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Extracellular ATP and uridine triphosphate (UTP) have a range of effects on a wide variety of cells through the activation of P2 receptors. The aim of this work was to establish if stimulation with ATP and UTP enhances airway smooth muscle (ASM) cell proliferation and to determine the type of receptor mediating this effect. Proliferation of rat ASM cells was assessed through bromodeoxyuridine (BrdU) uptake and by cell counting. At concentrations of 10-6 and 10-5 M, ATP and UTP induced significant increases in BrdU incorporation. ATP analogs specific for the P2X and P2Y1 receptor subtypes had no effect. UDP (a P2Y6 receptor agonist) produced significant decreases in BrdU incorporation and cell counts. Adenosine, the metabolite of ATP, produced an increase in cell proliferation through stimulation of the A1 receptor. A2 and A3 receptor stimulation had no effect. Reverse transcription and polymerase chain reaction analysis showed that mRNA transcripts for the P2Y2, P2Y4, P2Y6, A1, A2, and A3 receptor subtypes were present in cultured ASM cells. These data show that extracellular UTP, ATP, and their metabolites may affect airway remodeling by increasing or by reducing (P2Y6 receptor) ASM cell proliferation.