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Mechanisms of Repair of the Alveolar Epithelium after Lung Injury

肺损伤后肺泡上皮的修复机制

基本信息

批准号：
9898424
负责人：
Rachel Lynne Zemans
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898424
关键词：
Address Adult Respiratory Distress Syndrome Air Sacs Alveolar Alveolar Cell Type I Animal Model Area Basement membrane Biological Assay CXCL12 gene CXCR CXCR4 gene Cell Death Cell Line Cell Proliferation Cell division Cells Clinical Data Daughter Development Disease Edema Epithelial Epithelial Cells Epithelium Foundations Genes Goals HIF1A gene Health Care Costs Hour Hydrochloric Acid Hypoxemia Hypoxia Inducible Factor Inflammatory Injury Investigation Label Link Liquid substance Lung Measurement Measures Mechanical ventilation Mediating Methods Mitotic Modeling Molecular Morbidity - disease rate Morphology Mus Outcome Permeability Phase Process Proliferating Pulmonary Edema Recovery Refractory Research Resolution Role Signal Pathway Signal Transduction Surface Techniques Testing Therapeutic Therapeutic Intervention Time alveolar epithelium alveolar type II cell base chemokine clinically relevant daughter cell hypoxia inducible factor 1 in vivo injury and repair innovation keratinocyte loss of function lung injury mortality new therapeutic target novel novel therapeutic intervention public health relevance repaired response restoration severe injury targeted treatment therapy design transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Significance. The Acute Respiratory Distress Syndrome (ARDS) is responsible for significant morbidity and mortality. Aside from lung protective mechanical ventilation strategies and conservative fluid management, there are no specific therapies for ARDS. A hallmark of ARDS is injury to the alveolar epithelium, including cell death, primarily of alveolar type (AT) I cells, resulting in permeability and the influx of edma fluid, which in turn leads to refractory hypoxemia. This injury phase is followed by a reparative response during which surviving ATII cells spread onto the denuded basement membrane, proliferate, and transdifferentiate into ATI cells, thus restoring barrier integrity. Importantly, epithelial repair is a primary determinant of recovery from ARDS. Innovation. Historically, basic ARDS research has focused on the injury phase; unfortunately, therapeutic interventions designed to mitigate injury have generally been unsuccessful. Investigations into reparative mechanisms have explored ATII cell proliferation. In this proposal, we focus on ATII cell spreading onto the denuded basement membrane after the sloughing of ATI cells. This phenomenon has been recognized since the 1970s but has not been well studied in animal models. We define spreading as an increase in surface area resulting in increased coverage of the denuded basement membrane. We have developed a novel method to rigorously measure spreading of genetically-labeled ATII cells using stringent stereologic techniques. We will characterize ATII cell spreading after mild and severe injury in relationship to proliferation, transdifferentiation, and the restitution of barrier integrity. Hypothesis. Based on our preliminar data, we hypothesize that Hypoxia Inducible Factor (HIF) 1α promotes ATII cell spreading and the restitution of barrier integrity via CXCR4/SDF1 signaling. Research Plan. Aim 1 will test whether in limited lung injury, rapid, pre-mitotic ATII cell spreading is associated with barrier restoration; in addition, after severe injury, requiring proliferation to replace lost cells, whethr post-mitotic spreading correlates with barrier restoration. Aim 2 will determine whether HIF1α is critical for spreading. Aim 3 will test the hypothesis that CXCR/SDF1 signaling promotes and mediates the role of HIF1α in ATII cell spreading. We will use both gain- and loss-of-function techniques, including ATII cell specific gene deficient mice. Our primary readout will be morphometric measurement of spreading (area of alveolar surface covered) using stereologic techniques. We will directly link in vivo studies to mechanistic spreading assays in cultured primary ATII cells. Conclusion. Here, we study repair of the injured alveolar epithelium by ATII cell spreading with an emphasis on the restitution of epithelial barrier integrity, a highly cliniclly relevant outcome. These studies will identify novel therapeutic targets to accelerate epithelial repair in ARDS, ultimately promoting the resolution of pulmonary edema and clinical recovery.

描述（由申请人提供）：意义。急性呼吸窘迫综合征（ARDS）导致显着的发病率和死亡率。除了肺保护性机械通气策略和保守的液体管理外，ARDS 没有具体的治疗方法。 ARDS 的一个标志是肺泡上皮损伤，包括细胞死亡，主要是肺泡 I 型细胞死亡，导致通透性增加和水肿液流入，进而导致难治性低氧血症。此损伤阶段之后是修复反应，在此期间幸存的 ATII 细胞扩散到裸露的基底膜上、增殖并转分化为 ATI 细胞，从而恢复屏障完整性。重要的是，上皮修复是 ARDS 康复的主要决定因素。创新。从历史上看，ARDS 基础研究主要集中在损伤阶段。不幸的是，旨在减轻伤害的治疗干预措施通常并不成功。对修复机制的研究探索了 ATII 细胞增殖。在这个提案中，我们关注的是 ATII 细胞在 ATI 细胞脱落后扩散到裸露的基底膜上。这种现象自 20 世纪 70 年代以来就已被认识到，但尚未在动物模型中得到充分研究。我们将扩散定义为表面积的增加，导致裸露基底膜的覆盖范围增加。我们开发了一种新方法，使用严格的立体学技术来严格测量基因标记的 ATII 细胞的扩散。我们将描述轻度和重度损伤后 ATII 细胞扩散与增殖、转分化和屏障完整性恢复的关系。假设。根据我们的初步数据，我们假设缺氧诱导因子 (HIF) 1α 通过 CXCR4/SDF1 信号传导促进 ATII 细胞扩散和屏障完整性的恢复。研究计划。目标 1 将测试在有限的肺损伤中，快速、有丝分裂前的 ATII 细胞扩散是否与屏障恢复相关；此外，在严重损伤后，需要增殖来替代丢失的细胞，有丝分裂后扩散是否与屏障恢复相关。目标 2 将确定 HIF1α 是否对传播至关重要。目标 3 将检验以下假设：CXCR/SDF1 信号传导促进并介导 HIF1α 在 ATII 细胞扩散中的作用。我们将使用功能获得和功能丧失技术，包括 ATII 细胞特异性基因缺陷小鼠。我们的主要读数将是使用体视技术对扩散（覆盖的肺泡表面面积）进行形态测量。我们将直接将体内研究与培养的原代 ATII 细胞中的机械扩散测定联系起来。结论。在这里，我们研究 ATII 细胞扩散对受损肺泡上皮的修复，重点是上皮屏障完整性的恢复，这是一个高度临床相关的结果。这些研究将确定新的治疗靶点，加速 ARDS 上皮修复，最终促进肺水肿的解决和临床康复。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TGF beta inhibits HGF, FGF7, and FGF10 expression in normal and IPF lung fibroblasts.

DOI：
10.14814/phy2.13794
发表时间：
2018-08
期刊：
Physiological reports
影响因子：
2.5
作者：
Correll KA;Edeen KE;Redente EF;Zemans RL;Edelman BL;Danhorn T;Curran-Everett D;Mikels-Vigdal A;Mason RJ
通讯作者：
Mason RJ

Diversity at the border.

边境的多样性。