title: Inhibition of extracellular nucleotides hydrolysis intensifies the allergic bronchospasm. A novel protective role of ectonucleotidases.
abstract: BACKGROUND
  Nucleotides released to the extracellular space stimulate purinergic receptors, and their effects are modulated by ectonucleotidases. The role of ATP in the allergic bronchospasm has been scantly studied.
  
  
  METHODS
  We used several techniques (plethysmography, organ baths, confocal microscopy, RT-PCR, ATP measurement) to explore the role of nucleotides and ectonucleotidases in the allergic bronchospasm in guinea pigs.
  
  
  RESULTS
  While allergenic challenge with a low-dose ovalbumin (OVA) only produced a small bronchospasm (~2-fold the basal lung resistance), previous inhibition of ectonucleotidases by ARL-67156 greatly intensified this response (~11-fold the basal lung resistance, with 44% mortality). Bronchoalveolar lavage fluid obtained during this bronchospasm contained increased ATP concentration. This potentiation was abolished by antagonism of purinergic receptors (suramin+RB2) or TXA2 receptor (SQ29548), or by intratracheal apyrase. In tracheal rings and lung parenchyma strips, OVA caused a concentration-dependent contraction. Suramin+RB2 or levamisole produced a significant rightward displacement of this response, and ARL-67156 did not modify it. Platelets stimulated with OVA released ATP. Confocal images of nonsensitized tracheas showed slight fluorescence for P2Y6 receptors in epithelium and none for P2Y4 . Sensitized animals showed strong fluorescence to both receptors and to alkaline phosphatase in the airway epithelium. This correlated with a large increment in mRNA for P2Y4 and P2Y6 receptors in sensitized animals.
  
  
  CONCLUSIONS
  Nucleotides greatly potentiate the allergic bronchospasm when ectonucleotidases activity is diminished, and this effect is probably favored by the upregulation of P2Y4 and P2Y6 receptors in airway epithelium during sensitization. These results prompt for further research on these mechanisms in human asthma.
authors: Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México, DF México.
authors: J
authors: J
authors: Chávez
authors: M H
authors: MH
authors: Vargas
authors: D C
authors: DC
authors: Rebollar-Ayala
authors: V
authors: V
authors: Díaz-Hernández
authors: J E
authors: JE
authors: Cruz-Valderrama
authors: E
authors: E
authors: Flores-Soto
authors: M
authors: M
authors: Flores-García
authors: N N
authors: NN
authors: Jiménez-Vargas
authors: C
authors: C
authors: Barajas-López
authors: L M
authors: LM
authors: Montaño
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001986:Bronchial Spasm / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D006168:Guinea Pigs; D006868:Hydrolysis / Q000187:drug effects; D006967:Hypersensitivity / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D009708:Nucleotidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism
chemical_list: C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D009711:Nucleotides; D018048:Receptors, Purinergic P2; C104749:purinoceptor P2Y4; C099845:purinoceptor P2Y6; D000255:Adenosine Triphosphate; D010047:Ovalbumin; D009708:Nucleotidases; D000469:Alkaline Phosphatase; C030287:nucleotidase