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

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

doi:10.1074/jbc.m313890200

Cited by 71 publications

(42 citation statements)

References 65 publications

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“…This result suggests that extracellular ATP induces rapid and transient phosphorylation of ERK1/2, consistent with previous studies [12,19,20,23] . However, in contrast to previous studies, we found that stimulation of rat mesangial cells with ATP for 60 min resulted in decreased p-ERK1/2 levels when compared with the control.…”

Section: Discussionsupporting

confidence: 81%

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

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Aim: To investigate the role of adenosine 5′-triphosphate (ATP)-induced generation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the production of transforming growth factor-β1 (TGF-β1) in cultured rat glomerular mesangial cells under high-glucose conditions. Methods: Subconfluent glomerular mesangial cells were serum-starved for 24 h and pretreated with suramin, diphenylenechloride iodonium (DPI) or PD98059 followed by stimulation with a high concentration of glucose (30 mmol/L D-glucose) or ATP (300 μmol/L). Extracellular and total ATP and ROS production were detected using commercially available kits. Phosphorylation of ERK1/2 was evaluated by Western blot. TGF-β1 mRNA expression was examined by real-time PCR. Results: Suramin had a dose-dependent inhibitory effect on the generation of ROS induced by high glucose. Extracellular ATP production by mesangial cells increased markedly after a 2-h incubation with high glucose. ROS production was upregulated in mesangial cells after 5 min incubation with 300 μmol/L ATP and was sustained for 120 min. ERK1/2 was significantly activated after 5 min incubation of mesangial cells with ATP, this activation was partially inhibited by DPI. The effects of high glucose on TGF-β1 mRNA were markedly inhibited by suramin, DPI or PD98059. Conclusion: Our results suggest that a high concentration of glucose increases the extracellular levels of ATP in mesangial cells within a short time-frame. ATP, in turn, activates ERK1/2, an effect which is at least partially dependent on ROS, which results in the upregulation of TGF-β1.

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Section: Discussionsupporting

confidence: 81%

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

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“…Adenoviral-mediated transduction of Akt led to increased phospho-RPS6KB1 expression upon hyperoxia exposure in human lung microvascular endothelial cells (HLMVECs), and was considered protective against hyperoxia stress (30). In HLMVECs, hyperoxia exposure increased extracellular adenosine triphosphate at 30 minutes; within the same time frame, ATP treatment induced phosphorylation of RPS6KB1, which is downstream of MTORC1 (31). When HLMVECs were exposed to hyperoxia for 48 hours, there appears to be no change in phospho-MTOR and phospho-RPS6KB1 (30).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Sureshbabu

Syed

Das

et al. 2016

Am J Respir Cell Mol Biol

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Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor 1/2 , limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomalassociated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.Keywords: cell death; oxygen; newborn; pulmonary; bronchopulmonary dysplasia Premature infants provided with supplemental oxygen are at higher risk for developing a chronic respiratory disease, bronchopulmonary dysplasia (BPD) (1). BPD occurs in developing lungs resulting in impaired alveolarization and dysregulated vascularization-the pathologic hallmarks (2). Premature infants diagnosed with BPD have diminished pulmonary function and reduced lung capacity as they grow older and up to adulthood (3). This disease represents a common yet complicated clinical issue associated with significant long-term morbidity and mortality (2, 3). Pulmonary-specific oxygen toxicity is This work was supported in part by National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) grants HL63039 (G.P.) and HL116632 (A.R.), by the Sigrid Jusélius Foundation (S.A.), and by NHLBI/NIH grant HL85103 (V.B.).Author Contributions: Concept and design-A.S. and V.B.; acquisition of data-A.S., M.S., P.D., C.J., G.P., A.R., S.A., R.J.H., and V.B.; data analysis and interpretation-A.S., M.S., P.D., C.J., G.P., A.R., S...

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“…(30 -32). For example, exposure of pulmonary endothelial cells to oxidative stress or to hyperoxia resulted in rapid but transient ATP release (31). As such, extracellular ATP can either signal directly to ATP receptors, or may function as a metabolic substrate for extracellular generation of adenosine via CD39 and CD73.…”

Section: Discussionmentioning

confidence: 99%

Identification of Ectonucleotidases CD39 and CD73 in Innate Protection during Acute Lung Injury

Eckle¹,

Füllbier²,

Wehrmann

et al. 2007

The Journal of Immunology

237

286

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Acute lung injury (ALI), such as that which occurs with mechanical ventilation, contributes to morbidity and mortality of critical illness. Nonetheless, in many instances, ALI resolves spontaneously through unknown mechanisms. Therefore, we hypothesized the presence of innate adaptive pathways to protect the lungs during mechanical ventilation. In this study, we used ventilator-induced lung injury as a model to identify endogenous mechanisms of lung protection. Initial in vitro studies revealed that supernatants from stretch-induced injury contained a stable factor which diminished endothelial leakage. This factor was subsequently identified as adenosine. Additional studies in vivo revealed prominent increases in pulmonary adenosine levels with mechanical ventilation. Because ectoapyrase (CD39) and ecto-5′-nucleotidase (CD73) are rate limiting for extracellular adenosine generation, we examined their contribution to ALI. In fact, both pulmonary CD39 and CD73 are induced by mechanical ventilation. Moreover, we observed pressure- and time-dependent increases in pulmonary edema and inflammation in ventilated cd39−/− mice. Similarly, pharmacological inhibition or targeted gene deletion of cd73 was associated with increased symptom severity of ventilator-induced ALI. Reconstitution of cd39−/− or cd73−/− mice with soluble apyrase or 5′-nucleotidase, respectively, reversed such increases. In addition, ALI was significantly attenuated and survival improved after i.p. treatment of wild-type mice with soluble apyrase or 5′-nucleotidase. Taken together, these data reveal a previously unrecognized role for CD39 and CD73 in lung protection and suggest treatment with their soluble compounds as a therapeutic strategy for noninfectious ALI.

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

Cited by 71 publications

References 65 publications

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Identification of Ectonucleotidases CD39 and CD73 in Innate Protection during Acute Lung Injury

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