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Effects of airway surface liquid height on the kinetics of extracellular nucleotides in airway epithelia. J Theor Biol 2014 Dec 21;363:427-35

Date

08/28/2014

Pubmed ID

25159000

DOI

10.1016/j.jtbi.2014.08.030

Scopus ID

2-s2.0-84907536913   1 Citation

Abstract

Experimental techniques aimed at measuring the concentration of signaling molecules in the airway surface liquid (ASL) often require an unrealistically large ASL volume to facilitate sampling. This experimental limitation, prompted by the difficulty of pipetting liquid from a very shallow layer (~15 μm), leads to dilution and the under-prediction of physiologic concentrations of signaling molecules that are vital to the regulation of mucociliary clearance. Here, we use a computational model to describe the effect of liquid height on the kinetics of extracellular nucleotides in the airway surface liquid coating respiratory epithelia. The model consists of a reaction-diffusion equation with boundary conditions that represent the enzymatic reactions occurring on the epithelial surface. The simulations reproduce successfully the kinetics of extracellular ATP following hypotonic challenge for ASL volumes ranging from 25 μl to 500 μl in a 12-mm diameter cell culture. The model reveals that [ATP] and [ADO] reach 1200 nM and 2200 nM at the epithelial surface, respectively, while their volumetric averages remain less than 200 nM at all times in experiments with a large ASL volume (500 μl). These findings imply that activation of P2Y2 and A2B receptors is robust after hypotonic challenge, in contrast to what could be concluded based on experimental measurements of volumetric concentrations in large ASL volumes. Finally, given the central role that ATP and ADO play in regulating mucociliary clearance, we investigated which enzymes, when inhibited, provide the greatest increase in ATP and ADO concentrations. Our findings suggest that inhibition of NTPDase1/highTNAP would cause the greatest increase in [ATP] after hypotonic challenge, while inhibition of the transporter CNT3 would provide the greatest increase in [ADO].

Author List

Amarante TD, da Silva JK, Garcia GJ

Author

Guilherme Garcia PhD Assistant Professor in the Biomedical Engineering department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine
Adenosine Diphosphate
Adenosine Triphosphate
Extracellular Space
Humans
Kinetics
Membrane Transport Proteins
Models, Biological
Nucleotides
Receptors, Purinergic P2Y2
Respiratory Mucosa
Surface Properties
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a