Absent Secretion to Vasoactive Intestinal Peptide in Cystic Fibrosis Airway Glands

Abstract

We are testing the hypothesis that the malfunctioning of airway gland serous cells is a component of cystic fibrosis (CF) airway disease. CF is caused by mutations that disrupt CF transmembrane conductance regulator, an anion channel essential for proper fluid secretion in some epithelia. Submucosal glands supply most of the mucus in upper airways, and gland serous cells are the primary site of CF transmembrane conductance regulator expression in airways. We have discovered a major defect in CF glands by in situ optical monitoring of secretions from single human airway glands. CF glands did not secrete to agents that elevated [cAMP] i (0 responses/450 glands, 8 subjects), whereas glands were responsive in all donor tracheas (605/827 glands, 15 subjects) and in bronchi from subjects who were transplanted because of other lung diseases (148/166 glands, n ‫؍‬ 10). CF glands secreted to cholinergic stimulation, and serous cells were abundant in glands from all CF subjects. The complete absence of secretion to agents that elevate [cAMP] i suggests that altered secretion of gland mucus could contribute to CF lung disease.

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

“…Thus, these observations conflict with previous reports suggesting CFTR is the predominant mediator of gland acinar secretion, based on high CFTR immunolocalization signals in acinar serous cells (Engelhardt et al, 1992), studies of agonist regulation of porcine and human gland secretion rates (Joo et al, 2002;Ballard and Inglis, 2004), and studies of CalU-3 cells, which have been used as a model system of acinar serous cells (Shen et al, 1994).…”

“…Our observations also appear to conflict with ex vivo studies of CF gland preparations that have shown decreased agonist-stimulated glandular secretion rates and a more viscous (increased mucin concentration) secretion, implying that CFTR is involved in regulating glandular fluid volume (Jayaraman et al, 2001;Joo et al, 2002). However, in every functional ex vivo study of normal and CF tissues, all the glandular components (e.g., acini and ducts) and adjacent gland tissue/cells (e.g., muscle cells) were exposed to the pharmacological stimulus, and glandular secretions were analyzed at the duct entrance onto the airway surface (Joo et al, 2002;Verkman et al, 2003;Ballard and Inglis, 2004).…”

“…However, in every functional ex vivo study of normal and CF tissues, all the glandular components (e.g., acini and ducts) and adjacent gland tissue/cells (e.g., muscle cells) were exposed to the pharmacological stimulus, and glandular secretions were analyzed at the duct entrance onto the airway surface (Joo et al, 2002;Verkman et al, 2003;Ballard and Inglis, 2004). Therefore, only the final secretion product was analyzed.…”

Pseudomonas aeruginosa triggers CFTR-mediated airway surface liquid secretion in swine trachea

“…The mucus layer is a complex mixture of water, salts, gel-forming mucins, and antimicrobial compounds that helps inactivate, kill, and trap pathogens and facilitates mucociliary clearance (10,11). In CF airways, both the bacteria-killing properties and ASL secretion are abnormal (3,9). The airway liquid produced by CFTR −/− swine has weaker bactericidal properties compared with that produced by WT littermates, owing to abnormal pH (3,4).…”

“…The failure to clear bacteria likely results from abnormal airway surface liquid (ASL) secretion and properties (6)(7)(8)(9)(10). The ASL consists of a layer of mucus that traps inhaled particles and a periciliary liquid layer that keeps the mucus an optimum distance from the underlying epithelia to maximize ciliary mobility (10,11).…”