4‐Methylumbelliferone Prevents E‐cadherin Downregulation Induced by Cigarette Smoke in Airway Epithelial Cells

Abstract

Cigarette smoke (CS) exposure induces airway epithelial barrier (EB) disruption that results in structural changes associated to COPD. EB integrity is maintained, in part, by E‐cadherin (E‐cad). We have shown that hyaluronan fragments (SHA) increased epithelial permeability and downregulated E‐cad expression. In the airways, hyaluronan (HA) is present in a high molecular weight form at the epithelial surface and exposure to oxidants induces its degradation. Thus, we hypothesized that SHA are generated in smokers and that inhibition of HA synthesis would prevent EB disruption induced by CS. To test this hypothesis, HA size was determined by agarose electrophoresis in bronchoalveolar samples from smokers and non‐smokers and in apical washes of human bronchial epithelial (HBE) cells exposed to CS or to air. In addition, to confirm the role of HA in EB disruption, HBE cells were pretreated with the HA synthesis inhibitor 4‐ methylumbelliferone (4MU, 1mM) and exposed to CS or to air and E‐cad expression was assessed by qPCR and WB. We found that secretions from smokers and apical washes from CS exposed cells contain SHA (< 100 kDa) and exposure to CS significantly reduced E‐cad mRNA and protein. Treatment with 4MU prevented these effects, confirming that HA fragmentation take place in vivo in the airways of smokers and SHA generation is able to induce EB disruption by regulating, at least in part, E‐cad expression.