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J. Biol. Chem., Vol. 283, Issue 39, 26805-26819, September 26, 2008

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Mathematical Model of Nucleotide Regulation on Airway Epithelia

IMPLICATIONS FOR AIRWAY HOMEOSTASIS^*

Peiying Zuo¹, Maryse Picher¹, Seiko F. Okada, Eduardo R. Lazarowski, Brian Button, Richard C. Boucher², and Timothy C. Elston^¶23

From the Department of Mathematics, the Cystic Fibrosis/Pulmonary Research and Treatment Center, and ^¶Department of Pharmacology and the UNC Virtual Lung Group, University of North Carolina, Chapel Hill, North Carolina 27599

In the airways, adenine nucleotides support a complex signaling network mediating host defenses. Released by the epithelium into the airway surface liquid (ASL) layer, they regulate mucus clearance through P2 (ATP) receptors, and following surface metabolism through P1 (adenosine; Ado) receptors. The complexity of ASL nucleotide regulation provides an ideal subject for biochemical network modeling. A mathematical model was developed to integrate nucleotide release, the ectoenzymes supporting the dephosphorylation of ATP into Ado, Ado deamination into inosine (Ino), and nucleoside uptake. The model also includes ecto-adenylate kinase activity and feed-forward inhibition of Ado production by ATP and ADP. The parameters were optimized by fitting the model to experimental data for the steady-state and transient concentration profiles generated by adding ATP to polarized primary cultures of human bronchial epithelial (HBE) cells. The model captures major aspects of ATP and Ado regulation, including their >4-fold increase in concentration induced by mechanical stress mimicking normal breathing. The model also confirmed the independence of steady-state nucleotide concentrations on the ASL volume, an important regulator of airway clearance. An interactive approach between simulations and assays revealed that feed-forward inhibition is mediated by selective inhibition of ecto-5'-nucleotidase. Importantly, the model identifies ecto-adenylate kinase as a key regulator of ASL ATP and proposes novel strategies for the treatment of airway diseases characterized by impaired nucleotide-mediated clearance. These new insights into the biochemical processes supporting ASL nucleotide regulation illustrate the potential of this mathematical model for fundamental and clinical research.

Received for publication, February 25, 2008 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants PPG-P01-HL034332, P30 DK065988, SCOR 1-P50-HL060280, SCCOR 1-P50-HL084934, and R01-GM079271. This work was also supported by Cystic Fibrosis Foundation Grants BUTTON06G0, OKADA06I0, and PICHER07I0. 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 Both authors contributed equally to this work.

² Both senior authors contributed equally to this work.

³ To whom correspondence should be addressed: Dept. of Pharmacology, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-962-8655; E-mail: telston{at}med.unc.edu.

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