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J. Biol. Chem., Vol. 283, Issue 33, 22875-22883, August 15, 2008

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Redox Regulation of Epithelial Sodium Channels Examined in Alveolar Type 1 and 2 Cells Patch-clamped in Lung Slice Tissue^*

My N. Helms, Lucky Jain^¶, Julie L. Self, and Douglas C. Eaton^¶1

From the Departments of Physiology and ^¶Pediatrics and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322

The alveolar surface of the lung is lined by alveolar type 1 (AT1) and type 2 (AT2) cells. Using single channel patch clamp analysis in lung slice preparations, we are able to uniquely study AT1 and AT2 cells separately from intact lung. We report for the first time the Na⁺ transport properties of type 2 cells accessed in live lung tissue (as we have done in type 1 cells). Type 2 cells in lung tissue slices express both highly selective cation and nonselective cation channels with average conductances of 8.8 ± 3.2 and 22.5 ± 6.3 picosiemens, respectively. Anion channels with 10-picosiemen conductance are also present in the apical membrane of type 2 cells. Our lung slice studies importantly verify the use of cultured cell model systems commonly used in lung epithelial sodium channel (ENaC) studies. Furthermore, we identify novel functional differences between the cells that make up the alveolar epithelium. One important difference is that exposure to the nitric oxide (NO) donor, PAPA-NONOate (1.5 µM), significantly decreases average ENaC NPo in type 2 cells (from 1.38 ± 0.26 to 0.82 ± 0.16; p < 0.05 and n = 18) but failed to alter ENaC activity in alveolar type 1 cells. Elevating endogenous superoxide () levels with Ethiolat, a superoxide dismutase inhibitor, prevented NO inhibition of ENaC activity in type 2 cells, supporting the novel hypothesis that and NO signaling plays an important role in maintaining lung fluid balance.

Received for publication, February 20, 2008 , and in revised form, June 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants 4R37 DK-37963 (to D. C. E.) and 2R01 HL063306-05A2 (to L. J.). This work was also supported by a Parker B. Francis Fellowship (to M. N. H.) and by Digestive Diseases Research Development Centers Grant DK064399. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Emory University, Dept. of Physiology, Center for Cell and Molecular Signaling, 615 Michael St., Atlanta, Georgia 30322. Tel.: 404-727-4533; Fax: 404-727-0329; E-mail: deaton{at}emory.edu.

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