The Biophysics of Mucus Hydration and Adhesion/Cohesion

粘液水合和粘附/内聚力的生物物理学

• 批准号: 8292396
• 负责人: MICHAEL C RUBINSTEIN
• 金额: $ 37.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292396
• 关键词: Acute; Adhesions; Adhesives; Animals; Back; Biophysics; Cell Adhesion; Cell Separation; Cell surface; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Coughing; Culture Media; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Dehydration; Development; Disease; Elasticity; Epithelial Cells; Exhibits; Functional disorder; Gel; Genetic; Goals; Goblet Cells; Human; Hydration status; Hyperplasia; In Vitro; Inflammatory Response; Injury; Instruction; Ion Transport; Lead; MUC4 mucin; MUC5AC gene; MUC5B gene; Measures; Modeling; Mucin-2 Staining Method; Mucins; Mucolytics; Mucous body substance; Obstruction; Obstructive Lung Diseases; Osmotic Pressure; Patients; Pharmaceutical Preparations; Phenotype; Reducing Agents; Rehydrations; Relative (related person); Role; Severity of illness; Sodium Chloride; Solid; Solvents; Surface; Swelling; Techniques; Testing; Therapeutic; Therapeutic Agents; Validation; Viscosity; Water; base; cigarette smoking; cohesion; cystic fibrosis patients; microorganism; mouse model; novel; novel strategies; novel therapeutics; patient population; physical model; physical process; physical property; response

Patients with cystic fibrosis (CF) and chronic bronchitis, i.e. COPD, exhibit a significantly reduced mucus clearance. The overarching goal of this project is to test the hypothesis that reduced rates of mucociliary and cough clearance in these patients are related to mucus dehydration and the resulting increased adhesion of mucus to cells as well as increased mucus cohesion strength. Both CF and COPD subjects exhibit an increase in ainvay mucus concentration, reflecting: 1) reduced ainway surface solvent (salt/water), e.g., as observed with CFTR dysfunction; 2) mucin hypersecretion, as observed with goblet cell hyperplasia; or 3) a combination of the two. Based on our recent theoretical and experimental data, we have developed a novel model, referred to as the "two-gel" model, that suggests that in addition to a mucus gel, ain/vays exhibit a "periciliary" layer (PCL), which is also a gel formed by tethered mucins (MUC1, MUC4, and MUC16). Efficient clearance requires hydration of the PCL that is sustained as long as its osmotic pressure is higher than that of the mucus gel layer. Importantly, the osmotic pressure of the mucus layer is largely determined by the concentration of the secreted mucins MUC5AC and MUC5B. To test our two-gel hypothesis, we have developed novel techniques to measure mucus osmotic pressure, adhesion/cohesion strength, viscosity, and elastic modulus and to determine the effect of these physical properties on mucus transport rate for both normal and CF cultures. We propose that reducing mucus concentration, cohesion strength, and mucus adhesion to epithelial cells will restore effective mucus clearance and thus benefit both CF and COPD patients. The novel approach to physical processes in airway surface layer will allow us to identify the optimal combination of rehydration and pharmacological agents to restore/accelerate the rate of mucus clearance. The identified agents that reduce the adhesion/cohesion strength and restore normal mucus clearance will be tested in mouse models of obstructive lung disease (Project II) and in COPD patients (Projects III).

囊性纤维化(CF)和慢性支气管炎(即COPD)患者的粘液清除率显著降低。该项目的主要目标是验证一种假设，即这些患者纤毛和咳嗽清除率的降低与粘液脱水以及由此导致的粘液与细胞的粘附性增加以及粘液凝聚力的增强有关。慢性阻塞性肺疾病和慢性阻塞性肺疾病患者均表现出粘液浓度增加，反映出：1)肺表面溶剂(盐/水)减少，如CFTR功能障碍；2)粘蛋白高分泌，如杯状细胞增生；或3)两者的结合。根据我们最近的理论和实验数据， 我们开发了一种新的模型，称为“双凝胶”模型，该模型表明，除了粘液凝胶外，AIN/VAY还表现出一层“纤毛层”(PCL)，这也是一种由拴系的粘蛋白(MUC1、MUC4和MUC16)形成的凝胶。有效的清除需要PCL的水合作用，只要它的渗透压高于粘液凝胶层的渗透压就能维持。重要的是，粘液层的渗透压在很大程度上取决于分泌的粘蛋白MUC5AC和MUC5B的浓度。 为了验证我们的双凝胶假设，我们开发了新的技术来测量粘液渗透压、粘附力/粘附力、粘度和弹性模数，并确定这些物理性质对正常和CF培养的粘液传输速率的影响。我们认为，降低粘液浓度、粘附力和粘液与上皮细胞的粘附性将恢复有效的粘液清除，从而使CF和COPD患者受益。对呼吸道表层物理过程的新方法将使我们能够确定再水化和药物的最佳组合，以恢复/加速粘液清除的速度。已确定的特工 将在阻塞性肺疾病的小鼠模型(项目II)和慢性阻塞性肺病患者(项目III)中进行测试，以降低粘附力/粘附力并恢复正常的粘液清除。