Mucus Microstructure and Osmotic Pressure: Biomarkers for CB in COPD

粘液微观结构和渗透压：COPD 中 CB 的生物标志物

• 批准号: 8852864
• 负责人: Justin S. Hanes
• 金额: $ 44.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852864
• 关键词: Acute; Affect; Biochemical; Biological Markers; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Coughing; DNA; Data; Development; Disease; Disease Progression; Epithelial Cells; Exercise; Focal Infection; Frequencies; Future; Gastroesophageal reflux disease; Gel; Grant; Hygiene; Inflammatory; Injury; Ions; Lead; Link; Measurement; Measures; Methodology; Mortality Decline; Mucins; Mucous body substance; Observational Study; Osmotic Pressure; Outcome; Parents; Pathology; Patients; Persons; Phase; Population; Population Study; Prevalence; Production; Property; Quality of life; Recruitment Activity; Reporting; Resolution; Respiratory physiology; Sampling; Severities; Severity of illness; Smoker; Solid; Specific qualifier value; Specimen; Sputum; Staging; Stereotyping; Symptoms; Testing; Therapeutic Trials; Visit; abstracting; adverse outcome; airway epithelium; airway obstruction; base; biophysical properties; cigarette smoking; clinical research site; cohort; design; disease classification; follow-up; innovation; mucus hypersecretion; nanoparticle; novel; particle; patient population; public health relevance; targeted treatment

 DESCRIPTION (provided by applicant): Mucus clearance, a critical mechanism for airway hygiene, relies on the biophysical properties of the mucus gel. In COPD, quantitative and qualitative changes in mucus contribute to airway obstruction, exacerbation rate, accelerated lung function decline and mortality. This COPD subphenotype, also known as chronic bronchitis (CB), affects up to 70% of patients with the disorder. Despite the prevalence, complexity and importance of mucus hypersecretion in COPD, our understanding of the qualitative changes in mucus that accompany COPD development and progression is quite limited. Given that the CB subphenotype of COPD, referred to as COPD-CB, is intimately linked to adverse outcomes, a better understanding of the signature pathology in this disorder may lead to more effective targeted therapies and more practical disease classifications. We have pioneered the use of high resolution multiple particle tracking of muco-inert nanoparticles, termed particle tracking-based structural analysis (PTSA), to probe mucus microstructure. Using this approach in addition to mucus content measurements, we have found that distinct properties of spontaneously expectorated sputum obtained from COPD patients associate with disease severity. We also have found that elevated solid content increases osmotic pressure in COPD sputum samples, which in turn impairs mucus clearance by collapsing periciliary layer above the airway epithelium. One of the stated objectives of SPIROMICS is a more refined characterization of COPD subphenotypes. We submit that a detailed assessment of the properties of spontaneous sputum samples obtained from a large, well-defined, study population of COPD-CB patients in the SPIROMICS cohort will avail informative biophysical and biochemical measures, which associate with disease severity and progression. Our hypotheses are 1) altered mucus microstructure, specifically, a tightening of the mucus mesh, and increased osmotic pressure associates with worsened lung function, accelerated lung function decline, increased symptoms, and worse quality of life in the COPD-CB population 2) frequent exacerbators will display stereotyped mucus alterations in both acute and quiescent settings. We plan to collect spontaneous expectorated sputum samples from 150 SPIROMICS patients who report cough and chronic sputum production at four clinical sites/subsites and assess osmotic pressure and microstructure using the innovative PTSA methodology, in addition to conventional biochemical analyses of sputum constituents.

 描述(由申请人提供)：粘液清除是呼吸道卫生的关键机制，依赖于粘液凝胶的生物物理性质。在慢性阻塞性肺疾病中，粘液的数量和质量的变化导致呼吸道阻塞、加重、加速肺功能下降和死亡率。这种COPD亚型，也称为慢性支气管炎(CB)，影响多达70%的疾病患者。尽管粘液高分泌在COPD中的患病率、复杂性和重要性，但我们对伴随COPD发生发展的粘液的质变的了解相当有限。鉴于慢性阻塞性肺疾病的CB亚型，称为COPD-CB，与不良后果密切相关，更好地了解这种疾病的标志性病理可能会导致更有效的靶向治疗和更实用的疾病分类。我们率先使用粘液惰性纳米颗粒的高分辨率多颗粒跟踪，称为基于颗粒跟踪的结构分析(PTSA)，以探测粘液微结构。除了粘液含量测量外，使用这种方法，我们还发现COPD患者自发咳出的痰的不同性质与疾病严重程度有关。我们还发现，固体含量的增加增加了COPD痰样本的渗透压，这反过来又通过塌陷呼吸道上皮上的纤毛层而损害粘液清除。SPIROMICS声明的目标之一是对COPD亚型进行更精细的表征。我们认为，对SPIROMICS队列中大量明确的COPD-CB患者研究人群的自发痰样本的性质进行详细评估将有助于提供与疾病严重程度和进展相关的信息的生物物理和生化指标。我们的假设是：1)在COPD-CB人群中，粘液微结构改变，具体地说，粘液网收紧，渗透压增加与肺功能恶化、肺功能加速下降、症状增加和生活质量下降相关。2)在急性期和静止期，频繁的加重者都会表现出刻板的粘液改变。我们计划收集150名SPIROMICS患者的自发咳痰样本，这些患者报告在四个临床地点/亚地点咳嗽和慢性痰产生，并使用创新的PTSA方法，以及对痰成分的传统生化分析，评估渗透压和微观结构。