title: Baseline Goblet Cell Mucin Secretion in the Airways Exceeds Stimulated Secretion over Extended Time Periods, and Is Sensitive to Shear Stress and Intracellular Mucin Stores.
abstract: Airway mucin secretion studies have focused on goblet cell responses to exogenous agonists almost to the exclusion of baseline mucin secretion (BLMS). In human bronchial epithelial cell cultures (HBECCs), maximal agonist-stimulated secretion exceeds baseline by ~3-fold as measured over hour-long periods, but mucin stores are discharged completely and require 24 h for full restoration. Hence, over 24 h, total baseline exceeds agonist-induced secretion by several-fold. Studies with HBECCs and mouse tracheas showed that BLMS is highly sensitive to mechanical stresses. Harvesting three consecutive 1 h baseline luminal incubations with HBECCs yielded equal rates of BLMS; however, lengthening the middle period to 72 h decreased the respective rate significantly, suggesting a stimulation of BLMS by the gentle washes of HBECC luminal surfaces. BLMS declined exponentially after washing HBECCs (t1/2 = 2.75 h), to rates approaching zero. HBECCs exposed to low perfusion rates exhibited spike-like increases in BLMS when flow was jumped 5-fold: BLMS increased >4 fold, then decreased within 5 min to a stable plateau at 1.5-2-fold over control. Higher flow jumps induced proportionally higher BLMS increases. Inducing mucous hyperplasia in HBECCs increased mucin production, BLMS and agonist-induced secretion. Mouse tracheal BLMS was ~6-fold higher during perfusion, than when flow was stopped. Munc13-2 null mouse tracheas, with their defect of accumulated cellular mucins, exhibited similar BLMS as WT, contrary to predictions of lower values. Graded mucous metaplasia induced in WT and Munc13-2 null tracheas with IL-13, caused proportional increases in BLMS, suggesting that naïve Munc13-2 mouse BLMS is elevated by increased mucin stores. We conclude that BLMS is, [i] a major component of mucin secretion in the lung, [ii] sustained by the mechanical activity of a dynamic lung, [iii] proportional to levels of mucin stores, and [iv] regulated differentially from agonist-induced mucin secretion.
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7248, United States of America.
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7248, United States of America.
authors.forename: Lubna H
authors.initials: LH
authors.lastname: Abdullah
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7248, United States of America.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Doyle
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7248, United States of America.
authors.forename: Kristine
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7248, United States of America.
authors.forename: Carla M P
authors.initials: CM
authors.lastname: Ribeiro
authors.affiliation: Department of Mathematics, University of North Carolina, Chapel Hill, North Carolina, 27599-3250, United States of America.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Vasquez
authors.affiliation: Department of Mathematics, University of North Carolina, Chapel Hill, North Carolina, 27599-3250, United States of America.
authors.forename: M Gregory
authors.initials: MG
authors.lastname: Forest
authors.affiliation: Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, Moulsecoomb, BN2 4GJ, United Kingdom.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Lethem
authors.affiliation: Department of Pulmonary Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, United States of America.
authors.forename: Burton F
authors.initials: BF
authors.lastname: Dickey
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7248, United States of America; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, 27599-7545, United States of America.
authors.forename: C William
authors.initials: CW
authors.lastname: Davis
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009077:Mucins / Q000378:metabolism*; D013314:Stress, Mechanical; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: D009077:Mucins; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate