Role of Monolayer Curvature in Lung Surfactant Morphology and Mechanics

摘要：天然肺表面活性物质（LS）覆盖肺泡的气-水界面，降低其表面活性。 面对紧张和稳定肺从崩溃。几乎LS的每个重要特征-例如，表面张力 降低和再扩展能力，流动性，抗坍塌性和气体渗透性-取决于其二维， 二维（2D）微结构。最近的证据表明，LS结晶域的形态（5- 30 μm）对肺泡气-水界面的曲率高度敏感（曲率半径为40- 150 μm）。传统的宏观物理化学分析方法，如Langmuir-Wilhelmy表面 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。这个omis- 最好的情况是，临床社区对不同的化学成分是如何产生的不完整的了解。 LS在其原生的高度弯曲的环境中相互作用。最坏的情况是肺泡的微小弯曲 在肺部疾病如急性呼吸窘迫综合征（ARDS）的发病机制中起重要作用。 我们假设ARDS进展的机制是酶降解和血清蛋白 吸附从根本上改变了弯曲LS单层的机械和形态性质。在我们 假定的机制，肺的初始损伤引起炎症和磷脂酶A2（PLA 2）水平升高 和血清蛋白（例如，白蛋白和纤维蛋白原）。磷脂酶A2抑制磷脂 以产生脂肪酸，其与LS共结晶以形成刚性域。纤维蛋白原吸附并嵌入 LS的二维流体相，形成结构域模板化的弹性网络并抑制LS的再吸附。好吧，建立- 连续介质力学的既定原理表明，具有刚性不均匀性的高弹性单分子层将 局部抵抗曲率变化，导致呼吸期间各向异性扩张或肺泡塌陷。等 异常不仅会导致肺泡募集减少，还会促进进一步的炎症， 最终血清蛋白和PLA 2水平升高。由于这种机制本质上取决于微观 由于肺泡的弯曲，无法通过常规理化分析阐明。 为了验证我们的假设，我将测量和模拟脂肪酸、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的单层。胆固醇和脂肪 酸存在于某些临床LS替代品中，而脂肪酸和纤维蛋白原与进展有关。 ARDS的锡永。我将使用一种新型的张力计来测量LS涂层的微观结构和表面张力， 球形微泡作为化学成分和泡半径的函数。我们期待着戏剧性的差异 在形态和力学的弯曲LS从那些揭示了传统的朗缪尔-威廉测量- 平面LS的部分。最后，我们的建议包含一个重要的建模组件。我会用连续统理论 模拟弯曲LS单层的静态和动态形态，这将有助于连接变化， 化学组成对正常和病理的材料和几何方面的影响（即，（L.S.）

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.