Inhibition of uPA-uPAR signaling restores respiratory epithelial barrier function in asthma and COPD
2019
In addition to uPA’s well-characterized role in fibrinolysis, recent publications have indicated a role for uPA-uPAR signaling in respiratory epithelia barrier function. Furthermore, uPA and uPAR expression/signaling are enhanced in severe asthmatic and COPD airway epithelium. We therefore hypothesised that uPA-uPAR signaling promotes epithelial barrier dysfunction and airway remodeling in severe asthma and COPD. We showed that exogenous addition of uPA to primary airway basal cells during differentiation resulted in reduced epithelial thickness and remodeling. Exposure of fully differentiated airway cultures to various damage stimuli (TNFα, IL-1β, LPS, PolyIC) induced endogenous uPA secretion. Supernatant uPA concentrations directly correlated with epithelial barrier breakdown (P = 0.01), as measured by TEER and dextran permeability. Treatment of fully differentiated airway epithelial cultures from healthy, severe asthmatic and COPD donors, with an uPA-uPAR inhibitor (IPR-1110; Liu et al. ACSChem.Biol.2015,10,1521-1534) attenuated TNFα-induced increases in epithelial permeability. Moreover, addition of IPR-1110 72hours post TNFα-induced epithelial damage restored epithelial permeability by ~55% (relative to TNFα only control). Preliminary data indicates that IPR-1110 reduced the phosphorylation of kinases previously shown to be linked to uPA-uPAR signaling, including Erk, Akt and p38. Screening of epithelial tight/adherens junction proteins, revealed that IPR-1110 induced changes in epithelial barrier function correlated with enhanced expression of JAM-A. Thus, targeting uPA-uPAR signaling has therapeutic potential to restore epithelial barrier function in severe asthma and COPD.
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