Chapter

Purinergic Regulation of Respiratory Diseases

Volume 55 of the series Subcellular Biochemistry pp 51-74

Date:

Computational Model for the Regulation of Extracellular ATP and Adenosine in Airway Epithelia

  • Guilherme J. M. GarciaAffiliated withDepartment of Pharmacology, University of North Carolina Email author 
  • , Maryse PicherAffiliated withCystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina
  • , Peiying ZuoAffiliated withDepartment of Pharmacology, University of North Carolina
  • , Seiko F. OkadaAffiliated withCystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina
  • , Eduardo R. LazarowskiAffiliated withCystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina
  • , Brian ButtonAffiliated withCystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina
  • , Richard C. BoucherAffiliated withCystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina
  • , Tim C. ElstonAffiliated withDepartment of Pharmacology, University of North Carolina

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Abstract

Extracellular nucleotides are key components of the signaling network regulating airway clearance. They are released by the epithelium into the airway surface liquid (ASL) to stimulate cilia beating activity, mucus secretion and airway hydration. Understanding the factors affecting their availability for purinoceptor activation is an important step toward the development of new therapies for obstructive lung diseases. This chapter presents a mathematical model developed to gain predictive insights into the regulation of ASL nucleotide concentrations on human airway epithelia. The parameters were estimated from experimental data collected on polarized primary cultures of human nasal and bronchial epithelial cells. This model reproduces major experimental observations: (1) the independence of steady-state nucleotide concentrations on ASL height, (2) the impact of selective ectonucleotidase inhibitors on their steady-state ASL concentrations, (3) the changes in ASL composition caused by mechanical stress mimicking normal breathing, (4) and the differences in steady-state concentrations existing between nasal and bronchial epithelia. In addition, this model launched the study of nucleotide release into uncharted territories, which led to the discovery that airway epithelia release, not only ATP, but also ADP and AMP. This study shows that computational modeling, coupled to experimental validation, provides a powerful approach for the identification of key therapeutic targets for the improvement of airway clearance in obstructive respiratory diseases.

Keywords

Extracellular nucleotide regulation Mathematical model Cystic fibrosis Airway surface liquid volume regulation Signaling pathway