Effect of Bacteria on Airway Submucosal Glands Liquid Secretion in Swine

Abstract

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Currently, more than 4,100 Canadians have CF. The major cause of CF morbidity and mortality is airway disease, for which there is no cure. The events leading from CFTR gene mutation to CF airway disease are not fully understood, and there is controversy regarding the primary defect responsible for CF airway disease pathogenesis. Newborn CFTRΔF508/ΔF508 and CFTR-/- swine show no sign of infection and inflammation in the lung but suffer from defective bacteria eradication caused by abnormal innate immune system. The cornerstone of the airway’s innate immune defense is mucociliary clearance, which relies on the normal regulation of airway surface liquid (ASL), which covers the airway epithelium. It has been hypothesized that abnormal ASL is the primary defect that leads to the failure of the airway innate immune defense in CF. Evidence show that the airway submucosal gland functions abnormally in both CF patients and in animal models of CF. This is not surprising since airway submucosal glands normally express CFTR. However, the function of the gland in health and disease is not fully understood. The response of airway submucosal gland to inhaled bacteria has never been tested and its ion transport properties have not been fully described. Our objective is to investigate the effect of inhaled bacteria on airway submucosal gland secretion, and to study and compare the function of different segments of airway submucosal gland in wild-type and CF airway. Knowledge generated by this thesis would help better understand CF airway pathophysiology and may contribute to improving treatment methods.