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.

项目摘要 急性肺损伤及其更严重的急性呼吸窘迫综合征 （ARDS）是毁灭性疾病，发病率较高和死亡率高。 通常使用正面提供急性肺损伤的患者补充氧气 压力机械通气，但这可能导致额外的损伤，称为呼吸机 - 诱导肺损伤（VILI）。该提议的长期目标是改善 理解过度存在（或拉伸）肺的机制 上皮细胞有助于呼吸机诱导的肺损伤。中心假设是 过度存在既有助于通过损失细胞开始上皮损伤 通过减少细胞迁移来粘附和抑制修复机制。 将使用暴露于酸性损伤的大鼠研究VILI开始的机制 或表面活性剂的耗竭和直接可视化空域力学的微焦点X- 射线成像。体外，体内和离体方法的结合将用于 研究机械拉伸会导致细胞粘附的丧失和 通过局灶性粘附激酶（FAK）信号传导抑制修复机制。这些 方法包括分离的大鼠牙槽II型（AT2）上皮细胞的原发性培养物 从机械通气后的大鼠，将细胞暴露于机械伸展 分离大鼠肺的体外和共聚焦显微镜。最后，原子力显微镜 将用于测试机械刚度局部变化的假设 调节培养物中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 并提供有关机械转移的新见解，即转换的过程 生物信号的机械信号。

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