Role of Monolayer Curvature in Lung Surfactant Morphology and Mechanics

单层曲率在肺表面活性剂形态和力学中的作用

基本信息

批准号：
10415829
负责人：
Joseph Michael Barakat
金额：
$ 6.98万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415829
关键词：
Acute Respiratory Distress Syndrome Adsorption Adult Affect Air Albumins Alveolar Alveolus Binding Proteins Biological Assay Biomimetics Breathing Chemicals Cholesterol Clinical Communities Complex Crystallization Devices Diffusion Dilatation - action Elasticity Engineering Environment Enzymes Evolution Fatty Acids Fibrinogen Fluorescence Fluorescence Microscopy Functional disorder Gases Geometry Goals Heterogeneity In Vitro Inflammation Inflammatory Response Injury Lead Length Liquid substance Literature Lung Lung diseases Measurement Measures Mechanics Methods Microbubbles Microscopic Modeling Modulus Morphology Outcome Pathogenesis Pathologic Penetration Permeability Phase Phospholipase A2 Phospholipids Physiological Plasma Proteins Play Pneumonia Positioning Attribute Property Pulmonary Surfactants Pulmonary alveolar structure Radial Resistance Respiration Rest Role Serum Serum Proteins Shock Stress Surface Surface Tension System Testing Theoretical model Therapeutic Time Trauma Validation Variant Water Work base crystallinity design experimental study fluidity inhibitor interfacial lung injury monolayer mortality novel recruit surfactant replacement theories two-dimensional virtual

项目摘要

ABSTRACT: Native lung surfactant (LS) coats the air-water interface of the pulmonary alveoli, reducing its sur- face tension and stabilizing the lung from collapse. Virtually every important feature of LS – e.g., surface-tension lowering and respreading ability, fluidity, collapse resistance, and gas permeability – depends on its two-dimen- sional (2D) domain microstructure. Recent evidence suggests that the morphology of LS crystalline domains (5- 30 μm in size) are highly sensitive to the curvature of the alveolar air-water interface (radii of curvature of 40- 150 μm). Traditional macroscopic methods of physicochemical analysis, such as Langmuir-Wilhelmy surface tensiometry or pulsating bubble surfactometry, do not examine LS at these microscopic length scales. This omis- sion leaves the clinical community with, at best, an incomplete picture of how different chemical components of LS interact within their native, highly curved environment. At worst, the microscopic curvature of the alveoli plays a nontrivial role in the pathogenesis of pulmonary diseases such as acute respiratory distress syndrome (ARDS). We hypothesize a mechanism of ARDS progression by which enzyme degradation and blood serum protein adsorption fundamentally alters the mechanical and morphological properties of curved LS monolayers. In our putative mechanism, initial injury to the lung causes inflammation and elevated levels of phospholipase A2 (PLA2) and blood serum proteins (e.g., albumin and fibrinogen) in the alveolar hypophase. PLA2 digests phospholipids to produce fatty acids, which co-crystallize with LS to form stiff domains. Fibrinogen adsorbs and intercalates the 2D fluid phase of LS, forming a domain-templated elastic network and inhibiting re-adsorption of LS. Well estab- lished principles of continuum mechanics suggest that highly elastic monolayers with stiff heterogeneities will locally resist changes in curvature, causing anisotropic dilatation or alveolar collapse during respiration. Such abnormalities would not only result in decreased alveolar recruitment, but promote further inflammation and ultimately higher levels of serum protein and PLA2. Since this mechanism depends inherently on the microscopic curvature of the alveoli, it could not be elucidated through conventional physicochemical assays. To test our hypothesis, I will measure and model the impact of fatty acid, cholesterol, and fibrinogen on LS monolayers formed on spherical microbubbles under physiologically relevant conditions. Cholesterol and fatty acid are present in certain clinical LS replacements, while fatty acid and fibrinogen are implicated in the progres- sion of ARDS. I will use a novel tensiometer to measure the microstructure and surface tension of LS-coated, spherical microbubbles as a function of chemical composition and bubble radius. We expect dramatic differences in the morphology and mechanics of curved LS from those revealed by traditional Langmuir-Wilhelmy measure- ments of planar LS. Finally, our proposal contains a significant modeling component. I will use continuum theory to model the static and dynamic morphologies of curved LS monolayers, which will help connect variations in chemical makeup to the material and geometrical aspects of normal and pathological (i.e., ARDS-afflicted) LS.

摘要：天然肺表面活性剂（LS）覆盖肺泡的空气-水界面，减少其表面活性剂。 LS 的几乎所有重要特征，例如表面张力。降低和再扩散能力、流动性、抗塌陷性和透气性 – 取决于其二维最近的证据表明 LS 晶域 (5-) 的形态。 30μm大小）对肺泡空气-水界面的曲率高度敏感（曲率半径为40- 150 μm) 物理化学分析的传统宏观方法，例如 Langmuir-Wilhelmy 表面。张力测定法或脉动气泡表面测定法，不要在这些微观长度尺度上检查 LS。临床界充其量只能得到一个不完整的图景，即不同的化学成分是如何发挥作用的。 LS 在其原生的、高度弯曲的环境中相互作用，在最坏的情况下，肺泡的微观弯曲会发挥作用。在急性呼吸窘迫综合征（ARDS）等肺部疾病的发病机制中发挥着重要作用。我们探究了 ARDS 进展的机制，通过酶降解和血清蛋白吸附从根本上改变了弯曲 LS 单层的机械和形态特性。推测的机制是，肺部的初始损伤会导致炎症和磷脂酶 A2 (PLA2) 水平升高肺泡缺相中的血清蛋白（例如白蛋白和纤维蛋白原）PLA2 消化磷脂。产生脂肪酸，与 LS 共结晶形成刚性结构域，吸附并插入纤维蛋白原。 LS 的二维流体相，形成域模板弹性网络并抑制 LS 的再吸附。连续介质力学的公开原理表明，具有刚性异质性的高弹性单层将局部抵抗曲率变化，导致呼吸过程中各向异性扩张或肺泡塌陷。异常不仅会导致肺泡募集减少，还会促进进一步的炎症和最终血清蛋白和 PLA2 水平较高，因为这种机制最初取决于微观。肺泡的曲率，无法通过传统的物理化学测定来阐明。为了验证我们的假设，我将测量并模拟脂肪酸、胆固醇和纤维蛋白原对 LS 的影响在生理相关条件下在球形微泡上形成单层。某些临床 LS 替代品中存在脂肪酸，而脂肪酸和纤维蛋白原则与进展有关。我将使用一种新型张力计来测量 LS 涂层的微观结构和表面张力，球形微泡作为化学成分和气泡半径的函数，我们预计会有显着差异。弯曲 LS 的形态和力学与传统 Langmuir-Wilhelmy 测量所揭示的最后，我们的建议包含一个重要的建模部分，我将使用连续介质理论。模拟弯曲 LS 单层的静态和动态形态，这将有助于连接正常和病理（即患有 ARDS 的）LS 的材料和几何方面的化学组成。