Mucus and hypoxia in heterogeneous and progressive CF lung disease

描述(申请人提供)：囊性纤维化(CF)的肺部表现反映了肺防御的失败，导致慢性呼吸道细菌感染。为了获得最佳的治疗方法和生物标记物的开发，必须了解早期CF肺部疾病发病机制的几个关键方面，包括观察到出生时有轻微的CF肺部疾病，以及疾病的发生/发展具有高度的异质性。基于这样的假设：1)慢性阻塞性肺疾病表现出对疾病的脆弱性，从而产生“外界”侮辱；2) 易损性缺陷反映了由于呼吸道表面脱水引起的局部粘液清除机制的丧失，以及3)固定的相对脱水的粘液团阻塞呼吸道，刺激炎症，并作为慢性细菌感染的核心，我们假设最早的慢性肺病的特征是呼吸道粘蛋白水合/功能的可量化变化，粘蛋白刺激的巨噬细胞激活，以及呼吸道低氧。这项建议将在新生儿筛查确定的独特的CF队列中检验这一假设，并定期通过CT扫描和支气管镜检查进行研究。使用成功的澳大利亚EST-CF计划中获得的样本，我们将在美国北卡罗来纳州开发三个新的测量小组，包括：1)粘液水合/功能的生化和生物物理测量；2)新的炎症标志物，侧重于巨噬细胞；3)细菌及其代谢环境光谱的微生物组和代谢组学分析。我们将确定这些面板是否能从横断面和纵向上量化胸部CT所定义的CF肺部疾病的负担。同时，我们将开发基于呼气冷凝液的微创方法来评估这些生物标志物。这些假说的成功测试将产生对CF肺部疾病发病机制的新见解，以及跟踪疾病进展/治疗干预的新生物标记物。(摘要结束)

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)