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.
BackgroundPatients with acute respiratory distress syndrome receiving mechanical ventilation show inhomogeneous lung aeration. Atelectasis during uneven mechanical ventilation leads to alveolar hypoxia and could therefore result in lung inflammation and injury. We aimed to elucidate whether and how atelectasis causes alveolar hypoxia-induced inflammation during uneven mechanical ventilation in an open-chest differential-ventilation rat model.MethodsWe first investigated inflammatory and histological changes in the bilateral lungs of unilaterally ventilated rats, in which the right lung was atelectatic and the left lung was ventilated with high tidal volume (HTV). In the next series, we investigated the effects of normal tidal volume (NTV) ventilation of the right lungs with 60 % O2 or 100 % N2 during HTV ventilation of the left lungs. Then, proinflammatory cytokine secretions were quantified from murine lung epithelial (MLE15) and murine alveolar macrophage (MH-S) cells cultured under a hypoxic condition (5 % O2) mimicking atelectasis. Further, activities of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)-1 were assessed in the nonventilated atelectatic lung and MLE15 cells cultured under the hypoxic condition. Finally, effects of NF-κB inhibition and HIF-1α knockdown on the cytokine secretions from MLE15 cells cultured under the hypoxic condition were assessed.ResultsThe nonventilated atelectatic lungs showed inflammatory responses and minimal histological changes comparable to those of the HTV-ventilated lungs. NTV ventilation with 60 % O2 attenuated the increase in chemokine (C-X-C motif) ligand (CXCL)-1 secretion and neutrophil accumulation observed in the atelectatic lungs, but that with 100 % N2 did not. MLE15 cells cultured with tumor necrosis factor (TNF)-α under the hypoxic condition showed increased CXCL-1 secretion. NF-κB and HIF-1α were activated in the nonventilated atelectatic lungs and MLE15 cells cultured under the hypoxic condition. NF-κB inhibition abolished the hypoxia-induced increase in CXCL-1 secretion from MLE15 cells, while HIF-1α knockdown augmented it.ConclusionsAtelectasis causes alveolar hypoxia-induced inflammatory responses including NF-κB-dependent CXCL-1 secretion from lung epithelial cells. HIF-1 activation in lung epithelial cells is an anti-inflammatory response to alveolar hypoxia in atelectatic lungs.
Background The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4–8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.
Alveolar epithelial injury and increased alveolar permeability are hallmarks of acute respiratory distress syndrome. Apoptosis of lung epithelial cells via the Fas/Fas ligand (FasL) pathway plays a critical role in alveolar epithelial injury. Activation of hypoxia-inducible factor (HIF)-1 by inhibition of prolyl hydroxylase domain proteins (PHDs) is a possible therapeutic approach to attenuate apoptosis and organ injury. Here, we investigated whether treatment with dimethyloxalylglycine (DMOG), an inhibitor of PHDs, could attenuate Fas/FasL-dependent apoptosis in lung epithelial cells and lung injury. DMOG increased HIF-1α protein expression in vitro in MLE-12 cells, a murine alveolar epithelial cell line. Treatment of MLE-12 cells with DMOG significantly suppressed cell surface expression of Fas and attenuated FasL-induced caspase-3 activation and apoptotic cell death. Inhibition of the HIF-1 pathway by echinomycin or small interfering RNA transfection abolished these antiapoptotic effects of DMOG. Moreover, intraperitoneal injection of DMOG in mice increased HIF-1α expression and decreased Fas expression in lung tissues. DMOG treatment significantly attenuated caspase-3 activation, apoptotic cell death in lung tissue, and the increase in alveolar permeability in mice instilled intratracheally with FasL. In addition, inflammatory responses and histopathological changes were also significantly attenuated by DMOG treatment. In conclusion, inhibition of PHDs protects lung epithelial cells from Fas/FasL-dependent apoptosis through HIF-1 activation and attenuates lung injury in mice.
Background Surgical site infection is a major perioperative issue. The morbidity of surgical site infection is high in major digestive surgery, such as pancreaticoduodenectomy. The comprehensive risk factors, including anesthetic factors, for surgical site infection in pancreaticoduodenectomy are unknown. The aim of this study was to investigate the perioperative and anesthetic risk factors of surgical site infection in pancreaticoduodenectomy. Methods This was a retrospective cohort study conducted in a single tertiary care center. A total of 326 consecutive patients who underwent pancreaticoduodenectomy between January 2009 and March 2018 were evaluated. Patients who underwent resection of other organs were excluded. The primary outcome was the incidence of surgical site infection, based on a Clavien-Dindo classification of grade 2 or higher. Multivariable logistic regression analysis was performed to investigate the association between surgical site infection and perioperative and anesthetic factors. Results Of the 326 patients, 116 (35.6%) were women. The median age was 70 years (interquartile range; 64-75). The median duration of surgery was 10.9 hours (interquartile range; 9.5-12.4). Surgical site infection occurred in 60 patients (18.4%). The multivariable analysis revealed that the use of desflurane as a maintenance anesthetic was associated with a significantly lower risk of surgical site infection than sevoflurane (odds ratio, 0.503; 95% confidence interval [CI], 0.260-0.973). In contrast, the duration of surgery (odds ratio, 1.162; 95% CI, 1.017-1.328), cerebrovascular disease (odds ratio, 3.544; 95% CI, 1.326-9.469), and ischemic heart disease (odds ratio, 10.839; 95% CI, 1.887-62.249) were identified as significant risk factors of surgical site infection.
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