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J. Biol. Chem., Vol. 279, Issue 19, 20234-20241, May 7, 2004

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Metabolism of P2 Receptor Agonists in Human Airways

IMPLICATIONS FOR MUCOCILIARY CLEARANCE AND CYSTIC FIBROSIS^*

Maryse Picher, Lauranell H. Burch¶, and Richard C. Boucher

From the Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 and the ^¶Department of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710

Extracellular nucleotides are among the most potent mediators of mucociliary clearance (MCC) in human lungs. However, clinical trials revealed that aerosolized nucleotides provide only a transient improvement of MCC to patients diagnosed with cystic fibrosis (CF). In this study, we identified the mechanism that eliminates extracellular nucleotides from human airways. Polarized primary cultures of human bronchial epithelial cells were impermeable to extracellular nucleotides but rapidly dephosphorylated ATP into ADP, AMP, and adenosine. The half-life of a therapeutic ATP concentration (0.1 mM) was 20 s within the periciliary liquid layer. The mucosal epithelial surface eliminated P2 receptor agonists (ATP = UTP > ADP > UDP) at 3-fold higher rates than the serosal surface. We also showed that mucosal (not serosal) ectoATPase activity increases toward areas most susceptible to airway obstruction (nose < bronchi << bronchioles). Bronchial cultures from patients with CF, primary ciliary dyskinesia, or 1-antitrypsin deficiency exhibited 3-fold higher mucosal (not serosal) ectoATPase activity than normal cultures. Time course experiments indicated that CF enhances ATP elimination and adenosine accumulation on the mucosal surface. Furthermore, nonspecific alkaline phosphatase was identified as the major regulator of airway nucleotide concentrations in CF, primary ciliary dyskinesia, and 1-antitrypsin deficiency. The ectoAT-Pase activity and mRNA expression of mucosally restricted nonspecific alkaline phosphatase were 3-fold higher on bronchial cultures from these patients than from healthy subjects. This study demonstrates that the duration of nucleotide-mediated MCC is limited by epithelial ectonucleotidases throughout human airways, with the efficiency of this mechanism enhanced in chronic inflammatory lung diseases, including CF.

Received for publication, January 12, 2004 , and in revised form, February 17, 2004.

^* This work was supported by National Institutes of Health Grant PO1 HL34322 and Grants R026 and PICHER 00G0 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.

To whom correspondence should be addressed: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, 7010 Thurston-Bowles Bldg., Chapel Hill, NC 27599. Tel.: 919-966-7047; Fax: 919-966-5178; E-mail: pichm{at}med.unc.edu.

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