Determining the physiological optimal surface viscosity

确定生理最佳表面粘度

• 批准号: 8691920
• 负责人: Prajnaparamita Dhar
• 金额: $ 18.74万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691920
• 关键词: Acute Lung Injury; Adsorption; Adult Respiratory Distress Syndrome; Affect; Air; Alveolar; Chemical Surfactants; Cholesterol; Clinical; Complex Mixtures; Coupled; Coupling; Curosurf; Disease Pathway; Economic Inflation; Effectiveness; Equation; FDA approved; Failure; Film; Fluorescence Microscopy; Functional disorder; Goals; Incidence; Infasurf; Infectious Agent; Lead; Lipids; Lung; Lung diseases; Measurement; Mechanics; Modeling; Molecular; Molecular Analysis; Monitor; Newborn Respiratory Distress Syndrome; Physiological; Premature Infant; Property; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Research; Structure; Surface; Surface Tension; Survanta; Synchrotrons; Techniques; Technology; Thermodynamics; Time; United States; Viscosity; Water; Work; Work of Breathing; X ray diffraction analysis; X-Ray Diffraction; cholesterol control; clinically relevant; cohesion; cost; design; improved; in vivo; insight; interfacial; monolayer; saturated fat; surfactant

The primary goal of this research is to determine, for the first time, the physiologically optimal surface viscosity of the lung surfactant using an active microrheology technique unique to our lab. We hypothesize that there exists an optimal surface viscosity in an effective lung surfactant that provides both rapid adsorption to the air-water interface and ultra-low surface tensions. Our goal is to determine how best to achieve this optimum by controlling the cholesterol fraction of a synthetic replacement lung surfactant. Three orders of magnitude increased sensitivity of our microrheology technique as compared to macroscopic rheometers allows precise monitoring of changes in the molecular organization of the lung surfactant film in the presence of cholesterol, enabling accurate measurements of surface viscosity of surfactant films. Ultimately, determining the optimal cholesterol concentration will enable a better design of synthetic surfactants to treat Neonatal Respiratory Distress Syndrome (NRDS) and may give insights into the causes of surfactant inactivation in Adult Respiratory Distress Syndrome (ARDS). We hypothesize that small fractions (1-5 wt. %) of cholesterol reduce the crystalline ordering of saturated lipids in lung surfactant monolayers, leading to a reduction in the shear viscosity, which enhances the surfactant's ability to flow and cover the alveolar interface. We also hypothesize that excess cholesterol ( >10 wt %) decreases the effectiveness of lung surfactants in ARDS by increasing the minimum surface tension of the interfacial film. This inability to reach ultra-low surface tensions is hypothesized to be a consequence of significantly reduced interfacial energy of the film (line tension). Low interfacial film energy can influence the mechanical cohesion in the surfactant film and lead to the failure of the film on compression, which ultimately causes the film to become unstable at lower surface tensions. Furthermore, lipid(cholesterol)- protein interactions can also alter these mechanical and structural properties by changing their molecular organization at the interface. By determining the mechanical properties of both model and clinically relevant surfactant film in the presence of physiological and elevated amounts of cholesterol, we can understand how increased cholesterol might lead to surfactant inactivation in ARDS and determine better replacement surfactants for treatment. The mechanical properties thus determined by the active microrheology technique will be correlated with isotherms, fluorescence microscopy, and grazing incidence synchrotron X-ray diffraction to determine how cholesterol alters the molecular packing of lung surfactant lipids, which determines the mechanical properties of monolayers.

本研究的主要目标是确定，第一次，使用我们实验室独有的活性微流变学技术的肺表面活性剂的生理最佳表面粘度。我们假设，存在一个最佳的表面粘度在一个有效的肺表面活性剂，提供快速吸附到空气-水界面和超低的表面张力。我们的目标是确定如何通过控制合成替代肺表面活性剂的胆固醇分数来最好地实现这一最佳效果。与宏观流变仪相比，我们的微流变技术的灵敏度增加了三个数量级，可以精确监测胆固醇存在下肺表面活性剂膜的分子组织变化，从而能够准确测量表面活性剂膜的表面粘度。最终，确定最佳胆固醇浓度将使合成表面活性剂的更好的设计，以治疗新生儿呼吸窘迫综合征（NRDS），并可能提供洞察表面活性剂失活的原因在成人呼吸窘迫综合征（ARDS）。 我们假设小部分（1-5 wt. %）的胆固醇降低了肺表面活性剂单层中饱和脂质的结晶有序性，导致剪切粘度降低，这增强了表面活性剂流动和覆盖肺泡界面的能力。我们还假设过量胆固醇（>10重量%）通过增加界面膜的最小表面张力而降低肺表面活性剂在ARDS中的有效性。这种无法达到超低表面张力的情况被假设为是膜的界面能（线张力）显著降低的结果。低的界面膜能会影响表面活性剂膜中的机械内聚，并导致膜在压缩时失效，这最终导致膜在较低的表面张力下变得不稳定。此外，脂质（胆固醇）-蛋白质相互作用也可以通过改变它们在界面处的分子组织来改变这些机械和结构特性。通过确定模型和临床相关的表面活性剂膜在生理和升高量的胆固醇存在下的机械性能，我们可以理解胆固醇增加如何导致表面活性剂在ARDS中失活，并确定更好的替代表面活性剂用于治疗。因此，由活性微流变学技术确定的机械性能将与等温线，荧光显微镜，掠入射同步加速器X-射线衍射，以确定胆固醇如何改变肺表面活性剂脂质的分子堆积，这决定了单分子层的机械性能。