title: Lung epithelial cells release ATP during ozone exposure: signaling for cell survival.
abstract: The common air pollutant ozone causes acute toxicity to human airways. In primary and transformed epithelial cells from all levels of human or rat airways, ozone levels relevant to air pollution (50-200 ppb) increased extracellular [ATP] within 7-30 min. A human bronchial epithelial cell line (16HBE14o(-)) that forms electrically resistant polarized monolayers had up to 10-fold greater apical than basolateral surface extracellular [ATP] within 7 min of ozone exposure. Increased extracellular [ATP] appeared due to ATP secretion or release because (1) inhibition of ectonucleotidase (cell surface enzyme(s) which degrade ATP) by ozone did not occur until >120 min of ozone exposure and (2) brefeldin A, a secretory inhibitor, eliminated elevation of extracellular [ATP] without affecting intracellular ATP. Extracellular ATP protected against ozone toxicity in a P2Y receptor-dependent manner as (1) removal of ATP and adenosine by apyrase and adenosine deaminase, respectively, potentiated ozone toxicity, (2) extracellular supplementation with ATP, a poorly hydrolyzable ATP analog ATPgammaS, or UTP inhibited apoptotic and necrotic ozone-mediated cell death, and (3) ATP-mediated protection was eliminated by P2 and P2Y receptor inhibitors suramin and Cibacron blue (reactive blue 2), respectively. The decline in glucose uptake caused by prolonged ozone exposure was prevented by supplemental extracellular ATP, an effect blocked by suramin. Further, Akt and ERK phosphorylation resulted from exposure to supplemental extracellular ATP. Thus, extracellularly released ATP signals to prevent ozone-induced death and supplementation with ATP or its analogs can augment protection, at least in part via Akt and /or ERK signaling pathways and their metabolic effects.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
authors.forename: Shama
authors.initials: S
authors.lastname: Ahmad
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmad
authors.forename: Glen
authors.initials: G
authors.lastname: McConville
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Schneider
authors.forename: Corrie B
authors.initials: CB
authors.lastname: Allen
authors.forename: Rizwan
authors.initials: R
authors.lastname: Manzer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001081:Apyrase / Q000378:metabolism; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003847:Deoxyglucose / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology*; D005089:Exocytosis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000493:pharmacokinetics; D006801:Humans; D006868:Hydrolysis; D008168:Lung / Q000166:cytology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D010126:Ozone / Q000378:metabolism*; D010766:Phosphorylation; D011755:Pyrophosphatases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014132:Trachea / Q000166:cytology
chemical_list: C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D020126:Brefeldin A; D004533:Egtazic Acid; D010126:Ozone; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011755:Pyrophosphatases; C092064:ectonucleotide pyrophosphohydrolase; D001081:Apyrase; D005947:Glucose; D000241:Adenosine