Advanced in vitro exposure systems.

Transforming Growth Factor β1 and Cigarette Smoke Inhibit the Ability of β2-Agonists to Enhance Epithelial Permeability

30. Jun. 2014

www.atsjournals.org published on June 30, 2014 (doi: 10.1165/rcmb.2013-0538OC)

Authors
Hoshang J. Unwalla1, Pedro Ivonnet1, John S. Dennis, Gregory E. Conner1,2, and Matthias Salathe1
1Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, and
2Department of Cell Biology, University of Miami, Miller School of Medicine, Miami, Florida

Exposition of whole smoke on human bronchial epithelial cells in the air-liquid interface with attention on growth factor TGF-β1.

Abstract
Chronic bronchitis, caused by cigarette smoke exposure, is characterized by mucus hypersecretion and reduced mucociliary clearance (MCC). Effective MCC depends, in part, on adequate airway surface liquid. Cystic fibrosis transmembrane conductance regulator (CFTR) provides the necessary osmotic gradient for serosal to mucosal fluid transport through its ability to both secrete Cl- and regulate paracellular permeability, but CFTR activity is attenuated in chronic bronchitis and in smokers. β2-adrenergic receptor (β2-AR) agonists are widely used for managing chronic obstructive pulmonary disease, and can activate CFTR, stimulate ciliary beat frequency, and increase epithelial permeability, thereby stimulating MCC. Patients with chronic airway diseases and cigarette smokers demonstrate increased transforming growth factor (TGF)-β1 signaling, which suppresses β2-agonist–mediated CFTR activation and epithelial permeability increases. Restoring CFTR function in these diseases can restore the ability of β2-agonists to enhance epithelial permeability. Human bronchial epithelial cells, fully redifferentiated at the air–liquid interface, were used for 14C mannitol flux measurements, Ussing chamber experiments, and quantitative RT-PCR. β2-agonists enhance epithelial permeability by activating CFTR via the β2-AR/adenylyl cyclase/cAMP/ protein kinase A pathway. TGF-β1 inhibits β2-agonist–mediated CFTR activation and epithelial permeability enhancement. Although TGF-β1 down-regulates both β2-AR and CFTR mRNA, functionally it only decreases CFTR activity. Cigarette smoke exposure inhibits β2-agonist-mediated epithelial permeability increases, an effect reversed by blocking TGF-β signaling. β2-agonists enhance epithelial permeability via CFTR activation. TGF-β1 signaling inhibits β2-agonist-mediated CFTR activation and subsequent increased epithelial permeability, potentially limiting the ability of β2-agonists to facilitate paracellular transport in disease states unless TGF-β1 signaling is inhibited.

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