Ethyl pyruvate attenuates ventilation‐induced diaphragm dysfunction through high‐mobility group box‐1 in a murine endotoxaemia model

Abstract

Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator‐induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high‐mobility group box‐1 (HMGB1) levels are associated with patients requiring long‐term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti‐HMGB1 antibody could attenuate sepsis‐exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti‐HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor‐1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia ( P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti‐HMGB1 antibody ( P < 0.05). Our data suggest that EP attenuates endotoxin‐enhanced VIDD by inhibiting HMGB1 signalling pathway.

Low-Molecular-Weight Heparin Reduces Ventilation-Induced Lung Injury through Hypoxia Inducible Factor-1α in a Murine Endotoxemia Model

“…However, even MV with moderate tidal volumes can aggravate sepsis-induced lung injury by synergistically augmenting pulmonary cytokines, and this may play a central role in the evolution of ALI in patients with sepsis [21][22][23]. Thus, in this study, we employed our previously published animal model to simulate a clinical scenario to investigate the effects and molecular mechanisms of LMWH to attenuate VILI in endotoxemic mice [4,20]. We demonstrated that LMWH can (1) mitigate oxidative stress and improve antioxidant activity; (2) decrease inflammatory cytokines TNF-, IL-6, MIP-2 and VEGF, as well as neutrophil sequestration;…”

“…However, even MV with moderate tidal volumes can aggravate sepsis-induced lung injury by synergistically augmenting pulmonary cytokines, and this may play a central role in the evolution of ALI in patients with sepsis [21][22][23]. Thus, in this study, we employed our previously published animal model to simulate a clinical scenario to investigate the effects and molecular mechanisms of LMWH to attenuate VILI in endotoxemic mice [4,20]. We demonstrated that LMWH can (1) mitigate oxidative stress and improve antioxidant activity; (2) decrease inflammatory cytokines TNF-α, IL-6, MIP-2 and VEGF, as well as neutrophil sequestration; (3) ameliorate lung edema and microvascular leakage; (4) attenuate caspase-3 activity and epithelial apoptosis; (5) improve gross and microscopic epithelial pathology; and (6) restore the ultrastructural integrity, Penh physiological index and functional gas exchange in a mouse model of VILI with endotoxemia.…”

“…In addition to its role in oxidative stress, caspase-3 is central to the intrinsic apoptotic pathway [20]. Capase-3 expression, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining and transmission electron microscopy (TEM) were performed to explore the functions of the caspase-3 pathway and the apoptosis of airway epithelial cells in endotoxin-associated VILI (Figure 7A).…”

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Medel

“…The administration of AS605240 substantially reduced damage to the diaphragmatic fibers (Figure 1F,G). Ultrasonography is a noninvasive tool for assessing the diaphragm in patients receiving MV [6,8]; therefore, to determine the effects of MV and bleomycin on diaphragm contractile function, we measured diaphragm dysfunction in the mice by using small animal ultrasound (VEVO 2100, Visual Sonics, Toronto, Canada). Relative to the VT6 group and the nonventilated control mice, the VT10 group exhibited decreased diaphragm excursion and thickening fraction (Figure 1H,I).…”

“…The injurious effects of MV on the ECM are triggered by increased transpulmonary pressure, heterogeneous distribution of ventilation, and increased tissue stretching and are exacerbated by limited pulmonary lymphatic drainage [1,4,5]. In addition to causing ventilator-induced lung injury, MV can result in diaphragmatic weakness and the rapid decline of diaphragm muscle contractility and endurance, a phenomenon commonly referred to as ventilator-induced diaphragm dysfunction (VIDD) [6][7][8][9]. Diaphragm muscle dysfunction can aggravate underlying respiratory insufficiency, contributing to the disability burden of critically ill patients.…”