Mechanics and Deformation Responses of Lung Cells

肺细胞的力学和变形反应

基本信息

批准号：
7193465
负责人：
Rolf D Hubmayr
金额：
$ 34.96万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7193465
关键词：
Abbreviations Acid-Base Equilibrium Acidosis Acids Adverse effects Affect Alveolar Antigens Appearance Area Bicarbonates Boron Bovine Serum Albumin Buffers Caveolae Cell Death Cell Differentiation process Cell membrane Cell surface Cells Cholesterol Clathrin Confocal Microscopy Data Defect Dependence Dextrans Dyes Economic Inflation Electron Microscopy Environment Epidermal Growth Factor Receptor Epithelial Epithelial Cells Evolution Exudate Failure Figs - dietary Fluorescent Probes Funding Glycosphingolipids Goals Green Fluorescent Proteins Hand Healed High Density Lipoproteins Hypercapnia IL8 gene Image Inflammation Injury Intercellular adhesion molecule 1 Intervention Knowledge Lecithin Life Lipids Low-Density Lipoproteins Lung Maintenance Measures Mechanical ventilation Mechanics Membrane Methods Modeling Molecular Target Motivation Nature Necrosis Nuclear Numbers Pathogenesis Pathway interactions Perchlorates Phenotype Phosphatidylinositol 4,5-Diphosphate Plasma Population Positive-Pressure Respiration Predisposition Probability Propidium Diiodide Protein Kinase C Rate Rattus Reaction Recycling Regulation Resistance Reverse Transcriptase Polymerase Chain Reaction Risk Role Sorting - Cell Movement Source Sphingolipids Sphingomyelins Stress Stretching Surface Temperature Testing Therapeutic Therapeutic Intervention Tidal Volume Tissues Tromethamine Ventilator Ventilator-induced lung injury Very low density lipoprotein Work Wound Healing Xanthenes alveolar lamellar body analog base caveolin 1 cell injury clinically relevant dextran extracellular healing injured interest lipid transport methyl-beta-cyclodextrin monolayer pneumocyte pressure prevent repaired research study response response to injury stem trafficking transcription factor uptake wound

项目摘要

DESCRIPTION (provided by applicant): We plan to characterize the responses of alveolar pneumocytes to deforming stress. Motivation for this work stems from our interest in ventilator-induced lung injury (VIM). The long-term goal of our effort is the pharmaco-protection of the lung from deformation injury. The proposed experiments build on key observations we have made during the past funding period, namely: a) stretching of alveolar epithelial cells in culture triggers a vigorous lipid trafficking response; b) the trafficking response is vesicular in nature, varies with strain rate and amplitude, is temperature and energy dependent and can be pharmacologically manipulated; c) inhibition of deformation induced lipid trafficking (DILT) increases the risk of plasma membrane (PM) stress failure and lowers the likelihood of subsequent PM repair; d) cell wounding and resealing as distinct from cell necrosis can be readily demonstrated and quantified in whole living lungs. These observations suggest that DILT is integral to the maintenance of sublytic PM tensions. Experiments are organized along 3 specific aims: 1) to measure the effects of pH and pCO2 on the separate probabilities of mechanical ventilation associated PM wounding and repair in whole living rat lungs; 2) to characterize in primary rat alveolar pneumocytes the effects of deforming stress on PM integrity and the uptake, sorting and recycling of sphingolipids; 3) to measure the effects of intra- and extracellular acid-base balance on DILT, on the susceptibility to stretch-related PM wounding and on the probability of subsequent wound repair. The proposed studies will expand our knowledge of intended and unintended consequences of permissive hypercapnia; will establish mechanistic relationships between alveolar epithelial phenotype, deformation induced sphingolipid trafficking and the susceptibility of alveolar pneumocytes to PM stress failure; and will suggest molecular targets for DILT and cell repair directed therapeutic interventions.

描述（由申请人提供）：我们计划表征肺泡肺炎对变形应激的反应。这项工作的动机源于我们对呼吸机诱导的肺损伤（VIM）的兴趣。我们努力的长期目标是对肺部变形损伤的药物保护。拟议的实验是建立在过去的资金期间所做的关键观察基础上的： b）运输反应本质上是囊泡的，随着应变速率和振幅而变化，是温度和能量依赖性的，可以在药理学上受到操纵； c）抑制变形诱导的脂质运输（DILT）增加了质膜（PM）应力衰竭的风险，并降低了随后的PM修复的可能性； d）在整个活肺中，可以很容易地证明和量化与细胞坏死不同的细胞损伤和重新密封。这些观察结果表明，DILT是维持Sublytic PM紧张局势不可或缺的一部分。实验沿3个特定目的组织：1）测量pH和PCO2对整个活大鼠肺的机械通气相关的PM伤和修复的单独概率的影响； 2）在一级大鼠肺泡肺炎中表征变形应力对PM完整性以及鞘脂的摄取，分类和回收的影响； 3）测量细胞内和细胞外酸基平衡对DILT的影响，对与拉伸相关的PM伤的易感性以及随后的伤口修复的可能性。拟议的研究将扩大我们对允许性超脑的预期和意想不到的后果的了解。将在肺泡上皮表型，变形引起的鞘脂运输与肺泡肺炎对PM应激衰竭的敏感性之间建立机械关系；并将提出针对DILT和细胞修复的分子靶标的定向治疗干预措施。