Enhancing Adsorption of Lung Surfactants at the Air-Water Interface Using Methods from Colloid Stability Theory

利用胶体稳定性理论的方法增强肺表面活性剂在空气-水界面的吸附

• 批准号: 9911287
• 负责人: Steven Iasella
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-20 至 2023-01-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911287
• 关键词: Acute Lung Injury; Address; Adjuvant; Adsorption; Adult; Adult Respiratory Distress Syndrome; Affect; Air; Albumins; Alveolar; Area; Atelectasis; Automobile Driving; Biochemical; Biophysics; Blood; Blood capillaries; Breathing; Cations; Child; Cholesterol; Clinical; Colloids; Diffusion; Disease; Electrolytes; Electrostatics; Event; Exhalation; Fatty Acids; Feedback; Fibrinogen; Formulation; Frequencies; Gases; Goals; Infasurf; Inflammation; Inflammation Process; Inhalation; Lead; Length; Lipids; Liquid substance; Lung; Lung Compliance; Maps; Measurement; Measures; Methods; Modeling; Modulus; Morphology; Palmitic Acids; Patients; Peptide Hydrolases; Phospholipase A2; Play; Polyethylene Glycols; Polymers; Property; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Radial; Respiratory physiology; Role; Science; Serum Proteins; Severities; Surface; Surface Tension; Surfactant therapy; Survanta; Techniques; Testing; Therapeutic Uses; Time; Trauma; Unsaturated Fats; Variant; Water; Work; acute symptom; aluminum sulfate; base; combat; design; inhibitor/antagonist; injured; interest; interfacial; macrophage; monolayer; mortality; novel; pressure; prevent; public health relevance; recruit; surfactant; surfactant function; surfactant replacement; theories

The role of Lung Surfactant (LS) in lowering the surface tension, γ, at the alveolar air-liquid interface is well known. A second essential function of LS is to prevent the Laplace instability, which drives gas out of smaller alveoli and into larger ones, leading to alveolar de-recruitment, atelectasis and loss of lung compliance. These are the core symptoms of Acute Respiratory Distress Syndrome (ARDS), which afflicts 150,000 people in the US with a 40% mortality rate. To quantify the factors leading to the Laplace instability, I will examine the dilatational modulus, 𝜀 = 𝐴(𝜕𝛾⁄𝜕𝐴), which relates the change in surface tension, 𝛾, to the change in interfacial area, A, as the interface is oscillated at breathing frequencies. For 2𝜀-𝛾 > 0, the Laplace pressure decreases with decreasing radius, suppressing the Laplace Instability. However, if 2𝜀-𝛾 < 0, variations in lung inflation drive the collapse of smaller alveoli, leading to decreased lung compliance and other symptoms of ARDS. We hypothesize that ARDS is exacerbated by the competitive adsorption of serum proteins and lysolipids, which increase in the alveolar fluids during ARDS-induced inflammation. These soluble inhibitors increase 𝛾 and also are theorized to dramatically decrease the dilatational modulus due to their diffusional exchange with the alveolar fluids, especially at low breathing frequencies. Such conditions arise in damaged areas of the lung with poor gas exchange and high levels of inflammation products and provoke the Laplace instability as 2𝜀-𝛾 < 0. This leads to further damage in injured areas of the lung and a negative feedback loop is established that may be responsible for the ineffectiveness of current ARDS treatments. To address this hypothesis, I will use a novel capillary pressure microtensiometer to measure 𝜀(ω) of LS, serum proteins, and lysolipids for the first time. I will map out 𝜀 for clinical and model lung surfactants as a function of surfactant composition, morphology, surface pressure and frequency to determine the effects of saturated vs. unsaturated lipid fraction, domain morphology, and lung surfactant proteins SP-B and SP-C, cholesterol and fatty acid fractions. I will examine how e changes due to subphase compositions of lysolipids, albumin, and fibrinogen, all of which have elevated levels in the ARDS lung. These first of their kind measurements should provide a map of the conditions under which the Laplace instability plays a role in the progression of ARDS. Reversing the Laplace instability requires removing inhibitors that do adsorb. From our new understanding of e we will create LS formulations with optimized rheological properties to promote LS respreading via the Marangoni effect. We also propose that minimizing the anionic lipid fraction in LS and adding low concentrations of polyethylene glycol (PEG) and trivalent cations from adjuvants such as alum, will provide an electrostatic and osmotic assist to promote LS adsorption. Maximizing LS adsorption relative to serum proteins and lysolipids would lower g, increase e and reverse the conditions leading to the Laplace instability, thereby restoring proper lung function.

众所周知，肺表面活性剂（LS）在降低表面张力γ中的作用是众所周知的。 LS的第二个基本功能是防止拉普拉斯不稳定性，该拉普拉斯不稳定性将气体从较小的肺泡中驱动到较大的肺泡中，从而导致肺泡脱落，息肉性和肺部顺应性丧失。这些是急性呼吸窘迫综合征（ARDS）的核心症状，在美国，其死亡率为40％。为了量化导致拉普拉斯不稳定性的因素，我将检查扩张模量𝜀 =𝐴（𝜕𝛾 ⁄𝜕𝐴），这将表面张力的变化与界面区域的变化相关联，因为界面在呼吸频率下振荡。对于2𝜀-𝛾> 0，拉普拉斯压力随着半径的降低而降低，从而抑制了拉普拉斯的不稳定性。但是，如果2𝜀-𝛾 <0，则肺通胀的变化驱动较小的肺泡的崩溃，从而导致肺部依从性降低和其他ARDS症状。我们假设血清蛋白和溶酶脂质的竞争成瘾加剧了ARDS，在ARDS诱导的炎症过程中增加了肺泡液的增加。这些可溶性抑制剂增加了𝛾 𝛾，并且理论上也可以大大减少扩散模量，因为它们与Alloolar Flues的扩散交换，尤其是在低呼吸频率下。这种情况位于肺部的损伤区域，气体交换和高水平的感染产品，并引起拉普拉斯不稳定的2𝜀-𝛾 <0。这会导致肺部受伤区域进一步损害，并确定可能导致当前ARDS治疗效率低下的反馈回路。为了解决这一假设，我将首次使用新型的毛细管微晶计测量LS，血清蛋白和溶血脂的𝜀（ω）。我将映射𝜀临床和模型的肺表面与表面活性剂组成，形态，表面压力和频率的函数，以确定饱和脂质分数，结构域形态和肺表面蛋白SP-B和SP-C，胆固醇和脂肪酸分数的影响。我将研究溶质脂，白蛋白和纤维蛋白原的子阶段组成引起的E变化，所有这些都在ARDS肺中均具有升高的水平。这些首先进行的测量应提供一张映射，以绘制拉普拉斯不稳定性在ARDS进展中起作用的条件。逆转拉普拉斯不稳定性需要消除吸附的抑制剂。从我们对E的新理解中，我们将创建具有优化的流变特性的LS公式，以通过Marangoni效应促进LS。我们还提出，将LS的阴离子脂质分数最小化，并添加低浓度的聚乙烯乙二醇（PEG）和来自校友等调节器的三价阳离子，将提供静电和渗透辅助，以促进LS吸附。最大化LS相对于血清蛋白和溶酶体的吸附最大化，将降低G，增加E并逆转导致拉普拉斯不稳定的条件，从而恢复适当的肺功能。