Lipid and Protein Effects on Monolayer Stability

脂质和蛋白质对单层稳定性的影响

• 批准号: 9330388
• 负责人: Joseph Anthony Zasadzinski
• 金额: $ 42.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330388
• 关键词: Acute Lung Injury; Address; Adjuvant; Adsorption; Adult; Adult Respiratory Distress Syndrome; Affect; Air; Albumins; Alveolar; Area; Atelectasis; Biochemistry; Blood capillaries; Breathing; Cations; Charge; Child; Cholesterol; Clinical; Confocal Microscopy; Coupling; Dependence; Diffusion; Disease; Distress; Economic Inflation; Electrostatics; Fatty Acids; Feedback; Fibrinogen; Floods; Formulation; Frequencies; Functional disorder; Gases; Goals; Infasurf; Infiltration; Inflammation; Inflammation Process; Inflammatory; Injury; Ions; Label; Lead; Lipase; Lipids; Liquid substance; Lung; Lung Compliance; Maps; Measurement; Measures; Meconium Aspiration; Methods; Modeling; Modulus; Morphology; Newborn Infant; Physiological; Play; Polyethylene Glycols; Polymers; Premature Birth; Property; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Radial; Recruitment Activity; Residual state; Resistance; Respiratory Signs and Symptoms; Respiratory physiology; Role; Serum Proteins; Surface; Surface Tension; Survanta; Syndrome; Time; Tissues; Unsaturated Fats; Variant; Vascular Permeabilities; Water; Work; acute symptom; aluminum sulfate; capillary; design; hydrophilicity; inhibitor/antagonist; injured; interfacial; lung injury; monolayer; mortality; neonatal respiratory distress; novel; pressure; prevent; public health relevance; success; surfactant; surfactant function; surfactant replacement

The role of Lung Surfactant (LS) in lowering the surface tension, γ, at the alveolar air-liquid interface is well known. We hypothesize that 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. We hypothesize that the dynamic resistance of the LS monolayer to changes in area can reverse the Laplace instability. The dilatational modulus, 𝜀 = 𝐴 𝜕𝛾 𝜕𝐴 , relates the change in surface tension, γ, to the change in interfacial area, A. 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 collapse of smaller alveoli, leading to the alveolar flooding and decreased lung compliance. Our preliminary work shows that serum proteins and lysolipids, which increase in the alveolar fluids during ARDS-induced inflammation, increase γ by competitively adsorbing to the alveolar interface. These inhibitors also dramatically decrease the dilatational modulus due to their diffusional exchange with the subphase, especially at low interfacial area strain rates (ΔA(t)/A). 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, we have built a novel capillary pressure microtensiometer to measure ε(ω) of LS, serum proteins, and lysolipids for the first time. We will map out ε(ω) 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. We will examine how ε(ω) 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 us with a map of the conditions under which the Laplace instability plays a role in the progression of ARDS. Reversing the Laplace instability requires understanding how to prevent inhibitors from reaching the alveolar interface, or removing inhibitors that do adsorb. From our new understanding of ε(ω) we will create LS formulations with optimized rheological properties to promote LS respreading. 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. Minimizing the inhibitor concentration and maximizing LS would lower γ, increase ε(ω) and reverse the conditions leading to the Laplace instability, thereby restoring proper lung function.

肺表面活性剂（LS）在降低肺泡空气界面处的表面张力γ中的作用很好 已知。我们假设LS的第二个基本功能是防止拉普拉斯不稳定性，这 将气体从较小的肺泡中驱逐出较大的气体，从而导致肺泡去核，肺不骨和损失 肺合规。这些是急性呼吸窘迫综合征（ARDS）的核心症状， 在美国，死亡率为40％。我们假设 LS单层改变面积可以逆转拉普拉斯的不稳定性。扩张模量，𝜀 =𝐴𝜕𝐴， 将表面张力（γ）的变化与界面区域的变化相关联。 随着半径的减小减小，抑制拉普拉斯不稳定性。但是，如果2ε-γ<0，则肺的变化 通货膨胀驱动较小的肺泡的崩溃，导致肺泡洪水和改善的肺依从性。 我们的初步工作表明，血清蛋白和溶酶脂质在肺泡液中增加 ARDS诱导的炎症，通过竞争性吸附到肺泡界面来增加γ。这些抑制剂 还大大减少了扩张模量，因为它们与亚相扩散交换， 特别是在低界面面积应变速率（ΔA（t）/A）下。这种情况在肺部受损区域发生 气体交换不足和高水平的感染产物，并引起拉普拉斯不稳定性为2ε-γ<0。 这会导致肺部受伤区域进一步损害，并建立了负面反馈回路 负责当前ARDS治疗的无效性。 为了解决这一假设，我们已经建立了一种新型的毛细管微观计，以测量 LS，血清蛋白和溶酶脂质首次。我们将为临床和模型肺表面活性剂绘制ε（ω） 作为表面活性剂组成，形态，表面压力和频率的函数，以确定影响 饱和与非饱和脂质分数，结构域形态和肺表面活性剂蛋白SP-B和SP-C的含量 胆固醇和脂肪酸级分。我们将检查ε（ω）如何由于子相组成而改变 溶酶脂质，白蛋白和纤维蛋白原，所有这些在ARDS肺中的水平升高。这些首先 测量应为我们提供laplace不稳定性起作用的条件的地图 在ards的进展中。逆转拉普拉斯不稳定性需要了解如何预防抑制剂 从达到牙槽界面或去除吸附的抑制剂。从我们对ε（ω）的新理解中 我们将创建具有优化的流变特性的LS公式，以促进LS重新剥夺。我们也是 提议将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 （钉）和来自明矾等调节器的三价阳离子将提供静电和渗透辅助 促进LS吸附。最小化抑制剂浓度并最大化LS会降低γ，增加ε（ω） 并扭转导致拉普拉斯不稳定性的条件，从而恢复适当的肺功能。