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J. Biol. Chem., Vol. 281, Issue 11, 7392-7398, March 17, 2006

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Hyposecretion, Not Hyperabsorption, Is the Basic Defect of Cystic Fibrosis Airway Glands^*

Nam Soo Joo¹, Toshiya Irokawa, Robert C. Robbins, and Jeffrey J. Wine

From the Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California 94305-2130 and the Cardiothoracic Surgery and School of Medicine, Stanford University, Stanford, California 94305-5407

Human airways and glands express the anion channel cystic fibrosis transmembrane conductance regulator, CFTR, and the epithelial Na⁺ channel, ENaC. Cystic fibrosis (CF) airway glands fail to secrete mucus in response to vasoactive intestinal peptide or forskolin; the failure was attributed to loss of CFTR-mediated anion and fluid secretion. Alternatively, CF glands might secrete acinar fluid via CFTR-independent pathways, but the exit of mucus from the glands could be blocked by hyperabsorption of fluid in the gland ducts. This could occur because CFTR loss can disinhibit ENaC, and ENaC activity can drive absorption. To test these two hypotheses, we measured single gland mucus secretion optically and applied ENaC inhibitors to determine whether they augmented secretion. Human CF glands were pretreated with benzamil and then stimulated with forskolin in the continued presence of benzamil. Benzamil did not rescue the lack of secretion to forskolin (50 glands, 6 CF subjects) nor did it increase the rate of cholinergically mediated mucus secretion from CF glands. Finally, neither benzamil nor amiloride increased forskolin-stimulated mucus secretion from porcine submucosal glands (75 glands, 7 pigs). One possible explanation for these results is that ENaC within the gland ducts was not active in our experiments. Consistent with that possibility, we discovered that human airway glands express Kunitz-type and non-Kunitz serine protease inhibitors, which might prevent proteolytic activation of ENaC. Our results suggest that CF glands do not display excessive, ENaC-mediated fluid absorption, leaving defective, anion-mediated fluid secretion as the most likely mechanism for defective mucus secretion from CF glands.

Received for publication, November 29, 2005 , and in revised form, January 4, 2006.

^* This work was supported by National Institutes of Health Grant DK51817 and 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Cystic Fibrosis Research Laboratory, Rm. 516, Bldg. 420, Main Quad, Stanford University, Stanford, CA 94305-2130. Tel.: 650-725-2468; Fax: 650-725-5699; E-mail: nsjoo{at}psych.stanford.edu.

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