Airway liquid secretion and its inhibition: Possible relevance to cystic fibrosis lung disease.

摘要

Cystic fibrosis (CF) is an inherited disorder causing chronic airway obstruction and inflammation in the lungs which ultimately lead to respiratory failure and death. CF arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which functions as a cAMP-regulated anion channel and is highly expressed in the serous cells of the airway submucosal glands. In order to establish how defective CFTR gives rise to the pulmonary pathology seen in CF, a better understanding of the physiological role of CFTR in the airway is needed.; Using isolated airways and perfused lung from pigs, experimental models were developed to determine the possible role of anion and liquid secretion in the development of CF lung disease. In isolated airways, potential liquid secretion agonists were evaluated and inhibitors of both Cl− and HCO₃− secretion were used to target the apical and basolateral membrane transport proteins. More complex pathologies resulting from inhibition of airway anion secretion were assessed using similar strategies in isolated perfused lungs.; We found that cholinergic and neurokinin receptor agonists or direct stimulators of adenylyl cyclase induced airway liquid secretion that was localized to the submucosal glands. This process was driven by both Cl− and HCO₃− secretion by a process that most likely required the CFTR. Inhibiting both Cl− and HCO₃− secretion resulted in a mucus that was less hydrated, had altered rheological properties, and was adhered to the airway surface. Inhibition of Cl− and HCO₃ − secretion also results in depletion of the airway surface liquid and in flattening of airway surface cilia under dense mucus. These findings parallel and likely explain the basis for pathologies found in CF lung disease such as mucus plugging of gland ducts, dehydrated mucus, and mucus retention in the airways.