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TOXICOLOGY

Paradoxical Effects of Hydrogen Peroxide on Human Airway Anion Secretion

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

The present study concerns intriguing effects of hydrogen peroxide (H₂O₂) on cAMP-mediated anion secretion in polarized human airway epithelia. Although H₂O₂ applied to the apical and basolateral membrane increases short-circuit currents (I_SC) with analogous properties, it has opposite effects on subsequent cAMP-activated I_SC responses. Namely, forskolin (FK)-induced I_SC responses were down-regulated by the apical presence of H₂O₂, whereas they were up-regulated by its basolateral presence. Despite this contrasting effect, oxidative stimuli from either aspect of the monolayer hindered FK-induced increments in cytosolic cAMP levels and apical membrane Cl^- conductance. The site-dependent effects of H₂O₂ were reproduced in the responses to 8-bromo-cAMP. Estimation of the anionic composition of the I_SC revealed that the FK up-regulated both bumetanide [an Na⁺-K⁺-2Cl^- cotransporter (NKCC1) inhibitor]-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid [an -dependent anion transporter (NBC1/AE2) inhibitor]-sensitive I_SC in the control, whereas the up-regulation evidently favored bumetanide-sensitive I_SC in the basolateral presence of H₂O₂. The FK-induced NKCC1 augmentation after exposure to basolateral H₂O₂ was counteracted by cytochalasin D, an inhibitor of microfilament function, but not by charybdotoxin, a blocker of the intermediate conductance Ca²⁺-activated K⁺ channel, whose activation could be related to NKCC1-mediated Cl^- secretion. These observations suggest that basolaterally but not apically applied H₂O₂ potentiates subsequent cAMP-mediated Cl^- secretion by an increase in Cl^- uptake via basolateral NKCC1, whose sensitivities to cAMP/protein kinase A are up-regulated, overcoming the H₂O₂-induced inhibition of cAMP-mediated apical anion conductance. The basolateral membrane-specific effects of H₂O₂ may be relevant to the basolateral cytoskeleton, which is believed to interact with NKCC1.

Address correspondence to: Yasushi Ito, Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showaku, Nagoya, 466-8550, Japan. E-mail: itoyasu{at}med.nagoya-u.ac.jp

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