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. β(2)-adrenergic receptor (β(2)-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 β(2)-agonist–mediated CFTR activation and epithelial permeability increases. Restoring CFTR function in these diseases can restore the ability of β(2)-agonists to enhance epithelial permeability. Human bronchial epithelial cells, fully redifferentiated at the air–liquid interface, were used for (14)C mannitol flux measurements, Ussing chamber experiments, and quantitative RT-PCR. β(2)-agonists enhance epithelial permeability by activating CFTR via the β(2)-AR/adenylyl cyclase/cAMP/protein kinase A pathway. TGF-β1 inhibits β(2)-agonist–mediated CFTR activation and epithelial permeability enhancement. Although TGF-β1 down-regulates both β(2)-AR and CFTR mRNA, functionally it only decreases CFTR activity. Cigarette smoke exposure inhibits β(2)-agonist–mediated epithelial permeability increases, an effect reversed by blocking TGF-β signaling. β(2)-agonists enhance epithelial permeability via CFTR activation. TGF-β1 signaling inhibits β(2)-agonist–mediated CFTR activation and subsequent increased epithelial permeability, potentially limiting the ability of β(2)-agonists to facilitate paracellular transport in disease states unless TGF-β1 signaling is inhibited
