Mechanisms Regulating Airway Nucleotides

Abstract

In the respiratory system, extracellular nucleotides and nucleosides serve as signaling molecules for a wide spectrum of biological functions regulating airway defenses against infection and toxic material. Their concentrations are controlled by a complex network of cell surface enzymes named ectonucleotidases. This highly integrated metabolic network combines the activities of three dephosphorylating ectonucleotidases, namely nucleoside triphosphate diphosphohydrolases (NTPDases), nucleotide pyrophosphatase/phosphodiesterases (NPPs) and alkaline phosphatases (APs). Extracellular nucleotides are also inter-converted by the transphosphorylating activities of ecto adenylate kinase (ectoAK) and nucleoside diphosphokinase (NDPK). Different cell types use specific combinations of ectonucleotidases to regulate local concentrations of P2 receptor agonists (ATP, UTP, ADP and UDP). In addition, they provide AMP for the activity of ecto 5'-nucleotidase (ecto 5'-NT; CD73), which produces the P1 receptor agonist: adenosine (ADO). Finally, mechanisms are in place to prevent the accumulation of airway ADO, namely adenosine deaminases and nucleoside transporters. This chapter reviews the properties of each enzyme and transporter, and the current knowledge on their distribution and regulation in the airways.

Inhibition of extracellular nucleotides hydrolysis intensifies the allergic bronchospasm. A novel protective role of ectonucleotidases

“…In the in vitro experiments, however, the catabolism sensitive to ARL-67156 appears to be insignificant because this drug failed to potentiate the OVA-induced contraction, despite the fact that the contraction was partially mediated by nucleotides release (as suramin plus RB2 caused rightward displacement of the concentration-response curve to OVA). It is reasonable to speculate that in airways, the catabolism of these compounds is locally carried out by ARL-67156-insensitive ectonucleotidases such as NPP2, NPP3, TNAP, and PLAP (8,41), which have been detected in airway epithelium and lung parenchyma (42)(43)(44)(45). Moreover, we were able to demonstrate that sensitization procedure dramatically increased the alkaline phosphatase activity in airway epithelium, thus providing a more powerful system to metabolize ATP and other nucleotides.…”

Metabolic Adaptation of Neutrophils in Cystic Fibrosis Airways Involves Distinct Shifts in Nutrient Transporter Expression

“…Under the nutrient-rich conditions provided by the CF airway milieu (9,11,12,14), environmental strains of autotrophic bacteria acquired by patients overcome the many negative aspects of this hypoxic and antimicrobial-, protease-, and oxidant-laden environment to thrive and undergo auxotrophic adaptation over time (10). Hence, the CF airway milieu exerts significant selective pressure on incoming bacteria, in large part through metabolic routes.…”

“…Both glucose (9) and amino acids (10) tend to accumulate in CF airway fluid as the result of an apparent failure of the epithelium, lacking functional CFTR protein, to transport these anabolic nutrients (11)(12)(13). Additionally, CF airway fluid is enriched in breakdown products of phosphonucleotides (14), which fuel cellular energy production. To investigate the process of metabolic adaptation by neutrophils recruited to CF airways, we used novel retroviral envelope glycoprotein (Env)-derived ligands (15,16) combined with multicolor flow cytometry to characterize the expression of glucose/ dehydroascorbic acid (Glut1), neutral amino acid (ASCT2), and inorganic phosphate (PiT1 and PiT2) transporters on CF blood and airway neutrophils.…”

NTPDase1/CD39 and aberrant purinergic signalling in the pathogenesis of COPD

“…CD39/NTPDase1/ecto-apyrase is the dominant purinergic ecto-enzyme in the immune and vascular barrier in the lung, and it is also a key regulator of the functionality of immune cells [8]. It regulates ATP-mediated P2 receptor signalling by hydrolysing ATP/ ADP to AMP, which is then further metabolised by CD73/ecto-5′-nucleotidase to adenosine [9].…”