In depth characterisation of the site and nature of airway obstruction and associated vascular remodeling in congenital airway disease

Cystic Fibrosis (CF) and Primary Ciliary Dyskinesia (PCD) are congenital airway disorders that are characterized by an abnormal mucociliary clearance.  This leads to persistent infection, inflammation and eventually airway obstruction with bronchiectasis. Cystic fibrosis (CF) is a life-shortening disease with more than 90% of individuals dying from respiratory insufficiency. Detailed information on the lung remodeling is lacking. Although PCD seems to be different from CF in several aspects, its treatment is mainly based on the treatment for CF. Albeit the mechanism of disease is similar, there is great difference in the evolution of the diseases and their functional and structural assessments. As cilia are more abundant in proximal airways and CFTR is expressed until the level of the preterminal bronchioles, we hypothesize that the site of most pronounced airway obstruction is located more proximally in PCD. We therefore aim now to perform a comprehensive multimodal strategy to characterize and investigate the nature of airway obstruction in CF and PCD airways in more detail. This is crucially important as the airway obstruction is the key factor limiting pulmonary function. End-stage CF and PCD lungs collected at transplantation will be used and compared to unused donor lungs (n=10 per group). Using a combination of state-of the-art technologies, we will study the bronchovascular axis in more detail. Specifically, whole lung microCT will be used to perform an in depth characterization of the degree of airway obstruction starting from the large down to the small airways. Furthemore we will use a combination of microCT and serial immunofluorescence to characterize the inflammatory and epithelial changes proximal from and at the site of the airway obstruction and relate this directly to the presence of Pseudomonas, the main bacteria colonizing CF lungs. Secondary changes to the lung parenchyma will also be investigated using scanning electron microscopy. The changes in the macro- and micro-vasculature in proximity of the airway obstruction will be investigated in more detail using immune staining and microvascular corrosion casting. Lastly, longitudinal correlations between spirometry, multiple breath washout (MBW) and chest CT parameters will be studied in a pediatric cohort and specific MBW derived ventilation inhomogeneity parameters (Sacin and scond) will be compared. We anticipate that this research will provide a comprehensive overview of the pathophysiological mechanisms leading to airway obstruction in CF and PCD.