Mucus and hypoxia in heterogeneous and progressive CF lung disease

描述（由申请人提供）：囊性纤维化（CF）的肺部表现反映了肺防御功能的失败，导致慢性气道细菌感染。为了获得最佳治疗方法和生物标志物开发，必须了解早期CF肺病发病机制的几个关键方面，包括观察到出生时存在最小CF肺病以及疾病发作/进展具有高度异质性。基于以下假设：1）CF肺表现出对产生“外部”损伤的疾病的脆弱性; 2） “脆弱性缺陷”反映了由于气道表面脱水而导致的粘液清除机制的局部丧失，以及3）固定的、相对脱水的粘液团阻塞气道，刺激炎症，并作为慢性细菌感染的病灶，我们假设最早期的CF肺病的特征在于气道粘蛋白水合/功能、粘蛋白刺激的巨噬细胞活化和气道缺氧的可量化的变化。该提案将在通过新生儿筛查确定的独特CF队列中检验这一假设，并定期进行CT扫描和支气管镜检查。利用在澳大利亚成功的AREST-CF计划中获得的样品，我们将在美国开发一个新的测量面板三元组。北卡罗来纳州包括：1）粘液水化/功能的生物化学和生物物理测量; 2）炎症的新标志物，重点是巨噬细胞和3）细菌谱及其代谢环境的微生物组和代谢组学分析。我们将确定这些面板是否可以量化CF肺部疾病的负担，如胸部CT横断面和纵向所定义的。与此同时，我们将开发基于呼出气冷凝物的微创方法来评估这些生物标志物。这些假设的成功测试将产生对CF肺病发病机制的新见解和跟踪疾病进展/治疗干预的新生物标志物。 (End摘要）

DESCRIPTION (provided by applicant): The pulmonary manifestations of cystic fibrosis (CF) reflect a failure of lung defense leading to chronic airways bacterial infection. Several key aspects of the pathogenesis of early CF lung disease must be understood for best treatment approaches and biomarker development, including the observations that there is minimal CF lung disease at birth and that disease onset/progression is highly heterogeneous. Based on assumptions that 1) the CF lung exhibits a vulnerability to disease producing "outside" insults; 2) the "vulnerability defect" reflects localized loss of mucus clearance mechanisms due to airway surface dehydration, and 3) immobilized, relatively dehydrated mucus masses obstruct airways, stimulate inflammation, and serve as nidus for chronic bacterial infection, we hypothesize that the earliest CF lung disease will be characterized by quantifiable changes in airway mucin hydration/function, mucin stimulated macrophage activation, and airway hypoxia. This proposal will test the hypothesis in a unique CF cohort identified by newborn screening and studied at regular intervals with CT scans and bronchoscopy. Using samples obtained in the successful Australian AREST-CF program, we will develop a triad of novel measurement panels at U. North Carolina including: 1) biochemical and biophysical measurements of mucus hydration/function; 2) novel markers of inflammation, focusing on macrophages and 3) microbiome and metabolomic analysis of the spectrum of bacteria and their metabolic environment. We will determine whether these panels can quantify the burden of CF lung disease as defined by chest CT cross- sectionally and longitudinally. In parallel, we will develop minimally invasive, exhaled breath condensate based methods to assess these biomarkers. Successful testing of these hypotheses will generate both novel insights into the pathogenesis of CF lung disease and novel biomarkers to follow disease progression/therapeutic interventions. (End of Abstract)