Lipid and Protein Effects on Monolayer Stability

肺表面活性物质(LS)对降低肺泡气-液界面表面张力γ的作用良好 为人所知。我们假设LS的第二个基本功能是防止拉普拉斯不稳定性，它 促使气体从较小的肺泡进入较大的肺泡，导致肺泡关闭不全、肺不张和肺功能丧失。 肺顺应性。这些是急性呼吸窘迫综合征(ARDS)的核心症状， 在美国，15万人因40%的死亡率而饱受折磨。我们假设地球表面的动态阻力 LS单分子膜的面积变化可以逆转拉普拉斯不稳定性。膨胀系数，𝜀=𝐴𝜕𝛾𝜕𝐴， 将表面张力γ的变化与界面面积A的变化联系起来。对于2ε−γ&gt；0，拉普拉斯压力 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；0，肺的变异 充气导致较小的肺泡塌陷，导致肺泡泛滥，降低肺顺应性。 我们的初步工作表明，血清蛋白和溶脂在肺泡液中增加 ARDS诱导的炎症，通过竞争性地吸附到肺泡界面上而增加γ。这些抑制剂 还由于它们与亚相的扩散交换而极大地降低了扩张模数， 特别是在低界面应变率(ΔA(T)/A)下。这种情况发生在肺的受损区域， 不良的气体交换和高水平的炎症产物，并引发拉普拉斯不稳定为2ε−γ&lt；0。 这会导致肺损伤区域的进一步损害，并建立负反馈环路 对目前ARDS治疗的无效负责。 为了解决这一假设，我们建立了一种新型的毛细管压力微张力计来测量ε(ω) LS、血清蛋白和溶菌脂均为首次报道。我们将为临床和模拟肺表面活性物质制定ε(ω) 作为表面活性剂组成、形态、表面压力和频率的函数来确定效果 饱和与不饱和脂组分、结构域形态以及肺表面活性物质蛋白SP-B和SP-C， 胆固醇和脂肪酸组分。我们将研究ε(ω)如何因以下的子阶段组成而发生变化 溶脂、白蛋白和纤维蛋白原，所有这些在ARDS肺中都有升高的水平。这是他们同类中的第一个 测量应该为我们提供拉普拉斯不稳定性发挥作用的条件图。 在急性呼吸窘迫综合征的进程中。扭转拉普拉斯不稳定性需要了解如何预防抑制剂 从到达肺泡界面，或清除确实吸附的抑制剂。来自我们对ε(ω的新理解) 我们将创造具有优化的流变特性的LS配方，以促进LS的再扩散。我们也 建议最大限度地减少LS中的阴离子脂质含量，并添加低浓度的聚乙二醇 (聚乙二醇酯)和来自明矾等佐剂的三价阳离子将提供静电和渗透辅助作用 促进LS吸附。最小缓蚀剂浓度和最大LS将降低γ，增加ε(ω) 并逆转导致拉普拉斯不稳定的情况，从而恢复正常的肺功能。

The role of Lung Surfactant (LS) in lowering the surface tension, γ, at the alveolar air-liquid interface is well known. 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.