title: PAR2 activation interrupts E-cadherin adhesion and compromises the airway epithelial barrier: protective effect of beta-agonists.
abstract: The airway epithelium is an important barrier between the environment and subepithelial tissues. The epithelium is also divided into functionally restricted apical and basolateral domains, and this restriction is dependent on the elements of the barrier. The protease-activated receptor-2 (PAR2) receptor is expressed in airway epithelium, and its activation initiates multiple effects including enhanced airway inflammation and reactivity. We hypothesized that activation of PAR2 would interrupt E-cadherin adhesion and compromise the airway epithelial barrier. The PAR2-activating peptide (PAR2-AP, SLIGRL) caused an immediate approximately 50% decrease in the transepithelial resistance of primary human airway epithelium that persisted for 6-10 min. The decrease in resistance was accompanied by an increase in mannitol flux across the epithelium and occurred in cystic fibrosis transmembrane conductance receptor (CFTR) epithelium pretreated with amiloride to block Na and Cl conductances, confirming that the decrease in resistance represented an increase in paracellular conductance. In parallel experiments, activation of PAR2 interrupted the adhesion of E-cadherin-expressing L cells and of primary airway epithelial cells to an immobilized E-cadherin extracellular domain, confirming the hypothesis that activation of PAR2 interrupts E-cadherin adhesion. Selective interruption of E-cadherin adhesion with antibody to E-cadherin decreased the transepithelial resistance of primary airway epithelium by >80%. Pretreatment of airway epithelium or the E-cadherin-expressing L cells with the long-acting beta-agonist salmeterol prevented PAR2 activation from interrupting E-cadherin adhesion and compromising the airway epithelial barrier. Activation of PAR2 interrupts E-cadherin adhesion and compromises the airway epithelial barrier.
authors.affiliation: Department of Internal Medicine, University of Iowa College of Medicine, 140E EMRB, Iowa City, IA 52242, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Winter
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Shasby
authors.forename: Dana R
authors.initials: DR
authors.lastname: Ries
authors.forename: D Michael
authors.initials: DM
authors.lastname: Shasby
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D010539:Permeability / Q000187:drug effects; D044464:Receptor, PAR-2 / Q000378:metabolism / Q000502:physiology*; D011969:Receptors, Histamine H1 / Q000378:metabolism / Q000502:physiology; D000068299:Salmeterol Xinafoate; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D015820:Cadherins; D044464:Receptor, PAR-2; D011969:Receptors, Histamine H1; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000068299:Salmeterol Xinafoate; D000242:Cyclic AMP; D000420:Albuterol