Submucosal gland dysfunction as a primary defect in cystic fibrosis.
It has been proposed that defective submucosal gland function in CF airways is a major determinant of CF airway disease. We tested the hypothesis that submucosal gland function is defective early in CF subjects with minimal clinical disease. Functional assays of gland fluid secretion rate and viscosity were performed on freshly obtained nasal biopsies from 6 CF subjects and 5 non-CF controls (age range 2-22 years). Secretions from individual submucosal glands were visualized by light/fluorescence microscopy after orienting and immobilizing biopsy specimens in a custom chamber. The viscosity of freshly secreted gland fluid after pilocarpine, measured by fluorescence recovery after photobleaching of microinjected FITC-dextran, was 4.9 +/- 0.2- vs. 2.2 +/- 0.2-fold greater than water viscosity in CF vs. non-CF specimens, respectively (SE, P<10(-4)). Gland fluid secretion rate in CF specimens, measured by video imaging (4.5+/-0.5 nL/min/gland, n=6), was 2.7-fold reduced compared to non-CF specimens (n=3, P<0.05). Quantitative histology revealed similar size and morphology of submucosal glands in CF and non-CF specimens. Our results suggest that defective airway submucosal gland function is an early, primary defect in CF. Therapies directed at normalizing gland fluid secretion early in CF may thus reduce lung disease.
Salinas
Danieli
D
Department of Medicine, University of California, San Francisco, California 94143-0521, USA.
Haggie
Peter M
PM
Thiagarajah
Jay R
JR
Song
Yuanlin
Y
Rosbe
Kristina
K
Finkbeiner
Walter E
WE
Nielson
Dennis W
DW
Verkman
A S
AS
D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000473:pathology / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology; D003911:Dextrans; D005088:Exocrine Glands / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D005456:Fluorescent Dyes; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D009666:Nose; D038761:Photobleaching; D010862:Pilocarpine / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014783:Viscosity
C505032:CFTR protein, human; D003911:Dextrans; D005456:Fluorescent Dyes; C015219:fluorescein isothiocyanate dextran; D010862:Pilocarpine; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016650:Fluorescein-5-isothiocyanate