G-CSF and STAT3 link inflammation to alveolar epithelial regeneration

项目摘要 急性呼吸窘迫综合征（ARDS）是一种弥漫性炎症性肺病， 与多种直接和间接肺损伤相关。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， 肺泡本身充满蛋白质液体。因此，氧合严重受损。 尽管临床护理取得了进展，但死亡率仍然很高，ARDS药物治疗的发展 仍然是一个主要的未满足的医疗需求。 从历史上看，研究主要集中在ARDS的炎症过程。这导致了几个 抗炎药物如皮质类固醇和非甾体抗炎药的临床试验 毒品该策略试图限制组织损伤，但不能促进正常肺结构的恢复 本质上迄今为止，没有抗炎药物显示出令人信服的死亡率效益在ARDS。 在这个建议中，我们假设抗炎药物没有表现出令人信服的效果的一个原因是， 益处可能是因为炎症细胞本身促进正常肺结构的恢复 ARDS之后。事实上，初步数据显示炎症反应和随后的再发性炎症反应之间存在联系。 上皮化该项目将增强我们对肺修复机制的了解，并支持肺修复机制。 寻求直接促进肺泡上皮恢复作为治疗 ARDS。 这项建议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因子，在酸诱导的小鼠模型中促进肺泡再生 肺损伤，这与人类的ARDS相似。初步数据表明，这些小鼠招募较少的中性粒细胞 肺损伤后肺泡的损伤，并且在肺损伤后三天也显示出肺泡修复显著受损。 酸吸入因此，本建议的目的是：1）阐明G-CSF产生的机制， 了解它如何刺激II型肺细胞，一个关键的水库祖I型肺细胞，修复 急性肺损伤后肺泡上皮细胞的变化。2)确定AT 2中STAT 3激活的贡献 细胞，由G-CSF介导，肺泡上皮再生。 该提案的另一个关键目标是在肺上皮细胞的新生领域培养候选人 再生该提案概述了指导，教学课程和专业的个性化计划 发展，以帮助候选人成为了解先天炎症反应如何 影响急性呼吸窘迫综合征后肺部的修复机制。

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.