In-depth investigation of small airway remodeling in COPD phenotypes and its relation with clinical and physiological markers.

Chronic obstructive pulmonary disease (COPD) is a common disease, characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities, usually caused by cigarette smoke. The small airways form the major site of resistance within the lung and small airway destruction has been demonstrated before the onset of emphysema. Since, there are no reliable markers on pulmonary function testing or imaging, small airways are difficult to analyze in vivo. We hypothesize that an in-depth investigation of the association between the in-vivo presentation and physiology (i.e. detailed clinical characterization, pulmonary function and radiology) and ex-vivo morphology of the small airways (microCT, histopathology) will result in clinical meaningful markers of small airway dysfunction in COPD phenotypes which is important for early diagnosis and better treatment. Using an innovative approach, we will combine in vivo assessments of small airway dysfunction with morphological assessment of excised lung specimens. Patients with isolated lung nodules in whom surgical treatment by lobectomy or pneumonectomy is indicated (smoking and non-smoking controls and mild COPD GOLD I and II) and patients undergoing lung transplantation (severe GOLD III and IV) will be recruited. In parallel, we will also collect donor lungs or lobes that could not be used for lung transplantation as controls. We aim to include at least 15 patients in each group, leading to a total of 75 patients. Patients will undergo detailed assessment of their clinical phenotype, pulmonary function (including small airways function), and inspiratory and expiratory CT-thorax (degree of functional small airway disease, emphysema, mucus plugging, airtrapping and bronchiectasis). Next, the excised specimen will undergo a standardized work-up including inflation and fixation in liquid nitrogen, and will then undergo ex vivo CT (resolution of 0.6 mm) and whole lung microCT (resolution 0.1 mm) to assess the entire airway tree from the main stem bronchus till the last generation of conducting airways. Based on these scans, the degree of mucus plugging, airway obliteration and airway loss will be measured in function of the airway generation and diameter. Subsequently, different cores will be extracted. The presence of pathological airway obstruction, quantification of small airway number and dimensions, and parenchymal measures will be assessed. Furthermore, the degree of collateral ventilation, an important compensatory mechanism of small airway loss, will be determined in function of the number of small airways and the local emphysema grade by using electron microscope scanning on the very same samples. The integration of the in vivo measurements and the ex vivo direct assessment of small airway remodeling will, for the first time, demonstrate the most optimal (combination of) tools to assess small airway disease in patients. We are convinced that this multi-modal approach will be useful to identify clinically meaningful parameters of small airway remodeling, which will improve monitoring of (early) disease progression and impact of treatment interventions. In the future, this unique cohort can be further exploited to obtain biological markers in biopsies that will be concomitantly collected and to further investigate the molecular mechanisms of small airway remodeling (i.e. inflammation, fibrosis) in more detail. With this grant, we want to initiate the banking and recruitment of patients, so that there is sufficient preliminary data to apply for internal and external competitive grant funding.

Keywords:CHRONIC OBSTRUCTIVE PULMONARY DISEASE, SMALL AIRWAY DISEASE, PULMONARY FUNCTION

Disciplines:Respiratory medicine