Impact of Fluid versus Solid Stresses on Air-Blood Integrity

流体与固体应力对气血完整性的影响

• 批准号: 7750100
• 负责人: Nicholas J Douville
• 金额: $ 3.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750100
• 关键词: Accounting; Adult Respiratory Distress Syndrome; Air; Air Movements; Alveolar; Alveolar sac; Alveolus; Back; Basal Cell; Biological Assay; Blood; Blood - brain barrier anatomy; Blood-Air Barrier; Brain; Cell Culture Techniques; Cell Line; Cell Survival; Cells; Cellular Membrane; Cessation of life; Classification; Clinical; Coculture Techniques; Cultured Cells; Development; Dimensions; Duct (organ) structure; Electrical Resistance; Electrodes; Endothelial Cells; Engineering; Environmental air flow; Epithelial; Epithelial Cells; Event; Exhibits; Experimental Designs; Fluorocarbons; Genetic Complementation Test; Gifts; Human; In Vitro; Infant; Injury; Lead; Life; Liquid Ventilation; Liquid substance; Lung; MDCK cell; Measurement; Measures; Mechanical Stress; Mechanical ventilation; Mechanics; Membrane; Meniscus structure of joint; Microfluidics; Modeling; Mus; Myoblasts; Neonatal; Pathology; Patients; Permeability; Phenotype; Physiological; Play; Pulmonary Gas Exchange; Relaxation; Research; Resistance; Respiratory distress; Role; Side; Solid; Stress; Stretching; Study models; Sum; Symptoms; System; Technology; Testing; Tight Junctions; Time; Tissue Engineering; Ventilator-induced lung injury; Volutrauma; base; cell injury; cell type; electric impedance; fluid flow; improved; in vitro Model; in vivo; injured airway; monolayer; poly(dimethylsiloxane); pressure; response; surfactant; time use

DESCRIPTION (provided by applicant): Mechanical ventilation is a crucial therapy for patients with acute respiratory distress syndrome (ARDS); however, improper ventilation has been shown to promote further cellular-level injury, leading to an exacerbation of ARDS-like symptoms, termed ventilator-induced lung injury (VILI). Cellular-level damage found in VILI is hypothesized to result from a combination of cyclic and fluidic mechanical stresses generated as atelectactic alveoli collapse and re-open. Solid mechanical stress (volutrauma) occurs as epithelial cells are exposed to the cyclic stretching and relaxation of the alveolus during over-expansion and contraction. The role of fluid mechanical stress in the breakdown of air-blood barrier integrity has been suggested based upon observations during liquid ventilation treatment. In liquid ventilation the alveolus is completely filled with perfluorocarbons, effectively eliminating the air-liquid interface responsible for most fluid mechanical stresses. These in vivo studies suggest that volutrauma alone is not sufficient to cause damage to the degree of air-blood barrier damage seen in VILI, but the lack of in vitro models capable of replicating fluid mechanical stress has limited research on fluid stress in ARDS-pathology. Recent advances in microfluidic fabrication have allowed in vitro study on the role fluid mechanical stress in the development of airway injuries. Similarly, as fluid is redistributed within an edematous alveolus, we hypothesize that high fluid mechanical stresses will be generated at the resulting air-liquid interface. This air-liquid interface moves in a cyclic fashion as alveolar pressure gradients are generated during mechanical ventilation. The small size of alveolar sacs and ducts enables shearing conditions at the air-liquid interface to cause cellular damage and death. The impact of these fluid mechanical stresses independently and in combination with cyclic stretching (solid mechanical) has been suggested by in vivo studies but has not been confirmed. What is required is a systematic study of the effect on alveolar epithelial cells of fluid mechanical stresses individually and in combination with solid mechanical stresses (stretch). Current systems lack the ability to simultaneously study the effects of both stretch and shear. This project will fill this gap by creating a micro- tissue engineered alveoli with a cellular air-blood interface where physiological fluid mechanical events can be recreated over the alveolar epithelial cells in a highly controlled in vitro format. As an initial application of this micro-engineered alveoli, I will study the effects of fluid flow and cyclic stretch independently and in combination. This proposal will specifically test the hypothesis that fluid mechanical stress damages the integrity of the air-blood barrier through a mechanism independent of mechanical cell stretching.

描述（由申请人提供）：机械通气是急性呼吸窘迫综合征（ARDS）患者的重要治疗方法；然而，不适当的通气已被证明会促进进一步的细胞水平损伤，导致 ARDS 样症状恶化，称为呼吸机诱发性肺损伤 (VILI)。据推测，VILI 中发现的细胞水平损伤是由于肺不张肺泡塌陷和重新打开时产生的循环机械应力和流体机械应力共同造成的。当上皮细胞在过度扩张和收缩期间暴露于肺泡的周期性拉伸和松弛时，会发生固体机械应力（体积伤）。根据液体通气治疗期间的观察，提出了流体机械应力在气血屏障完整性破坏中的作用。在液体通气中，肺泡完全充满全氟化碳，有效地消除了造成大多数流体机械应力的气液界面。这些体内研究表明，仅体积伤不足以造成 VILI 中所见的气血屏障损伤程度，但缺乏能够复制流体机械应力的体外模型，限制了 ARDS 病理学中流体应力的研究。微流体制造的最新进展使得体外研究流体机械应力在气道损伤发展中的作用成为可能。类似地，当流体在水肿肺泡内重新分布时，我们假设在由此产生的气液界面处将产生高流体机械应力。当机械通气期间产生肺泡压力梯度时，该气液界面以循环方式移动。肺泡囊和导管的小尺寸使得气液界面处的剪切条件能够导致细胞损伤和死亡。体内研究已经提出了这些流体机械应力的独立影响以及与循环拉伸（固体机械）相结合的影响，但尚未得到证实。需要系统地研究单独的流体机械应力以及与固体机械应力（拉伸）相结合对肺泡上皮细胞的影响。当前的系统缺乏同时研究拉伸和剪切效应的能力。该项目将通过创建具有细胞空气-血液界面的微组织工程肺泡来填补这一空白，其中可以以高度控制的体外形式在肺泡上皮细胞上重现生理流体机械事件。作为这种微工程肺泡的初步应用，我将独立和组合地研究流体流动和循环拉伸的影响。该提案将专门测试流体机械应力通过独立于机械细胞拉伸的机制破坏气血屏障完整性的假设。