Hydrogel properties on airway surfaces in health and muco-obstructive lung disease

Airway mucus has important homeostatic functions that are essential for lung health. Mucus dysfunction has been implicated as a key factor in the pathogenesis of chronic lung disease in patients with the severe genetic disorder cystic fibrosis (CF, also known as mucoviscidosis), that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for an epithelial Cl- channel implicated in salt and water transport across airway surfaces, as well as a spectrum of other muco-obstructive lung diseases such as chronic obstructive pulmonary disease (COPD), which has emerged as a leading cause of death worldwide. The mucus layer covering healthy airway surfaces is a complex hydrogel formed mainly by the two secreted mucins constituting large and complex glycoproteins (MUC5B and MUC5AC), salt, and water. The main biological function of this hydrogel at the airway interface is to bind constantly inhaled pathogens and irritants and transport them out of the lung by mucociliary clearance. Proper functioning of airway mucus is critically determined by its rheological properties that are in turn controlled by its mesoscopic structure and dynamics. However, i) the rheological properties and mesoscopic structure of airway mucus in health; ii) the changes that determine formation of abnormal mucus and impaired mucociliary clearance during the onset and progression of mucoobstructive lung disease; and iii) if these abnormalities can be corrected therapeutically remains poorly understood.

In the first funding period, we established a standardized protocol for robust and reproducible measurements of viscoelastic properties of native mucus and mucus-mimicking hydrogels that avoids evaporation effects in small samples and allows to study frequency-dependent behavior. This protocol was used for detailed characterization of i) viscoelastic properties of novel mucus-mimicking hydrogels (with B03|Haag/Block); ii) the impact of varying concentrations of salt, osmolytes, DNA and proteins on the rheology and structure of bovine submaxillary mucin (BSM) as model system; and iii) the comparison of rheology of native mucus from the airways and intestine of patients with CF and inflammatory bowel disease (IBD) (with B04|Siegmund/Weinhart). Further, rheological studies were used to assess the in vivo effect of a novel CFTR modulator therapy (Elexacaftor/Tezcaftor/Ivacaftor; ETI) that targets the underlying molecular defect in CF on airway mucus properties in patients, and highly differentiated airway epithelial cultures were established for studies of mucus properties under near physiological conditions (with Z02|Duerr/Siegmund/Weinhart).