Enhancement of glycolysis by inhibition of oxygen‐sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury

Abstract

Cellular bioenergetic failure caused by mitochondrial dysfunction is a key process of alveolar epithelial injury during acute respiratory distress syndrome (ARDS). Prolyl hydroxylases (PHDs) act as cellular oxygen sensors, and their inhibition activates hypoxia-inducible factor (HIF), resulting in enhanced cellular glycolytic activity, which could compensate for impaired mitochondrial function and protect alveolar epithelial cells from ARDS. Here, we evaluated the effects of pharmacological PHD inhibition with dimethyloxalylglycine (DMOG) on alveolar epithelial cell injury using in vitro and in vivo ARDS models. We established an in vitro model of alveolar epithelial injury mimicking ARDS by adding isolated neutrophils and LPS to cultured MLE12 alveolar epithelial cells. DMOG treatment protected MLE12 cells from neutrophil-LPS-induced ATP decline and cell death. Knockdown of HIF-1α or inhibition of glycolysis abolished the protective effect of DMOG, suggesting that it was exerted by HIF-1-dependent enhancement of glycolysis. Additionally, intratracheal DMOG administration to mice protected the alveolar epithelial barrier and improved arterial oxygenation, preventing ATP decline during LPS-induced lung injury. In summary, enhancement of glycolysis by PHD inhibition is a potential therapeutic approach for ARDS, protecting alveolar epithelial cells from bioenergetic failure and cell death.-Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury.

Depression of lncRNA NEAT1 Antagonizes LPS-Evoked Acute Injury and Inflammatory Response in Alveolar Epithelial Cells via HMGB1-RAGE Signaling

“…Recent evidence also has confirmed that patients with sepsis tend to have high levels of NEAT1, increased disease severity, and poor prognosis [13]. LPS-induced endotoxemia is a major inducer of ALI; thus, exposing AECs to LPS has been comprehensively applied as an in vitro model to investigate this condition [3,20]. We corroborated high expression of NEAT1 in LPS-exposed AECs.…”

“…Pulmonary alveolar epithelial cells (AECs) facilitate normal breathing by synthesizing and secreting surfactants. Accumulating evidence has corroborated that the pathophysiological process of ALI is characterized by AEC insult [3,4]. For example, AEC lesions disrupt cellular integrity and the ability to clear fluid from the alveolar space, clinically translating into lung edema.…”

<p>Mitochondria-Modulating Porous Se@SiO₂ Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

“…Bundles of studies observed mitochondrial dysfunction of airway epithelial cells (AECs) in ALI/ARDS. 5,9,10 Moreover, rescuing AECs from mitochondrial dysfunction through mitochondria transferring relieved LPS-induced ALI. 11 A more recent report also affirmed that compensation for mitochondrial impairment by enhancing cellular glycolytic activity could protect airway epithelium from acute injury.…”

“…11 A more recent report also affirmed that compensation for mitochondrial impairment by enhancing cellular glycolytic activity could protect airway epithelium from acute injury. 10 Therefore, preventing AECs from mitochondrial impairment might provide a promising therapeutic target for ALI/ARDS. In this regard, numerous "drugs" have been documented over the years ranging from mitochondria-targeted cation to triphenylphosphonium (TPP)-conjugated antioxidants.…”

Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

“…It is well reported that some metabolites are capable of inducing inflammation and regulating the activation of immune cells [7,8]. Kentaro Tojo et al have revealed that the enhancement of glycolysis attenuated the lung tissue injury by protecting alveolar epithelial cells from decline in energy [9]. Their results also indicated that metabolites played an important role in ARDS.…”