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1 Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, United States
* To whom correspondence should be addressed. E-mail: michael-shasby{at}uiowa.edu.
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 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 minutes. The decrease in resistance was accompanied by an increase in mannitol flux across the epithelium, and occurred in 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 more than 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.
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