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May 12, 2017

Euroanaesthesia 2017

Metabolic reprogramming by inhibition of prolyl hydroxylases protects alveolar epithelial cells from LPS-neutrophil-induced energy derangements and cell death

;

Nao Tamada;

Yusuke Nagamine;

Shuhei Ota;

Takahisa Goto

ards

acute respiratory distress syndrome

hif

hypoxia-inducible factor

proly hydroxylase

metabolic reprogramming

Abstract

Abstract

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Keywords

ards

acute respiratory distress syndrome

hif

hypoxia-inducible factor

proly hydroxylase

metabolic reprogramming

Abstract

Background and Goal of Study: ARDS causes mitochondrial dysfunction and energy derangements in lungs. We have reported that inhibition of prolyl hydroxylases (PHD), which act as a cellular oxygen sensor, protects alveolar epithelial barrier from LPS-induced injury. The protective effect of PHD inhibition may be mediated by metabolic reprogramming via HIF (hypoxia inducible factor), which shifts energy metabolism from oxidative phosphorylation to glycolysis. In this study, we have investigated the effects of DMOG, a PHD inhibitor, on LPS-neutrophil-induced energy derangements and cell death, and whether the effect is mediated by metabolic reprogramming. Materials and Methods: Neutrophils isolated from mice were added to MLE12 cells, a murine alveolar epithelial cell line, with or without LPS. 1h prior to the neutrophil challenge, DMOG or vehicle was added to the culture medium. 24h later, cell viability, membrane permeability, and ATP levels were quantified. To clarify the effects of DMOG is dependent on metabolic reprogramming via HIF activation, HIF siRNA transfection or glycolysis inhibition by 2-DG was performed. Moreover, we investigated the effects of DMOG on lung ATP and epithelial cell death in LPS-induced lung injury mice. Results and Discussion: Neutrophil challenge with LPS to MLE12 cells decreased cellular ATP levels and caused non-apoptotic cell death. DMOG increased cellular lactate production, medium acidification, and glucose consumption, and attenuated the ATP decline and cell death. The protective effect of DMOG was abolished by HIF-1a knock down or glycolysis inhibition by 2-DG, suggesting that metabolic reprogramming via HIF-1 attenuates the cell death. Moreover, intratracheal administration of DMOG to mice attenuated LPS-induced ATP decline in lung tissue and suppressed increase in an epithelial cell death marker, CK18 M65, levels in BALF. Conclusion: PHD inhibition protected lung epithelial cells from LPS-neutrophil-induced energy derangements and cell death through metabolic reprogramming. Metabolic reprogramming from oxidative phosphorylation to glycolysis may be a novel approach to protect alveolar epithelial cells from ARDS.

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All rights reserved.