Heme oxygenase­1 inhibits renal tubular epithelial cell pyroptosis by regulating mitochondrial function through PINK1.

Endotoxin-induced acute kidney injury (AKI) is commonly observed in clinical practice. Renal tubular epithelial cell (RTEC) pyroptosis is one of the main factors leading to the development of endotoxin-induced AKI. Mitochondrial dysfunction can lead to pyroptosis. However, the biological pathways involved in the potential lipopolysaccharide (LPS)-induced pyroptosis of RTECs, notably those associated with mitochondrial dysfunction, are poorly understood. Previous studies have demonstrated that heme oxygenase (HO)-1 confers cell protection via the induction of PTEN-induced putative kinase 1 (PINK1) expression through PTEN to regulate mitochondrial fusion/fission during endotoxin-induced AKI in vivo. Therefore, the present study investigated the role of HO-1/PINK1 in maintaining mitochondrial function and inhibiting the pyroptosis of RTECs exposed to LPS. Primary cultures of RTECs were obtained from wild-type (WT) and PINK1-knockout (PINK1KO) rats. An in vitro model of endotoxin-associated RTEC injury was established following treatment of the cells with LPS. The WT RTECs were divided into the control, LPS, Znpp + LPS and Hemin + LPS groups, and the PINK1KO RTECs were divided into the control, LPS and Hemin + LPS groups. RTECs were exposed to LPS for 6 h to assess cell viability, inflammation, pyroptosis and mitochondrial function. In the LPS-treated RTECs, the mRNA and protein expression levels of HO-1 and PINK1 were upregulated. Cell viability, adenosine triphosphate (ATP) levels and the mitochondrial oxygen consumption rate were decreased, whereas the inflammatory response, pyroptosis and mitochondrial reactive oxygen species (ROS) levels were increased. The cell inflammatory response and the induction of pyroptosis were inhibited, whereas the levels of mitochondrial ROS were decreased. In addition, the cell viability and ATP levels were increased in the WT RTECs following the upregulation of HO-1 expression. These effects were reversed by the downregulation of HO-1 expression. However, no statistically significant differences were noted between the LPS and the Hemin + LPS groups in the PINK1KO RTECs. Collectively, the findings of the present study indicate that HO-1 inhibits inflammation and regulates mitochondrial function by inhibiting the pyroptosis of LPS-exposed RTECs via PINK1.

Comparison of the supraglottic airway device BlockBusterTM and laryngeal mask airway Supreme in anaesthetised, paralyzed adult patients: a multicenter randomized controlled trial.

BACKGROUND: This multicenter prospective, randomized controlled clinical trial compared the clinical performance of supraglottic airway device (SAD) BlockBusterTM and laryngeal mask airway (LMA) Supreme for airway maintenance in anesthetized, paralyzed adult patients. METHODS: A total of 651 adult patients scheduled for elective surgery in 13 hospitals were randomly allocated into BlockBuster group (n = 351) or Supreme group (n = 300). The primary outcome was oropharyngeal leak pressure (OLP). Duration and ease of insertion, fiberscopic view of positioning, airway manipulations, and complications were also assessed. RESULTS: The OLP was significantly higher in BlockBuster group compared with Supreme group (29.9 ± 4.2 cmH2O vs 27.4 ± 4.3 cmH2O, p < 0.001). Success rate of insertion at the first attempt (90.2% vs 85.1%, p = 0.027), rate of optimal fiberscopic view (p = 0.002) and satisfactory positioning of SAD (p < 0.001) were significantly increased in BlockBuster group. CONCLUSIONS: Both SAD BlockBusterTM and LMA Supreme are safe, effective, and easy-to-use devices for airway maintenance in anesthetized, paralyzed adult patients, but the SAD BlockBusterTM is superior to LMA Supreme in terms of OLP, success rate at the first attempt, and fiber-optic view of positioning. TRIAL REGISTRATION: The trial is registered at www.chictr.org.cn (ChiCTR-ONC-16009105).

Analysis of clinical prognosis in patients with non-hepatic hyperammonemia.

ABSTRACT: The aim of this study was to evaluate the association of non-hepatic hyperammonemia (NHH) with the prognosis of critically ill patients with NHH.According to the serum ammonia level, the patients with NHH (n = 498) were retrieved by us. The risk factors of the mortality with NHH patients were investigated by conducting univariate and multivariate logistic regression analyses. A nomogram to predict the risk of hospital mortality was constructed. Receiver operating characteristic curve (ROC) analysis was conducted to compare nomogram (ammonia into a prognostic model, P1) with the simplified acute physiology II (SAPSII) and quick sequential organ failure assessment (qSOFA).Five independent factors for the mortality in patients with NHH were identified, including age, platelets, bun, hemoglobin, and ammonia. Models P1 using ammonia showed good prediction power. The AUROC of P1 (AUROC, 0.755 [95% CI, 0.713-0.796]) was higher than that of qSOFA (AUROC, 0.500 [95% CI, 0.449-0.551]), and SAPS II (AUROC, 0.703[95% CI, 0.658-0.748]).Ammonia was an independent prognostic predictor of mortality for NHH patients. We developed a nomogram that can predict hospital mortality with patients. Nomogram had superior discriminative power to qSOFA and SAPS II, indicating that the nomogram may have clinical utility.

HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury.

BACKGROUND: Endotoxin-associated acute kidney injury (AKI), a disease characterized by marked oxidative stress and inflammation disease, is a major cause of mortality in critically ill patients. Mitochondrial fission and pyroptosis often occur in AKI. However, the underlying biological pathways involved in endotoxin AKI remain poorly understood, especially those related to mitochondrial dynamics equilibrium disregulation and pyroptosis. Previous studies suggest that heme oxygenase- (HO-) 1 confers cytoprotection against AKI during endotoxic shock, and PTEN-induced putative kinase 1 (PINK1) takes part in mitochondrial dysfunction. Thus, in this study, we examine the roles of HO-1/PINK1 in maintaining the dynamic process of mitochondrial fusion/fission to inhibit pyroptosis and mitigate acute kidney injury in rats exposed to endotoxin. METHODS: An endotoxin-associated AKI model induced by lipopolysaccharide (LPS) was used in our study. Wild-type (WT) rats and PINK1 knockout (PINK1KO) rats, respectively, were divided into four groups: the control, LPS, Znpp+LPS, and Hemin+LPS groups. Rats were sacrificed 6 h after intraperitoneal injecting LPS to assess renal function, oxidative stress, and inflammation by plasma. Mitochondrial dynamics, morphology, and pyroptosis were evaluated by histological examinations. RESULTS: In the rats with LPS-induced endotoxemia, the expression of HO-1 and PINK1 were upregulated at both mRNA and protein levels. These rats also exhibited inflammatory response, oxidative stress, mitochondrial fission, pyroptosis, and decreased renal function. After upregulating HO-1 in normal rats, pyroptosis was inhibited; mitochondrial fission and inflammatory response to oxidative stress were decreased; and the renal function was improved. The effects were reversed by adding Znpp (a type of HO-1 inhibitor). Finally, after PINK1 knockout, there is no statistical difference in the LPS-treated group and Hemin or Znpp pretreated group. CONCLUSIONS: HO-1 inhibits inflammation response and oxidative stress and regulates mitochondria fusion/fission to inhibit pyroptosis, which can alleviate endotoxin-induced AKI by PINK1.

[Influence of lipopolysaccharide pretreatment on acute lung injury induced by lipopolysaccharide in rats].

OBJECTIVE: To evaluate the effect of lipopolysaccharide pretreatment on blocking the development of lipopolysaccharide (E.Coli O(55):B(5)) induced acute lung injury. The activity of nuclear factor-kappaB (NF-kappaB) in alveolar macrophages was assessed to elucidate its mechanism. METHODS: Thirty-six Wistar rats were divided into three groups: normal saline (A), lipopolysaccharide (B), lipopolysaccharide preconditioning (C). Rat model of acute lung injury was reproduced by administering intraperitoneally lipopolysaccharide in a dose of 6 mg/kg. Group A and B served as control. In the test group (group C) lipopolysaccharide was given intraperitoneally 0.5 mg/kg, 0.5 mg/kg and 1.0 mg/kg consecutively for 3 days before lipopolysaccharide challenge. Four hours after lipopolysaccharide/normal saline administration, the animals were killed. Blood gas was measured. And total protein of bronchoalveolar lavage fluid (BALF) was calculated by measuring the radioactivity of (99)Tc labeled serum albumin. Wet/dry ratios of the lungs of each group were determined. The nuclear protein of the alveolar macrophages was extracted from BALF, and the activity of NF-kappaB was assayed with electrophoretic mobility shift assay (EMSA). Microscopic examination of the lung was done. RESULTS: In group C, partial pressure of oxygen in artery (PaO(2)) was significantly higher than that in group B, and total protein content of BALF was significantly lower in group A and C than that in group B. Activity of NF-kappaB in group C was higher than group A and B. CONCLUSION: Lipopolysaccharide pretreatment can reduce the severity of acute lung injury induced by lipopolysaccharide challenge. This phenomenon may be related with change in the activity of NF-kappaB of the alveolar macrophages.