Mechanics and Deformation Responses of Lung Cells

肺细胞的力学和变形反应

• 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
• 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

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细胞对变形应力的反应。 这项工作的动机源于我们对呼吸机引起的肺损伤 (VIM) 的兴趣。 我们努力的长期目标是通过药物保护肺部免受变形损伤。 拟议的实验建立在我们在过去的资助期间进行的关键观察的基础上，即：a）培养物中肺泡上皮细胞的拉伸触发了剧烈的脂质运输反应； b) 运输反应本质上是囊泡状的，随应变率和幅度变化，依赖于温度和能量，并且可以通过药理学操纵； c) 抑制变形诱导的脂质运输（DILT）会增加质膜（PM）应力失效的风险，并降低随后 PM 修复的可能性； d) 与细胞坏死不同的细胞损伤和重新封闭可以在整个活体肺中容易地得到证明和量化。这些观察结果表明，DILT 对于维持微妙的 PM 紧张局势是不可或缺的。 实验按照 3 个具体目标组织：1) 测量 pH 和 pCO2 对整个活体大鼠肺中与 PM 损伤和修复相关的机械通气的单独概率的影响； 2) 表征原代大鼠肺泡肺细胞中变形应力对 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碱平衡对 DILT 的影响、对拉伸相关 PM 损伤的敏感性以及随后伤口修复的可能性的影响。 拟议的研究将扩大我们对允许性高碳酸血症的有意和无意后果的了解；将建立肺泡上皮表型、变形诱导的鞘脂运输和肺泡肺细胞对 PM 应激衰竭的易感性之间的机制关系；并将提出 DILT 和细胞修复定向治疗干预的分子靶点。