Transforming growth factor-β1 and cigarette smoke inhibit the ability of β2-agonists to enhance epithelial permeability

Hoshang J. Unwalla, Pedro Ivonnet, John S. Dennis, Gregory E Conner, Matthias A Salathe

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 Cl2 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 epithelialpermeability, thereby stimulatingMCC.Patientswith chronic airway diseases and cigarette smokers demonstrate increased transforming growth factor (TGF)-b1 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 14Cmannitol flux measurements, Ussing chamber experiments, and quantitative RT-PCR. β2-agonists enhance epithelial permeability by activatingCFTRvia the β2-AR/adenylyl cyclase/cAMP/ protein kinase A pathway. TGF-b1 inhibits β2-agonist-mediated CFTR activation and epithelial permeability enhancement. Although TGF-b1 down-regulates both β2-AR and CFTR mRNA, functionally it only decreases CFTR activity. Cigarette smoke exposure inhibits β2-agonist-mediated epithelialpermeability increases, an effect reversed by blocking TGF-b 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.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume52
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Transforming Growth Factors
Smoke
Tobacco Products
Permeability
Chemical activation
Mucociliary Clearance
Chronic Bronchitis
Adrenergic Receptors
Pulmonary diseases
Adrenergic Agonists
Liquids
Mucus
Cyclic AMP-Dependent Protein Kinases
Adenylyl Cyclases
Chronic Obstructive Pulmonary Disease
Chronic Disease
Down-Regulation
Epithelial Cells
Air

Keywords

  • Cigarette smoke
  • Cystic fibrosis transmembrane conductance regulator
  • Epithelial permeability
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Transforming growth factor-β1 and cigarette smoke inhibit the ability of β2-agonists to enhance epithelial permeability. / Unwalla, Hoshang J.; Ivonnet, Pedro; Dennis, John S.; Conner, Gregory E; Salathe, Matthias A.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 52, No. 1, 01.01.2015, p. 65-74.

Research output: Contribution to journalArticle

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