Mechanotransduction in Acute Lung Injury

急性肺损伤中的机械传导

• 批准号: 8235024
• 负责人: CHRISTOPHER M WATERS
• 金额: $ 51.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235024
• 关键词: AGTR2 gene; Acids; Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Alveolar; Alveolus; Atomic Force Microscopy; Biological; Blood capillaries; Cell Adhesion; Cell Adhesion Inhibition; Cell Migration Inhibition function; Cells; Clinical Research; Confocal Microscopy; Diagnostic radiologic examination; Disease; Endothelium; Epithelial; Epithelial Cells; Epithelium; Exhibits; Focal Adhesion Kinase 1; Gases; Heterogeneity; Imagery; In Vitro; Incidence; Infection; Injury; Intensive Care Units; Lead; Life; Lung; Mechanical ventilation; Mechanics; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Predisposition; Process; Property; Pulmonary Edema; Rattus; Signal Transduction; Stretching; Testing; Therapeutic Intervention; Ventilator-induced lung injury; capillary; cell motility; economic impact; improved; in vitro Model; in vivo; injured; insight; lung injury; migration; mortality; pressure; repaired; research study; restoration; surfactant; wound

Project Summary Acute lung injury and its more severe form, acute respiratory distress syndrome (ARDS), are devastating illnesses with high rates of incidence and high mortality rates. Patients with acute lung injury are typically provided supplemental oxygen using positive pressure mechanical ventilation, but this can lead to additional injury, termed ventilator- induced lung injury (VILI). The long term objective of this proposal is to improve understanding of the mechanisms by which overdistention (or stretch) of pulmonary epithelial cells contributes to ventilator-induced lung injury. The central hypothesis is that overdistention contributes both to the initiation of epithelial injury through loss of cell adhesion and to inhibition of repair mechanisms through decreased cell migration. Mechanisms of the initiation of VILI will be investigated using rats exposed to acid injury or surfactant depletion and direct visualization of airspace mechanics by microfocal X- ray imaging. A combination of in vitro, in vivo, and ex vivo approaches will be used to investigate the hypothesis that mechanical stretch causes loss of cell adhesion and inhibition of repair mechanisms through focal adhesion kinase (FAK) signaling. These approaches include primary cultures of rat alveolar type II (AT2) epithelial cells isolated from rats following mechanical ventilation, exposure of cells to mechanical stretch in vitro, and confocal microscopy of isolated rat lungs. Finally, atomic force microscopy will be used to test the hypothesis that localized changes in mechanical stiffness regulate the repair mechanisms of AT2 cells in culture. The proposed studies will investigate the mechanisms that contribute to lung injury during mechanical ventilation and provide new insights into mechanotransduction, the process of converting mechanical signals to biological signals.

项目概要 急性肺损伤及其更严重的形式，急性呼吸窘迫综合征 (ARDS) 是一种具有高发病率和高死亡率的毁灭性疾病。 急性肺损伤患者通常使用正压呼吸机补充氧气 压力机械通气，但这可能会导致额外的伤害，称为呼吸机- 诱发性肺损伤（VILI）。该提案的长期目标是改善 了解肺过度扩张（或牵拉）的机制 上皮细胞导致呼吸机引起的肺损伤。中心假设是 过度扩张会导致细胞损失而引发上皮损伤 通过减少细胞迁移来抑制粘附和修复机制。 将使用暴露于酸损伤的大鼠来研究 VILI 的启动机制 或表面活性剂消耗以及通过微焦 X- 直接观察空域力学 射线成像。将使用体外、体内和离体方法的组合 研究机械拉伸导致细胞粘附丧失的假设 通过粘着斑激酶 (FAK) 信号传导抑制修复机制。这些 方法包括分离大鼠肺泡 II 型 (AT2) 上皮细胞的原代培养物 来自机械通气后的大鼠，细胞暴露于机械拉伸 离体大鼠肺的体外和共聚焦显微镜检查。最后，原子力显微镜 将用于检验机械刚度局部变化的假设 调节培养中 AT2 细胞的修复机制。拟议的研究将 研究机械通气期间导致肺损伤的机制 并为机械转导提供新的见解，即转换的过程 机械信号转生物信号。

项目成果

Hyperoxia increases the elastic modulus of alveolar epithelial cells through Rho kinase.

• DOI: 10.1111/febs.12661
• 发表时间: 2014-02
• 期刊: The FEBS journal
• 作者: Wilhelm KR;Roan E;Ghosh MC;Parthasarathi K;Waters CM
• 通讯作者: Waters CM

Dynamic airway constriction in rats: heterogeneity and response to deep inspiration.

大鼠动态气道收缩：异质性和对深吸气的反应。

• DOI: 10.1152/ajplung.00050.2019
• 发表时间: 2019
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Phung,Thien-KhoiN;Sinclair,ScottE;Makena,Patrudu;Molthen,RobertC;Waters,ChristopherM
• 通讯作者: Waters,ChristopherM

Regulation and function of the two-pore-domain (K2P) potassium channel Trek-1 in alveolar epithelial cells.

• DOI: 10.1152/ajplung.00078.2011
• 发表时间: 2012
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: A. Schwingshackl;B. Teng;M. Ghosh;A. West;P. Makena;Vijay K. Gorantla;S. Sinclair;C. Waters

What do we know about mechanical strain in lung alveoli?

• DOI: 10.1152/ajplung.00105.2011
• 发表时间: 2011-11-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
• 影响因子: 4.9
• 作者: Roan, Esra;Waters, Christopher M.
• 通讯作者: Waters, Christopher M.

The 2-pore domain potassium channel TREK-1 regulates stretch-induced detachment of alveolar epithelial cells.

• DOI: 10.1371/journal.pone.0089429
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Roan E;Waters CM;Teng B;Ghosh M;Schwingshackl A
• 通讯作者: Schwingshackl A