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.

肺表面活性剂 (LS) 在降低肺泡气液界面表面张力 γ 方面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，拉普拉斯不稳定性将气体从较小的肺泡排出并进入较大的肺泡，导致肺泡复张、肺不张和肺顺应性丧失。这些是急性呼吸窘迫综合征 (ARDS) 的核心症状，该病困扰着美国 15 万人，死亡率为 40%。为了量化导致拉普拉斯不稳定性的因素，我将检查膨胀模量 𝜀 = 𝐴(𝜕𝛾⁄𝜕𝐴)，它将表面张力 𝛾 的变化与界面面积 A 的变化联系起来，因为界面以呼吸频率振荡。对于 2𝜀-𝛾 > 0，拉普拉斯压力随着半径的减小而减小，从而抑制了拉普拉斯不稳定性。然而，如果 2𝜀-𝛾 < 0，肺充气的变化会导致较小肺泡塌陷，导致肺顺应性下降和 ARDS 的其他症状。我们假设 ARDS 因血清蛋白和溶血脂的竞争性吸附而加剧，在 ARDS 诱导的炎症过程中，肺泡液中的蛋白质和溶血脂会增加。这些可溶性抑制剂会增加 𝛾，并且理论上由于它们与肺泡液的扩散交换而显着降低扩张模量，尤其是在低呼吸频率时。这种情况出现在气体交换不良和炎症产物水平较高的肺部受损区域，并引发拉普拉斯不稳定性（2𝜀-𝛾 < 0）。这会导致肺部受损区域进一步受损，并建立负反馈循环，这可能是当前 ARDS 治疗无效的原因。为了解决这个假设，我将使用一种新型毛细管压力微张力计首次测量 LS、血清蛋白和溶血脂的 𝜀(ω)。我将绘制临床和模型肺表面活性剂的 𝜀 作为表面活性剂成分、形态、表面压力和频率的函数，以确定饱和与不饱和脂质组分、结构域形态以及肺表面活性剂蛋白 SP-B 和 SP-C、胆固醇和脂肪酸组分的影响。我将研究 e 如何因溶血脂、白蛋白和纤维蛋白原的亚相成分而变化，所有这些物质在 ARDS 肺中的水平都升高。这些首次测量应该提供拉普拉斯不稳定性在 ARDS 进展中发挥作用的条件图。扭转拉普拉斯不稳定性需要去除吸附的抑制剂。根据我们对 e 的新理解，我们将创建具有优化流变特性的 LS 配方，以通过马兰戈尼效应促进 LS 重新铺展。我们还建议，尽量减少 LS 中的阴离子脂质部分，并添加低浓度的聚乙二醇 (PEG) 和明矾等佐剂中的三价阳离子，将提供静电和渗透辅助，以促进 LS 吸附。相对于血清蛋白和溶血脂，最大化 LS 吸附将降低 g、增加 e 并逆转导致拉普拉斯不稳定性的条件，从而恢复正常的肺功能。