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Isoprostane-Mediated Secretion from Human Airway Epithelial Cells

Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada

Isoprostanes are liberated when reactive oxygen species (ROS) mediate the peroxidation of arachidonic acid or other polyunsaturated fatty acids. Because exposure to ROS is associated with tissue damage in the lung, we examined whether exposure to isoprostanes elicited a response in airway epithelial cells, potentially implicating isoprostane production in the epithelial response to oxidant stress. Application of the isoprostane 8-iso-prostaglandin E₂ (8-iso-PGE₂) produced an increase in transepithelial anion secretion across monolayers of the human airway epithelial cell line Calu-3, measured as an increase in short circuit current (I_sc). This increase in I_sc was greater when 8-iso-PGE₂ was applied to the basolateral rather than the apical face of the Calu-3 monolayers and was almost entirely abolished by the addition of diphenylamine-2-carboxylate, implicating the cystic fibrosis transmembrane conductance regulator Cl^- channel in the response. Experiments with electrically isolated apical and basolateral membrane preparations revealed that 8-iso-PGE₂ stimulated both apical Cl^- and basolateral K⁺ conductances. Using reverse transcription-polymerase chain reaction, we found that Calu-3 cells express the TP, but not the TP, isoform of the receptor, and that these cells secrete in response to the thromboxane A₂ (TP) receptor agonist 9,11-dideoxy-9,11-methanoepoxy-prostaglandin F₂ (U-46619). However, although part of the response seems to mediated via TP receptors, there are significant non—TP receptor-mediated effects on both the apical and basolateral membranes of Calu-3 cells. This is the first report of an isoprostane eliciting an effect in airway epithelial cells and suggests a potential role for this class of molecules in pulmonary host defense.

Address correspondence to: Elizabeth Cowley, Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada. E-mail: elizabeth.cowley{at}dal.ca

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