury and also demonstrate significantly impaired alveolar repair three days after acid aspiration. The aims of this proposal are thus 1) Elucidate the mechanisms of G-CSF production and understand how it stimulates type II pneumocytes, a key reservoir of progenitor type I pneumocytes, to repair the alveolar epithelium following acute lung injury. 2) Determine the contribution of STAT3 activation in AT2 cells, mediated by G-CSF, to alveolar epithelial regeneration. This proposal's other key objective is to train the candidate in the nascent field of pulmonary epithelial regeneration. This proposal outlines an individualized plan of mentoring, didactic coursework and professional development to help the candidate become a leader in understanding how innate inflammatory responses influence the repair mechanisms in the lung following ARDS.

项目概要 急性呼吸窘迫综合征（ARDS）是一种弥漫性炎症性肺部疾病， 与多次直接和间接肺部损伤有关。在 ARDS 中，这些不同的病因有一个共同点： 常见的组织学模式称为弥漫性肺泡损伤，其中肺泡细胞受损，并且 肺泡本身充满蛋白质液体。结果，氧合作用严重受损。 尽管临床护理取得了进步，但死亡率仍然很高，ARDS 药物治疗的发展 仍然是一个未得到满足的重大医疗需求。 从历史上看，研究主要集中在 ARDS 背后的炎症过程上。这导致了几个 皮质类固醇和非甾体抗炎药等抗炎药物的临床试验 药物。该策略旨在限制组织损伤，但并未促进正常肺结构的恢复 本身。迄今为止，尚无任何抗炎药物能够令人信服地降低 ARDS 患者的死亡率。 在这项提案中，我们假设抗炎药物没有显示出令人信服的效果的一个原因是 好处可能是因为炎症细胞本身促进正常肺结构的恢复 继ARDS后。事实上，初步数据显示炎症反应与随后的再治疗之间存在联系。 上皮化。该项目将增强我们对肺部修复机制的了解，并支持 旨在直接促进肺泡上皮修复的治疗策略 ARDS。 该提案的科学目标是确定粒细胞集落刺激因子 (G-CSF)（一种 中性粒细胞稳态的关键调节剂，促进酸诱导小鼠模型中的肺泡再生 肺损伤，与人类 ARDS 类似。初步数据表明这些小鼠募集的中性粒细胞较少 肺损伤后的肺泡，三天后肺泡修复也明显受损 酸抽吸。因此，该提案的目的是 1) 阐明 G-CSF 产生的机制和 了解它如何刺激 II 型肺细胞（I 型肺祖细胞的关键储存库）进行修复 急性肺损伤后的肺泡上皮。 2)确定STAT3激活在AT2中的贡献 细胞，由 G-CSF 介导，促进肺泡上皮再生。 该提案的另一个关键目标是在肺上皮的新兴领域培训候选人 再生。该提案概述了指导、教学课程和专业的个性化计划 帮助候选人成为了解先天炎症反应如何进行的领导者 影响 ARDS 后肺部的修复机制。