Heterogeneous lung surfactant morphologies: effect on alveolar dynamics, and role in promoting acute respiratory distress syndrome

异质肺表面活性剂形态：对肺泡动力学的影响以及促进急性呼吸窘迫综合征的作用

• 批准号: 9219006
• 负责人: Todd Michael Squires
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219006
• 关键词: Acute Lung Injury; Adsorption; Adult; Adult Respiratory Distress Syndrome; Affect; Agitation; Albumins; Alveolar; Alveolar wall; Alveolus; Biological Assay; Blood Proteins; Breathing; Chemical Surfactants; Chemicals; Child; Cholesterol; Consensus; Economic Inflation; Elasticity; Enzymes; Epithelial; Epithelium; Ethers; Evolution; Fatty Acids; Fibrinogen; Formulation; Functional disorder; Heterogeneity; Individual; Inflammation; Inflammatory Response; Injury; Link; Lipase; Lipids; Literature; Lung; Lung Inflammation; LytA enzyme; Measurement; Measures; Mechanical Stress; Mechanics; Methods; Microbubbles; Modeling; Molecular; Monitor; Monounsaturated Fatty Acids; Morphology; Patients; Phospholipase; Phospholipase A2; Phospholipids; Physiological; Plasma Proteins; Play; Process; Property; Proteins; Psychological Techniques; Publishing; Pulmonary Surfactants; Respiration; Respiratory physiology; Rheology; Role; Saturated Fatty Acids; Serum Proteins; Spottings; Stress; Surface; Surface Tension; Techniques; Testing; Therapeutic; Tissues; Trauma; Viscosity; Work; alveolar epithelium; analog; base; design; effective therapy; inhibitor/antagonist; innovation; interfacial; lung injury; monolayer; mortality; neonatal respiratory distress; novel; phosphonolipids; response; success; surfactant; surfactant function; surfactant replacement; surfactant replacement therapy; theories; viscoelasticity

Abstract Native lung surfactant (LS) consists of a mixture of lipids and proteins that together posses the ability to lower the alveolar surface tension, and thus is essential for normal breathing. While the exact mechanisms of acute lung injury (ALI), and its more severe form, acute respiratory distress syndrome (ARDS), are currently not well understood, LS inactivation by surface active inhibitory proteins, enzymes, fatty acids and lyso-lipids are believed to play a contributing role. Published and preliminary work reveals that even small fractions of ARDS-implicated components may change the surface viscosity and elasticity of monolayers by orders of magnitude: thousand-fold increases in phospholipid monolayer stiffness when saturated fatty acids are added or albumin adsorbs, whereas 100-1000-fold decreases occur when 1-2% cholesterol is added. These results suggest a plausible mechanical mechanism for ARDS progression, and the central hypothesis of the proposed project: that the rheological (e.g. viscous and elastic) properties of ARDS- inactivated LS play a central, causative role in the ARDS cascade, and in the inability of RS therapies to effectively reverse ARDS progression. An initial insult to the lung introduces blood proteins through permeabilized alveolar walls, and heightened levels of the enzyme PLA2, as part of the inflammatory response. Previous results suggest that either of these situations would create heterogeneous, rheologically elastic domains deep in the lung: PLA2 by digesting phospholipids to produce lyso-lipids and fatty acids, and blood proteins through adsorption. Well-known phenomena in continuum mechanics suggest that elastic heterogeneities within the LS strongly resist the curvature changes that occur naturally during respiration, and may even `crack' or `crumple' rather than deform smoothly. Such abnormal deformations would thus exert strong, localized mechanical stresses on the alveolar epithelium, promoting further tissue damage and inflammation, and ultimately to greater levels of protein and PLA2. Notably, the hypothesized mechanism is physical in origin, and derives from how the organization of these components in the LS monolayer affects their ability to flow and deform. Such a mechanism could not be uncovered from chemical assays alone. To test this hypothesis, the impact of LS-inactivating factors (blood proteins, fatty acids, enzymes) on the rheology of model LS monolayers will be measured with first-of-their-kind techniques, as well components (e.g. natural or synthetic surfactant proteins, mono-unsaturated fatty acids, cholesterol) that may reduce or reverse the inactivation. Using both novel experimental techniques and theory, the molecular composition of inactivated LS will be related to elastic heterogeneities, and elastic heterogeneities to anisotropic alveolar inflation and deflation. Finally, the mixing and evolution of heterogeneous monolayers will be studied to identify strategies to dissolve, disrupt or displace these elastic heterogeneities, and ultimately guiding therapeutic formulations.

抽象的 天然肺表面活性剂（LS）由脂质和蛋白质的混合物组成，这些混合物具有能力 降低肺泡表面张力，因此对于正常呼吸至关重要。而确切的机制 急性肺损伤（ALI）及其更严重的急性呼吸窘迫综合征（ARDS） 不太了解，表面活性抑制蛋白，酶，脂肪酸和溶酶脂灭活 据信扮演着重要角色。出版和初步的工作表明，即使是一小部分 ARDS刺激的组件可能会通过订单来改变单层的表面粘度和弹性 幅度：添加饱和脂肪酸时，磷脂单层刚度增加了千倍 或白蛋白吸附剂，而当添加1-2％的胆固醇时，会减少100-1000倍。 这些结果表明ARDS进展的合理机械机制，中央 拟议项目的假设：Ards-的流变学（例如粘性和弹性）特性 灭活的LS在ARDS级联中起着中心的原因作用，而RS疗法无法进行 有效地逆转ARDS的进展。对肺的最初侮辱会通过 作为炎症反应的一部分，透化牙槽壁和酶PLA2的水平升高。 先前的结果表明，这些情况中的任何一个都会产生异质，流变学上的弹性 肺深处的结构域：PLA2，通过消化磷脂产生溶血脂和脂肪酸以及血液 蛋白质通过吸附。连续力学中众所周知的现象表明弹性 LS内的异质性强烈抵抗呼吸过程中自然发生的曲率变化，并且 甚至可以“裂缝”或“碎屑”，而不是顺利进行变形。因此，这种异常变形会施加 肺泡上皮上的强，局部的机械应力，促进了进一步的组织损伤和 炎症，最终达到蛋白质和PLA2的水平更高。值得注意的是，假设的机制是 物理起源，并源于LS单层中这些组件的组织如何影响其 流动和变形的能力。这种机制不能仅从化学测定中发现。 为了检验这一假设，LS灭活因子（血蛋白，脂肪酸，酶）的影响 LS单层模型的流变学将通过首次涉及的技术来衡量 （例如，天然或合成表面活性剂蛋白，一单不饱和脂肪酸，胆固醇）可能会降低或 扭转失活。使用新颖的实验技术和理论，即分子组成 灭活的LS将与弹性异质性以及各向异性肺泡的弹性异质性有关 通货膨胀和通货膨胀。最后，将研究异质单层的混合和演变 确定溶解，破坏或取代这些弹性异质性的策略，并最终指导 治疗配方。