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J. Biol. Chem., Vol. 279, Issue 16, 16317-16325, April 16, 2004

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Extracellular ATP-mediated Signaling for Survival in Hyperoxia-induced Oxidative Stress^*

Shama Ahmad, Aftab Ahmad, Moumita Ghosh, Christina C. Leslie, and Carl W. White¶

From the Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206 and the Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206

Respiratory failure is a serious consequence of lung cell injury caused by treatment with high inhaled oxygen concentrations. Human lung microvascular endothelial cells (HLMVEC) are a principal target of hyperoxic injury (hyperoxia). Cell stress can cause release of ATP, and this extracellular nucleotide can activate purinoreceptors and mediate responses essential for survival. In this investigation, exposure of endothelial cells to an oxidative stress, hyperoxia, caused rapid but transient ATP release (20.03 ± 2.00 nM/10⁶ cells in 95% O₂ versus 0.08 ± 0.01 nM/10⁶ cells in 21% O₂ at 30 min) into the extracellular milieu without a concomitant change in intracellular ATP. Endogenously produced extracellular ATP-enhanced mTOR-dependent uptake of glucose (3467 ± 102 cpm/mg protein in 95% oxygen versus 2100 ± 112 cpm/mg protein in control). Extracellular addition of ATP-activated important cell survival proteins like PI 3-kinase and extracellular-regulated kinase (ERK-1/2). These events were mediated primarily by P₂Y receptors, specifically the P₂Y₂ and/or P₂Y₆ subclass of receptors. Extracellular ATP was required for the survival of HLMVEC in hyperoxia (55 ± 10% surviving cells with extracellular ATP scavengers [apyrase + adenosine deaminase] versus 95 ± 12% surviving cells without ATP scavengers at 4 d of hyperoxia). Incubation with ATP scavengers abolished ATP-dependent ERK phosphorylation stimulated by hyperoxia. Further, ERK activation also was found to be important for cell survival in hyperoxia, as treatment with PD98059 enhanced hyperoxia-mediated cell death. These findings demonstrate that ATP release and subsequent ATP-mediated signaling events are vital for survival of HLMVEC in hyperoxia.

Received for publication, December 18, 2003 , and in revised form, January 29, 2004.

^* This work was supported by National Institute of Health Grants HL52732, HL57144, and HL56263 and United States Environmental Protection Agency Grant R82570201. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: 1400 Jackson St., Room J309, Denver, CO 80206. Tel.: 303-398-1617; Fax: 303-270-2189; E-mail: whitec{at}njc.org.

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