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: 9406343
• 负责人: Todd Michael Squires
• 金额: $ 36.04万
• 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/9406343
• 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; 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.

摘要 天然肺表面活性物质（LS）由脂质和蛋白质的混合物组成，这些脂质和蛋白质一起增强了肺表面活性物质的能力， 降低肺泡表面张力，因此对正常呼吸至关重要。虽然确切的机制 急性肺损伤（ALI）及其更严重的形式急性呼吸窘迫综合征（ARDS）， 不太清楚，LS通过表面活性抑制蛋白、酶、脂肪酸和溶血脂质失活 他们相信扮演了一个重要的角色。已发表的和初步的工作表明，即使是很小的一部分， 与ARDS有关的组分可能会改变单分子膜的表面粘度和弹性， 幅度：当加入饱和脂肪酸时，磷脂单层硬度增加千倍 或白蛋白吸附，而当加入1-2%胆固醇时，胆固醇减少100-1000倍。 这些结果提示了ARDS进展的一个合理的机械机制， 建议项目的假设：ARDS的流变学（例如粘性和弹性）特性- 失活的LS在ARDS级联反应和RS治疗不能 有效逆转ARDS进展。肺的初始损伤会将血液蛋白质通过 肺泡壁透化，和酶PLA 2水平升高，作为炎症反应的一部分。 以前的结果表明，这两种情况都会产生不均匀的流变弹性， 肺深处的结构域：PLA 2通过消化磷脂产生溶血脂质和脂肪酸， 蛋白质通过吸附连续介质力学中的著名现象表明， LS内的不均匀性强烈抵抗呼吸期间自然发生的曲率变化，并且 甚至可能“破裂”或“起皱”而不是平滑地变形。因此，这种异常变形会产生 肺泡上皮上的强局部机械应力，促进进一步的组织损伤， 炎症，并最终导致更高水平的蛋白质和PLA 2。值得注意的是，假设的机制是 物理起源，并从LS单层中这些组分的组织如何影响其 流动和变形的能力。这种机制不能仅仅从化学分析中发现。 为了验证这一假设，研究了LS失活因子（血液蛋白质、脂肪酸、酶）对 模型LS单分子层的流变学将用第一种技术测量，以及组分 (e.g.天然或合成的表面活性剂蛋白质、单不饱和脂肪酸、胆固醇），其可降低或 逆转失活。使用新的实验技术和理论， 失活的LS与弹性不均匀性有关，弹性不均匀性与各向异性肺泡 通货膨胀和通货紧缩。最后，将研究异质单分子膜的混合和演化， 确定消除、破坏或取代这些弹性不均匀性的策略，并最终指导 治疗制剂。