Mucus Microstructure and Osmotic Pressure: Biomarkers for CB in COPD

 描述（由申请方提供）：粘液清除是气道卫生的关键机制，依赖于粘液凝胶的生物物理特性。在COPD中，粘液的定量和定性变化有助于气道阻塞、加重率、加速肺功能下降和死亡率。这种COPD亚表型，也称为慢性支气管炎（CB），影响高达70%的疾病患者。尽管粘液高分泌在COPD中的普遍性、复杂性和重要性，但我们对伴随COPD发展和进展的粘液质变化的理解相当有限。鉴于COPD的CB亚表型（称为COPD-CB）与不良结局密切相关，因此更好地了解这种疾病的特征病理学可能会导致更有效的靶向治疗和更实用的疾病分类。我们开创了使用高分辨率多粒子跟踪粘膜惰性纳米粒子，称为基于粒子跟踪的结构分析（PTSA），以探测粘液微观结构。使用这种方法，除了粘液含量的测量，我们已经发现，从COPD患者获得的自发咳痰的痰液的不同性质与疾病的严重程度相关。我们还发现，固体含量升高会增加COPD痰液样品中的渗透压，这反过来又会通过使气道上皮上的纤毛周层塌陷而损害粘液清除。SPIROMICS的既定目标之一是更精确地表征COPD亚表型。我们认为，对SPIROMICS队列中大量定义明确的COPD-CB患者研究人群中获得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性生物物理和生化指标。我们的假设是：1）粘液微观结构的改变，特别是粘液网的收紧，以及渗透压的增加与COPD-CB人群中肺功能恶化、肺功能加速下降、症状增加和生活质量下降相关; 2）频繁加重者将在急性和静止环境中表现出定型的粘液改变。我们计划从150例报告咳嗽和慢性痰产生的SPIROMICS患者中收集自发咳痰样本，这些患者在4个临床中心/子中心报告，并使用创新的PTSA方法评估渗透压和微观结构，以及痰成分的常规生化分析。

 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.