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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 28, 2006; DOI: 10.1124/jpet.106.102541

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Received for publication February 7, 2006.
Revised March 23, 2006.
Accepted for publication March 24, 2006.

Paradoxical Effects of Hydrogen Peroxide on Human Airway Anion Secretion

Takamasa Ohashi 1, Yasushi Ito 1*, Tadakatsu Matsuno 1, Shinji Sato 1, Kaoru Shimokata 1, Hiroaki Kume 1

1 Nagoya University Graduate School of Medicine

* Address correspondence to: E-mail: itoyasu{at}med.nagoya-u.ac.jp

Abstract

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 (ISC) with analogous properties, it has opposite effects on subsequent cAMP-activated ISC responses. Namely, forskolin (FK)-induced ISC 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 (GCl). The site-dependent effects of H2O2 were reproduced in the responses to 8bromo-cAMP. Estimation of the anionic composition of the ISC revealed that the FK up-regulated both bumetanide (an Na+-K+-2Cl- cotransporter [NKCC1] inhibitor)- and DNDS (a HCO3--dependent anion transporter [NBC1/AE2] inhibitor)-sensitive ISC in the control, whereas the up-regulation evidently favored bumetanide-sensitive ISC 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 NKCC-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.


Key words: CFTR, anion secretion, bumetanide, cyclic AMP, hydrogen peroxide, short-circuit current


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