Modelo de regulação dos nucleotídeos extracelulares no líquido superficial das vias respiratórias

Abstract

Extracellular nucleotides play a key role in the regulation of mucociliary clearance and thus are essential in protecting the airways against inhaled pathogens. Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) nucleotides are secreted by the respiratory epithelium to the airway surface liquid, where they are metabolized by ecto-enzymes and converted into the nucleosides adenosine (ADO) and inosine (INO) which in turn are absorbed by the cells of the respiratory epithelium. The concentrations of extracellular ATP and ADO, by activating the membrane receptors P2Y2 and A2B, regulate the mucus secretion rate, the ciliary beating frequency, and mucus hydration and mucus viscosity. The biochemical network that regulates the concentrations of extracellular ATP and ADO was recently described quantitatively by a computer model based on experimental data collected in cultures of human respiratory epithelial cells. Although this model reproduced the experimental data, it could not be used to investigate the regulation of extracellular nucleotides in vivo, because it was based on cell cultures containing _uid at a height of _ 1500_m, while in vivo the height of the airway surface liquid is approximately 30_m. Aiming to adapt the computer model to describe the behavior of the system in vivo, we selected from the literature experimental data where the regulatory network was investigated for liquid surface heights ranging from 14_m to 2730_m. The new version of the model, proposed in this work, consists in the solution of the reactiondi _usion equation in cylindrical coordinates, with boundary conditions that express the reactions catalyzed by ectonucleotidases on the surface of the bronchial epithelium. The set of coupled di_erential equations was solved numerically using the _nite volume method. The numerical solution was validated by comparing it with the analytical solution of two particular cases of boundary conditions: re_ective barriers and constant _ux at z = 0. Using the model, we investigate the behavior of the nucleotides after hypotonic challenge, the results are in good agreement with the experimental data. This model can be important for the development of new therapies for respiratory pathologies, especially cystic _brosis. Individuals with this genetic disease have chronic bacterial infection in the lungs due to a failure in mucociliary clearance, that includes mucus dehydration and excessive mucus secretion.