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.

肺表面活性物质(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进入较大的肺泡，导致肺泡去复张、肺不张和肺顺应性丧失。这些都是急性呼吸窘迫综合征(ARDS)的核心症状，该综合症在美国困扰着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，我将检验膨胀系数(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，因为界面在呼吸频率下振荡。对于2𝜀-𝛾&gt；0，拉普拉斯压强随着半径的减小而减小，抑制了拉普拉斯不稳定性。然而，如果2𝜀-𝛾&lt；0时，肺充气的变化会导致较小的肺泡塌陷，导致肺顺应性降低和其他急性呼吸窘迫综合征症状。我们假设ARDS是由于血清蛋白和溶脂的竞争性吸附而加重的，在ARDS诱导的炎症过程中，血清蛋白和溶脂在肺泡液中的竞争吸附增加。这些可溶的抑制剂可增加𝛾，理论上还可显著降低扩张模数，这是因为它们与肺泡液的扩散交换，特别是在低呼吸频率时。这种情况发生在肺部受损区域，气体交换不良，炎症产物水平高，并引发拉普拉斯不稳定性，为2𝜀-𝛾&lt；0。这会导致肺损伤区域的进一步损害，并建立一个负反馈回路，这可能是目前ARDS治疗无效的原因。为了解决这一假设，我将首次使用一种新型的毛细管压力微张力计来测量LS、血清蛋白和溶质脂的𝜀(ω。我将绘制临床和模型肺表面活性物质的𝜀图，作为表面活性物质组成、形态、表面压力和频率的函数，以确定饱和与不饱和脂肪组分、结构域形态、肺表面活性物质蛋白SP-B和SP-C、胆固醇和脂肪酸组分的影响。我将研究由于溶脂、白蛋白和纤维蛋白原的亚相组成如何改变e，所有这些在ARDS肺中都有升高的水平。这些第一类测量应该提供拉普拉斯不稳定性在ARDS进展中起作用的条件图。要扭转拉普拉斯不稳定性，需要移除确实能吸附的抑制剂。根据我们对e的新理解，我们将创建具有优化流变性的LS配方，以通过Marangoni效应促进LS重新扩散。我们还提出，尽量减少LS中的阴离子脂质含量，并添加低浓度的聚乙二醇(PEG)和明矾等助剂中的三价阳离子，将提供静电和渗透辅助来促进LS的吸附。最大限度地增加LS相对于血清蛋白和溶质脂的吸附将降低g，增加e，并逆转导致拉普拉斯不稳定的条件，从而恢复正常的肺功能。