Mechanotransduction in Acute Lung Injury

急性肺损伤中的机械传导

基本信息

批准号：
7778281
负责人：
CHRISTOPHER M WATERS
金额：
$ 52.57万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-03 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778281
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 Figs - dietary Focal Adhesion Kinase 1 Gases Heterogeneity Image 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 Roentgen Rays 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 public health relevance repaired restoration surfactant wound

项目摘要

DESCRIPTION (provided by applicant): 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 Xray 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. PUBLIC HEALTH RELEVANCE: Acute lung injury is a devastating illness that results in significant loss of life and substantial economic impact due to extended stays in the intensive care unit. The proposed studies will investigate the mechanisms that contribute to lung injury during mechanical ventilation and will identify potential targets for therapeutic intervention.

描述（由申请人提供）：急性肺损伤及其更严重的形式，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。通常使用正压机械通气提供急性肺损伤的患者补充氧气，但这可能导致额外的损伤，称为呼吸机诱导的肺损伤（VILI）。该提案的长期目标是提高对肺上皮细胞过度（或拉伸）的机制的理解，这有助于呼吸机诱导的肺损伤。中心假设是，过度差异既有助于通过损失细胞粘附来开始上皮损伤，又通过减少细胞迁移而抑制修复机制。将使用暴露于酸性损伤或表面活性剂耗竭的大鼠来研究VILI启动的机制，并通过微量焦点X射线成像直接可视化空域力学。体外，体内和离体方法的结合将用于研究以下假设：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。这些方法包括机械通气后从大鼠分离的大鼠牙槽II型（AT2）上皮细胞的原发性培养物，在体外暴露于机械伸展的细胞以及分离的大鼠肺的共聚焦显微镜。最后，原子力显微镜将用于检验以下假设：机械刚度的局部变化调节培养物中AT2细胞的修复机制。拟议的研究将研究在机械通气过程中导致肺损伤的机制，并为机械转导的新见解，即将机械信号转换为生物信号的过程。公共卫生相关性：急性肺损伤是一种毁灭性的疾病，导致重大护理部门的长期住宿导致重大生命损失和实质性经济影响。拟议的研究将研究在机械通气过程中导致肺损伤的机制，并将确定治疗干预的潜在靶标。