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

肺表面活性物质（LS）在降低肺泡气液界面表面张力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，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，导致肺泡去募集、肺不张和肺顺应性的丧失。这些是急性呼吸窘迫综合征（ARDS）的核心症状，在美国有150，000人受到影响，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=（⁄），它将表面张力的变化与界面面积的变化A联系起来，因为界面以呼吸频率振荡。𝛾𝜕𝐴𝜕𝛾𝐴𝜀当2π-π> 0时，拉普拉斯压力随半径减小而减小，从而抑制了拉普拉斯不稳定性。然而，如果2μ-λ< 0，肺充气的变化会驱动较小肺泡的塌陷，导致肺顺应性降低和其他ARDS症状。我们推测，急性呼吸窘迫综合征是由于血清蛋白和溶血脂的竞争性吸附而加剧的，在急性呼吸窘迫综合征诱导的炎症过程中，血清蛋白和溶血脂在肺泡液中的含量增加。这些可溶性抑制剂增加呼吸，并且由于它们与肺泡液的扩散交换，特别是在低呼吸频率下，理论上还显著降低呼吸模量。这种情况出现在肺的受损区域，气体交换差，炎症产物水平高，并引起拉普拉斯不稳定性为2π-ε< 0。这导致肺损伤区域的进一步损伤，并且建立了负反馈回路，这可能是当前ARDS治疗无效的原因。为了解决这一假设，我将使用一种新的毛细管压力显微张力计来测量LS，血清蛋白和溶血脂质的ω（ω）的第一次。我将绘制出临床和模型肺表面活性剂作为表面活性剂组成、形态、表面压力和频率的函数的图，以确定饱和与不饱和脂质部分、结构域形态和肺表面活性剂蛋白SP-B和SP-C、胆固醇和脂肪酸部分的影响。𝜀我将研究由于溶血脂、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肺中水平升高。这些第一次的测量应该提供一个条件下，拉普拉斯不稳定性在ARDS的进展中发挥作用的地图。要逆转拉普拉斯不稳定性，就需要去除吸附的抑制剂。从我们对e的新理解，我们将创造具有优化流变性能的LS配方，以通过Marangoni效应促进LS再扩散。我们还建议，最大限度地减少LS中的阴离子脂质部分，并添加低浓度的聚乙二醇（PEG）和三价阳离子的佐剂，如明矾，将提供一个静电和渗透协助，以促进LS吸附。使LS相对于血清蛋白和溶血脂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性的条件，从而恢复适当的肺功能。

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.