Necrostatin-1 attenuates Caspase-1-dependent pyroptosis induced by the RIPK1/ZBP1 pathway in ventilator-induced lung injury.

BACKGROUND: Ventilator-induced lung injury (VILI) is a complex pathophysiological process leading to acute respiratory distress syndrome (ARDS) and poor outcomes in affected patients. As a form of programmed cell death, pyroptosis is proposed to play an important role in the development of ARDS. Here we investigated whether treating mice with the specific RIPK1 inhibitor Necrostatin-1 (Nec-1) before mechanical ventilation could inhibit pyroptosis and alleviate lung injury in a mouse model. METHODOLOGYS: Anesthetized C57BL/6J mice received a transtracheal injection of Nec-1 (5 mg/kg) or vehicle (DMSO) 30 min before the experiment which was ventilated for up to 4 h. Lung damage was assessed macroscopically and histologically with oedema measured as the wet/dry ratio of lung tissues. The release of inflammatory mediators into bronchoalveolar lavage fluid (BALF) was assessed by ELISA measurements of TNF-α,interleukin-1ß (IL-1ß), and IL-6. The expression of RIPK1, ZBP1, caspase-1, and activated (cleaved) caspase-1 were analyzed using western blot and immunohistochemistry, and the levels of gasdermin-D (GSDMD) and IL-1ß were analyzed by immunofluorescence staining. RESULTS: High tidal ventilation produced time-dependent inflammation and lung injury in mice which could be significantly reduced by pretreatment with Nec-1. Notably, Nec-1 reduced the expression of key pyroptosis mediator proteins in lung tissues exposed to mechanical ventilation, including caspase-1, cleaved caspase-1, and GSDMD together with inhibiting the release of inflammatory cytokines. CONCLUSION: Nec-1 pretreatment alleviates pulmonary inflammatory responses and protects the lung from mechanical ventilation damage. The beneficial effects were mediated at least in part by inhibiting caspase-1-dependent pyroptosis through the RIPK1/ZBP1 pathway.

Association between Body Mass Index and Early Renal Function after Kidney Transplantation: Observational and Mendelian Randomization Study.

INTRODUCTION: The relationship between BMI and early renal function recovery after kidney transplantation is important due to the rising global obesity rates. METHODS: A retrospective study on 320 patients who received allograft kidney transplantation at Guangxi Medical University Hospital explored the BMI-kidney function relationship using various statistical methods. Mendelian randomization (MR) was also employed to investigate causality. RESULTS: Based on the univariate analysis, multivariate linear regression models, and trend analysis, it was found that there were significant positive correlations between BMI and creatinine, urea, and cystatin C on the 7th day after kidney transplantation (p < 0.05). The sensitivity analysis further confirmed these correlations in different gender stratification, adolescents, and adults. However, the positive correlation with cystatin C was only significant in males. Additionally, after conducting smooth curve fitting analysis and threshold saturation analysis, it was revealed that the negative correlation between early renal function recovery was most significant when BMI was between 22.0 and 25.5 kg/m2, and early postoperative renal function may be optimal when BMI was at 22.2 kg/m2. Finally, the MR analysis confirmed a causal relationship between BMI and renal failure, as indicated by the IVW method (p = 0.003), as well as the weighted median estimator (p = 0.004). CONCLUSION: This study on kidney transplant patients found that maintaining a BMI within the range of 22.0-25.5 kg/m2, with an optimal BMI of 22.2 kg/m2, improves early renal function recovery. This correlation holds true for different age-groups and genders. Monitoring and controlling BMI in high-risk patients can enhance post-transplantation renal function.

Causal Relationship Between Blood Triglyceride Levels and Age Spots: A Mendelian Randomization Analysis.

Objective: This study examined the association between blood triglyceride (TG) levels (TLIB) and age spots (AS). Methods: We acquired data from the Mendelian randomization (MR) Base database and evaluated the causal association between TLIB and AS. Results: From genome-wide association studies, we selected 33 single nucleotide polymorphisms (SNPs) that were significantly associated with TLIB and AS. The inverse variance-weighted (IVW) and weighted median estimation methods showed that TLIB had a protective effect on AS (IVW: ß=-0.214, P=0.019, odds ratio [OR]=0.807, 95% confidence interval [CI]=0.674-0.966; weighted median: ß=-0.277, P=0.032, OR=0.758, 95% CI=0.589-0.977). However, the MR-Egger analysis suggested no causal association (ß=-0.234, P=0.085, OR=0.792, 95% CI=0.612-1.024). The greater precision of the weighted median estimation and IVW suggests that our results support a potential causal association between TLIB and AS. Conclusion: The MR analysis proved that TLIB has a protective effect against AS and that triglycerides have potential preventive and therapeutic effects against AS. However, the specific dose-effect relationship requires further study.

Ulinastatin promotes macrophage efferocytosis and ameliorates lung inflammation via the ERK5/Mer signaling pathway.

Acute lung injury (ALI) is a pneumonic response characterized by neutrophil infiltration. Macrophage efferocytosis is the process whereby macrophages remove apoptotic cells, and is required for ALI inflammation to subside. The glycoprotein ulinastatin (UTI) has an anti-inflammatory effect during the acute stages of ALI, but its effect on efferocytosis and the subinflammatory stage of ALI is unclear. Extracellular signal-regulated kinase 5 (ERK5) is a key protein in efferocytosis, and we thus hypothesized that it may be activated by UTI to regulate efferocytosis and the resolution of pneumonia. To test this hypothesis, here we monitored phagocytosis of macrophages through in vivo and in vitro experiments. Pulmonary edema, neutrophil infiltration, protein exudation, and inflammatory factor regression were observed on days 1, 3, 5, and 7 in vivo. RAW264.7 cells were pretreated with different concentrations of UTI and ERK5 inhibitors, and the expression of tyrosine-protein kinase Mer (Mer) protein on macrophage membrane was detected. UTI increased the phagocytosis of apoptotic neutrophils by macrophages in vitro and in vivo, and promoted the resolution of pneumonia. The protein expression of ERK5 and Mer increased with UTI concentration, while the expression of Mer was down-regulated by ERK5 inhibitors. Therefore, our results suggest that UTI enhances efferocytosis and reduces lung inflammation and injury through the ERK5/Mer signaling pathway, which may be one of the targets of UTI in the treatment of lung injury.

Primary tracheal obstruction caused by adenoid cystic carcinoma during pregnancy: A case report.

The incidence of malignant tumors diagnosed during pregnancy is increasing, often ascribed to the recently recognized trend that many women are postponing childbirth. Although early diagnosis is optimal for both mothers and fetuses, the diagnosis of malignant tumors during pregnancy is often delayed until an advanced stage, because generalized symptoms of pregnancy and malignancy may overlap, such as shortness of breath, chest or abdominal discomfort. The study patient was 21 years old, and 31 weeks-pregnant when she was diagnosed with primary tracheal adenoid cystic carcinoma (ACC). The patient initially presented with dyspnea and decreased blood oxygen saturation and underwent a cesarean section on the first night of hospitalization, resulting from fetal distress. This case report intended to investigate potential barriers to the timely diagnosis of tracheal ACC and consider optimal management strategies when it is diagnosed during pregnancy.

Effect of dexmedetomidine on perioperative hemodynamics and organ protection in children with congenital heart disease: A randomized controlled trial.

BACKGROUND: This study aimed to investigate the effects of dexmedetomidine (Dex) on hemodynamics and organ protection in congenital heart disease (CHD) children who underwent open-heart surgery under cryogenic cardiopulmonary bypass. METHODS: Ninety children were randomly allocated to group C (0.9% saline 0.2 µg/kg/hour), group D1 (Dex 0.2 µg/kg/hour), and group D2 (Dex 0.4 µg/kg/hour) (n = 30 per group). All participants received fentanyl, propofol and 1% sevoflurane for anesthesia induction. Hemodynamic data were measured from T0 (before the induction) to T7 (30 minutes after extubation). The difference of arterial internal jugular vein bulbar oxygen difference and cerebral oxygen extraction ratio were calculated according to Fick formula. Enzyme-linked immunosorbent assay was performed to detect the serum myocardial, brain and kidney injury markers. The incidence of acute kidney injury (AKI) was calculated by serum creatinine level. Tracheal extubation time, postoperative pain score and emergence agitation score were also recorded. RESULTS: Compared with group C, group D1, and D2 exhibited reduction in hemodynamic parameters, myocardial and brain injury indicators, and tracheal extubation time. There were no significant differences in blood urea nitrogen and neutrophil gelatinase-associated lipocalin or incidence of AKI among the 3 groups. Besides, the incidence of tachycardia, nausea, vomiting and moderate agitation, and the FLACC scale in group D1 and D2 were lower than those in group C. Moreover, Dex 0.4 g/kg/hour could further reduce the dosage of fentanyl and dopamine compared with Dex 0.2 g/kg/hour. CONCLUSIONS: Dex anesthesia can effectively maintain hemodynamic stability and diminish organ injuries in CHD children.

Effect of different administration and dosage of dexmedetomidine in the reduction of emergence agitation in children: a meta-analysis of randomized controlled trials with sequential trial analysis.

BACKGROUND: Beneficial effects of dexmedetomidine (DEX) against emergence agitation (EA) in children remain controversial. We performed a more comprehensive meta-analysis to evaluate the protective effect of different administration routes, timing, patterns, and doses of DEX on EA in children. METHODS: The randomized controlled trials about DEX preventing EA in children were searched in PubMed, Cochrane Library, Embase, and Web of Sciences up to October 7, 2020. The traditional meta-analysis and subgroup analysis were performed to study the influence of DEX on EA in children. The sequential trial analysis (TSA) further analyzed the pooled results to evaluate meta-analyses' robustness. Grading of recommendation, assessment, development, and evaluation (GRADE) was used to assess evidence quality. RESULTS: Sixty-seven studies with 5,688 pediatric patients were included. DEX significantly decreased EA in children compared to placebo [RR 0.29, 95% confidence intervals (CI): 0.25-0.34] and midazolam (RR 0.34, 95% CI: 0.25-0.45), with firm evidence from TSA. Notably, using DEX significantly reduced severe EA incidence (RR 0.23, 95% CI: 0.16-0.32), with firm evidence by TSA and high quality of GRADE. Pre-specified subgroup analyses revealed firm and high-quality evidence for a reduction of EA, only if the perineural route administers DEX (RR 0.24, 95% CI: 0.14-0.41), as premedication (RR 0.27, 95% CI: 0.20-0.36), as continuous dosage (RR 0.25, 95% CI: 0.18-0.33), at high dose (RR 0.24, 95% CI: 0.18-0.31). The pooled results also showed that DEX reduced the incidence of PONV compared to placebo (RR 0.43, 95% CI: 0.33-0.55). Evidence for DEX's influence on other secondary outcomes (emergence time, time in PACU, rescue analgesia, hypotension, and bradycardia) is insufficient to draw any conclusion. CONCLUSIONS: Our findings confirm the beneficial effects of DEX on EA, severe EA, and PONV in children. There was firm and high-quality evidence for the efficacy of DEX in preventing EA in children when perineural routes administered DEX, as premedication, as continuous dosage, and at a high dose. The best dose, route, patterns, and timing of DEX and influence on other outcomes call for further studies.

Perioperative dexmedetomidine and postoperative delirium in non-cardiac surgery: a meta-analysis.

BACKGROUND: To compare the effects of perioperative dexmedetomidine with placebo (or other sedation) on the rate of postoperative delirium in adult patients who underwent non-cardiac surgeries. METHODS: A meta-analysis was performed on randomized, controlled trials. MEDLINE, the Cochrane Central Register of Controlled Trials, and Embase (to March 20, 2019) were searched for literature retrieval. The standardized primary outcome was postoperative delirium. We pooled risk ratios using a random-effects model. RESULTS: From 10 trials with 2,286 total participants, we recorded 363 postoperative delirium events during the follow-up periods. Compared with the control group, patients in the dexmedetomidine group had a postoperative delirium relative risk of 0.53 [95% confidence interval (CI), 0.37-0.76]. When the dexmedetomidine infusion rate was higher than 0.2 µg/kg/h, the relative risk of postoperative delirium reduced significantly by 34%, compared with other sedation methods (relative risk =0.66; 95% CI, 0.47-0.94; P=0.02), with no heterogeneity (I²=31%, P=0.18). While it reduced by 62% when the dexmedetomidine infusion rate was lower than 0.2 µg/kg/h (relative risk =0.38; 95% CI, 0.27-0.54). CONCLUSIONS: Compared to the placebo (or other sedation methods), perioperative dexmedetomidine sedation resulted in lower rates of postoperative delirium in adult patients who underwent non-cardiac surgery.