Acinar origin of CFTR-dependent airway submucosal gland fluid secretion

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 292; no. 1; pp. L304 - L311
• Main Authors: Wu, Jin V, Krouse, Mauri E, Wine, Jeffrey J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2007
• Subjects: Animals; Body fluids; Bronchi - anatomy & histology; Bronchi - secretion; Cystic fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - physiology; Exocrine Glands - anatomy & histology; Exocrine Glands - secretion; Humans; In Vitro Techniques; Ligation; Models, Anatomic; Proteins; Respiratory diseases; Swine; Trachea - anatomy & histology; Trachea - secretion
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00286.2006

Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California Submitted 28 July 2006 ; accepted in final form 19 September 2006 Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial Na + channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus. innate defense; mucus Address for reprint requests and other correspondence: J. J. Wine, Cystic Fibrosis Research Laboratory, Rm. 450, Bldg. 420, Main Quad, Stanford Univ., Stanford, CA 94305-2130 (e-mail: wine{at}stanford.edu )