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J. Biol. Chem., Vol. 280, Issue 42, 35751-35759, October 21, 2005

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Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis

THE EFFECTS OF PHASIC SHEAR STRESS AND VIRAL INFECTIONS^*

Robert Tarran1, Brian Button, Maryse Picher, Anthony M. Paradiso, Carla M. Ribeiro, Eduardo R. Lazarowski, Liqun Zhang, Peter L. Collins, Raymond J. Pickles, Jeffrey J. Fredberg¶, and Richard C. Boucher

From the Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0720, and ^¶School of Public Health, Harvard University, Boston, Massachusetts 02115

Mammalian airways normally regulate the volume of a thin liquid layer, the periciliary liquid (PCL), to facilitate the mucus clearance component of lung defense. Studies under standard (static) culture conditions revealed that normal airway epithelia possess an adenosine-regulated pathway that blends Na⁺ absorption and Cl^- secretion to optimize PCL volume. In cystic fibrosis (CF), the absence of CF transmembrane conductance regulator results in a failure of adenosine regulation of PCL volume, which is predicted to initiate mucus stasis and infection. However, under conditions that mimic the phasic motion of the lung in vivo, ATP release into PCL was increased, CF ion transport was rebalanced, and PCL volume was restored to levels adequate for lung defense. This ATP signaling system was vulnerable, however, to insults that trigger CF bacterial infections, such as viral (respiratory syncitial virus) infections, which up-regulated extracellular ATPase activity and abolished motion-dependent ATP regulation of CF PCL height. These studies demonstrate (i) how the normal coordination of opposing ion transport pathways to maintain PCL volume is disrupted in CF, (ii) the hitherto unknown role of phasic motion in regulating key aspects of normal and CF innate airways defense, and (iii) that maneuvers directed at increasing motion-induced nucleotide release may be therapeutic in CF patients.

Received for publication, May 27, 2005 , and in revised form, July 18, 2005.

^* This work was supported by National Institutes of Health Grants HL34322, HL60280, HL074158, CFF R026, and TARRAN01I0. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

Deceased.

¹ To whom correspondence should be addressed. E-mail: robert_tarran{at}med.unc.edu.

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