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J. Biol. Chem., Vol. 281, Issue 35, 25803-25812, September 1, 2006

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Hypertonic Saline Therapy in Cystic Fibrosis

EVIDENCE AGAINST THE PROPOSED MECHANISM INVOLVING AQUAPORINS^*

Marc H. Levin^**1, Shannon Sullivan^¶, Dennis Nielson^¶, Baoxue Yang, Walter E. Finkbeiner^||, and A. S. Verkman^**2

From the Departments of Medicine, Physiology, ^¶Pediatrics, and ^||Pathology, and ^**Graduate Group in Biophysics, University of California, San Francisco, California 94143-0521

Recent data indicate the clinical benefit of nebulized hypertonic saline in cystic fibrosis lung disease, with a proposed mechanism involving sustained increase in airway surface liquid volume. To account for the paradoxical observation that amiloride suppresses the beneficial effect of hypertonic saline, it has been previously concluded (Donaldson, S. H., Bennett, W. D., Zeman, K. L., Knowles, M. R., Tarran, R., and Boucher, R. C. (2006) N. Engl. J. Med. 354, 241-250) that amiloride-inhibitable aquaporin (AQP) water channels in airway epithelia modulate airway surface liquid volume. Here, we have characterized water permeability and amiloride effects in well differentiated, primary cultures of human airway epithelial cells, stably transfected Fisher rat thyroid epithelial cells expressing individual airway/lung AQPs, and perfused mouse lung. We found high transepithelial water permeability (P_f, 54 ± 5 µm/s) in airway epithelial cells that was weakly temperature-dependent and inhibited by >90% by reduced pH in the basal membrane-facing solution. Reverse transcription-PCR and immunofluorescence suggested the involvement of AQPs 3, 4, and 5 in high airway water permeability. Experiments using several sensitive measurement methods indicated that amiloride does not inhibit water permeability in non-cystic fibrosis (non-CF) or CF airway epithelia, AQP-transfected Fisher rat thyroid cells, or intact lung. Our data provide evidence against the mechanism proposed by Donaldson et al. to account for the effects of amiloride and hypertonic saline in CF lung disease, indicating the need to identify alternate mechanisms.

Received for publication, May 5, 2006 , and in revised form, July 5, 2006.

^* This work was supported by National Institutes of Health Grants HL59198, HL73856, DK35124, EB00415, and EY13574, Cystic Fibrosis Research and Translational Core Center Grant DK72517, and a Research Development Program grant from the Cystic Fibrosis Foundation. 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 Supported by a National Institutes of Health Medical Scientist Training Grant.

² To whom correspondence should be addressed: Cardiovascular Research Institute, 1246 Health Sciences E. Tower, University of California, San Francisco, CA 94143-0521. Tel.: 415-476-8530; Fax: 415-665-3847; E-mail: verkman{at}itsa.ucsf.edu.

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