Caffeic acid modulates activation of neutrophils and attenuates sepsis-induced organ injury by inhibiting 5-LOX/LTB4 pathway.

BACKGROUND: Sepsis is a critical systemic inflammatory syndrome which usually leads to multiple organ dysfunction. Caffeic acid (CA), a phenolic compound derived from various plants, has been proved to be essential in neuroprotection, but its role in septic organ damage is unclear. This research aimed to investigate whether CA protects against organ injury in a mouse model of cecal ligation and puncture (CLP). METHODS: CA (30 mg/kg) or vehicle was administered by intraperitoneal injection immediately after CLP. The samples of blood, lungs, and livers were collected 24 h later. Organ injury was assessed by histopathological examination (HE staining), neutrophil infiltration (myeloperoxidase fluorescence), oxidative stress levels (MDA, SOD, HO-1), and inflammatory cytokines (TNF-α, IL-1ß, and IL-6) release in lung and liver tissues. Neutrophil extracellular trap (NET) formation was analyzed by immunofluorescence. In vitro experiments were performed to investigate the potential mechanisms of CA using small interfering RNA (siRNA) techniques in neutrophils, and the effect of CA on neutrophil apoptosis was analyzed by flow cytometry. RESULTS: Results showed that CA treatment improved the 7-day survival rate and attenuated the histopathological injury in the lung and liver of CLP mice. CA significantly reduced neutrophil infiltration in the lungs and livers of CLP mice. TNF-α, IL-1ß, IL-6 and LTB4 were reduced in serum, lung, and liver of CA-treated CLP mice, and phosphorylation of MAPK (p38, ERK, JNK) and p65 NF-κB was inhibited in lungs and livers. CA treatment further increased HO-1 levels and enhanced superoxide dismutase (SOD) activity, but reduced malondialdehyde (MDA) levels and NET formation. Similarly, in vitro experiments showed that CA treatment and 5-LOX siRNA interference inhibited inflammatory activation and NET release in neutrophils, suppressed MAPK and NF-κB phosphorylation in LPS-treated neutrophils, and decreased LTB4 and cfDNA levels. Flow cytometric analysis revealed that CA treatment reversed LPS-mediated delayed apoptosis in human neutrophils, and Western blot also indicated that CA treatment inhibited Bcl-2 expression but increased Bax expression. CA treatment did not induce further changes in neutrophil apoptosis, inflammatory activation, and NET release when 5-LOX was knocked down by siRNA interference. CONCLUSIONS: CA has a protective effect on lung and liver injury in a murine model of sepsis, which may be related to inhibition of the 5-LOX/LTB4 pathway.

Histone methyltransferase SETD2 inhibits M1 macrophage polarization and glycolysis by suppressing HIF-1α in sepsis-induced acute lung injury.

Sepsis is a severe syndrome caused by the imbalance of the host response to infection, accompanied by multiple organ damage, especially acute lung injury. SET Domain-Containing 2 (SETD2) is a methyltransferase catalyzing H3 lysine 36 trimethylation (H3K36me3) that regulates multiple biological processes. This study focused on explicating the action of SETD2 on macrophage function in sepsis and the precise mechanism involved. Enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting were used to determine expression. Luciferase reporter assay and chromatin immunoprecipitation assay were conducted to detect the binding of SETD2 or H3K36me3 with the hypoxia-inducible factor 1, alpha subunit (Hif1a) gene. A sepsis-induced acute lung injury model was constructed via cecal ligation and puncture (CLP). SETD2 was decreased in RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Besides, SETD2 suppressed M1 macrophage polarization and glycolysis caused by LPS. HIF-1α was enhanced in RAW 264.7 cells stimulated by LPS and inversely related to SETD2 expression. In addition, SETD2-catalyzed H3K36me3 bound to the Hif1a gene to modulate HIF-1α expression. Furthermore, Hif1a silencing suppressed Setd2 silencing-induced M1 macrophage polarization and glycolysis in RAW 264.7 cells. Moreover, overexpression of Setd2 inhibited CLP-induced lung injury and M1 macrophage polarization in mice. SETD2 suppressed M1 macrophage polarization and glycolysis via regulating HIF-1α through catalyzing H3K36me3 in sepsis.

Goldenhar syndrome complicated with subglottic airway stenosis: a case report.

BACKGROUND: Goldenhar syndrome is a congenital disease that involves an absence or underdevelopment of structures that arise from the first and second pharyngeal arches and more or less severe extracranial anomalies. A variety of supraglottic malformations may be observed, including mandibular hypoplasia, mandibular asymmetry and micrognathia. Subglottic airway stenosis (SGS), which can cause difficulties in airway management during the perioperative period, is seldom emphasized in literature descriptions of Goldenhar syndrome, but can be clinically significant. CASE PRESENTATION: An 18-year-old female with a history of Goldenhar syndrome presented for placement of a right mandibular distractor, right retroauricular dilator, and stage I transfer of a prefabricated expanded flap under general anesthesia. During tracheal intubation, the endotracheal tube (ETT) met resistance unexpectantly when attempting to pass through the glottis. Subsequently, we attempted the procedure with a smaller size ETT but again met resistance. With fiberoptic bronchoscope, we found that the whole segment of the trachea and bilateral bronchi were obvious narrow. Given the finding of unexpected severe airway stenosis and the associated risks with proceeding with the surgery, the operation was cancelled. We removed the ETT once the patient was fully awake. CONCLUSIONS: Anesthesiologists should be aware of this clinical finding when evaluating the airway of a patient with Goldenhar syndrome. Coronal and sagittal measurements on computerized tomography (CT) and three-dimensional image reconstruction can be used to evaluate the degree of subglottic airway stenosis and measure the diameter of the trachea.

ß-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice.

Sepsis-associated encephalopathy (SAE) is one of the common serious complications in sepsis, and the pathogenesis of SAE remains unclear. Sirtuin 1 (SIRT1) has been reported to be downregulated in the hippocampus and SIRT1 agonists can attenuated the cognitive dysfunction in septic mice. Nicotinamide adenine dinucleotide (NAD+) is a key substrate to maintain the deacetylation activity of SIRT1. As an intermediate of NAD+, ß-Nicotinamide Mononucleotide (NMN) has been reported to be promising in treating neurodegenerative diseases and cerebral ischemic injury. Thus we sought to investigate the potential role of NMN in SAE treatment. The SAE model was established by cecal ligation and puncture (CLP) in vivo, and neuroinflammation model was established with LPS-treated BV-2 cells in vitro. Memory impairment was assessed by Morris water maze and fear conditioning tests. As a result, the levels of NAD+, SIRT1 and PGC-1α were significantly reduced in the hippocampus of septic mice, while the acetylation of total lysine, phosphorylation of P38 and P65 were enhanced. All these changes induced by sepsis were inverted by NMN. Treating with NMN resulted in improved behavior performance in the fear conditioning tests and Morris water maze. Apoptosis, inflammatory and oxidative responses in the hippocampus of septic mice were attenuated significantly after NMN administration. These protective effect of NMN against memory dysfunction, inflammatory and oxidative injuries were reversed by the SIRT1 inhibitor, EX-527. Similarly, LPS-induced activation of BV-2 cells were attenuated by NMN, EX-527 or SIRT1 knockdown could reverse such effect of NMN in vitro. In conclusion, NMN is protective against sepsis-induced memory dysfunction, and the inflammatory and oxidative injuries in the hippocampus region of septic mice. The NAD+/SIRT1 pathway might be involved in one of the mechanisms of the protective effect.

PD-L1 promotes GSDMD-mediated NET release by maintaining the transcriptional activity of Stat3 in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE), as shown as acute and long-term cognitive impairment, is associated with increased mortality of sepsis. The causative factors of SAE are diverse and the underlying pathological mechanisms of SAE remain to be fully elucidated. Multiple studies have demonstrated a crucial role of microglia in the development of SAE, but the role of neutrophils and neutrophil extracellular traps (NETs) in SAE is still unclear. Here, we firstly show that in murine sepsis model, neutrophils and NETs promote blood-brain barrier (BBB) disruption, neuronal apoptosis and microglia activation in hippocampus and induce hippocampus-dependent memory impairment. Anti-Gr-1 antibody or DNase I treatment attenuates these sepsis-induced changes. Then, we find that genetic deletion of neutrophil GSDMD or PD-L1 reduces NET release and improves SAE in murine sepsis model. Finally, in human septic neutrophils, p-Y705-Stat3 binds to PD-L1, promotes PD-L1 nuclear translocation and enhances transcription of the gasdermin D (GSDMD) gene. In summary, our findings firstly identify a novel function of PD-L1 in maintaining transcriptional activity of p-Y705-Stat3 to promote GSDMD-dependent NET release in septic neutrophils, which plays a critical role in the development of SAE.

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome.

Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.

Preliminary evaluation of SaCoVLM video laryngeal mask-guided intubation in airway management for anesthetized children.

BACKGROUNDS: To preliminary evaluate the application of novel SaCoVLM video laryngeal mask -guided intubation for anesthetized children. METHODS: One hundred twenty-four children with microtia (ages 5-15 years,) who required general intubation anaesthesia, were enrolled in the study. After induction of general anesthesia,guided tracheal intubation under direct vision of the SaCoVLM was performed. Our primary outcome was first-pass success rate of guided tracheal tube placement. Secondary outcome included glottic visualization grades, the first-attempt success rate of LMA placement, the time for LMA placement and time to endotracheal intubation as well as the time for LMA removal after successful intubation, the fiberoptic grade of laryngeal view, the baseline and postinduction hemodynamic parameters were also recorded,and the incidence 24 h complications after operation. RESULTS: The first-pass success rate of guided tracheal tube placement was 91.1% (95%CI = 1.04-1.14), the status of glottic visualization was classified: grade 1 in 27cases, grade 2 in 36 cases, grade 3 in 41 cases and grade 4 in 20 cases. The first success rate of LMA placement was 92.7% (95%CI = 1.03-1.13), the time for LMA insertion was 15.7 (±9.1) s, intubation time was 30.9 (±17.6) s and withdrawl time was 24.9 (±9.3) s. The incidence of postoperative sore throat at 2 h was 29%, and 16.1% at 24 h, without dysphagia and hypoxia. CONCLUSION: The SaCoVLM video laryngeal mask-guided intubation is feasible in children, with a high success rate, could be a new promising device to guide intubation in airway management. TRIAL REGISTRATION: This study was approved by the University's Institutional Review Board and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (ChiCTR2200061481, http://www.chictr.org.cn . Principal investigator: Juan Zhi; Date of registration: 26/06/2022.

GSDMD-mediated NETosis promotes the development of acute respiratory distress syndrome.

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.

Nicotinamide Mononucleotide Attenuates LPS-Induced Acute Lung Injury With Anti-Inflammatory, Anti-Oxidative and Anti-Apoptotic Effects.

INTRODUCTION: Nicotinamide mononucleotide (NMN) is a nucleotide that is commonly recognized for its role as an intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis with multiple pharmacological effects. The purpose of this study was to evaluate the protective effect of nicotinamide mononucleotide (NMN) against lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: We investigated the effect of NMN on ALI-induced inflammatory response, oxidative stress, and cell apoptosis. The ALI mouse model was performed by injecting LPS intratracheally at a dose of 10 mg/kg in 50 µL saline. Flow cytometry was used to detect neutrophil infiltration in bronchoalveolar lavage fluid (BALF), and ELISA was used to detect the contents of inflammatory cytokines TNF-α, IL-1ß and IL-6 in BALF. Oxidative stress was evaluated by determining the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in lung tissue. ROS formation was analyzed by immunofluorescence. Western blotting was performed to detect apoptotic levels and p38MAPK/NF-κB phosphorylation levels in lung tissue. RESULTS: In the ALI mouse model, NMN showed a significant therapeutic effect compared to the LPS group. NMN attenuated the pathological damage and cell apoptosis in lung tissue, decreased the levels of TNF-α, IL-1ß, and IL-6 in BALF, and reduced the number of total cells and neutrophils in BALF. In addition, NMN attenuated the LPS-induced elevation of dry-to-wet ratio, MDA content, p38 MAPK and p65 NF-κB phosphorylation levels, and the SOD activity was increased by NMN treatment. CONCLUSIONS: In conclusion, the present study showed that NMN exerted a protective effect on LPS-induced ALI with anti-inflammatory, antioxidative, and antiapoptotic effects.

Intubation using video laryngeal mask airway SaCoVLM and laryngeal mask airway Ambu® Aura-i in anesthetized children with microtia: a randomized controlled study.

The Ambu Aura-i laryngeal mask is considered to be a device for blind intubation as well as for fiberoptic guided intubation. The novel video laryngeal airway mask SaCoVLM is a supraglottic airway device that allows intubation under direct vision. We hypothesized that success rates for device placement and tracheal intubation with the SaCoVLM would be comparable with the Ambu Aura-i mask. A prospective, randomized clinical trial was conducted from March 2021 to December 2021. One hundred and twenty patients were enrolled and randomized in the study. Direct intubation was performed with the SaCoVLM, and fiberoptic guided intubation was performed with the Ambu Aura-i mask. The primary outcome measure was the first success rate of LMA placement. Secondary outcome measures were the time from device placement and time from endotracheal intubation (as well as the time for LMA removal after successful intubation), differences in airway leak pressure, fiberoptic grade of the laryngeal view, and incidence of blood staining. The first success rate of LMA placement was similar for the two devices. There was no difference in the time for successful endotracheal intubation between the Ambu Aura-i and SaCoVLM groups (24.1 s ± 6.3 versus 25.7 s ± 2.1; p > 0.05). The time for removal was slower in the SaCoVLM group than in the Ambu Aura-i group (20.8 s ± 0.8 versus 14.7 s ± 6.1; p < 0.01). The airway leak pressure was higher in the SaCoVLM group than in the Ambu Aura-i group (27.0 s ± 1.0 versus 22.3 s ± 3.6; p < 0.01), and the incidence of blood staining was higher in the SaCoVLM group (16.7%). The SaCoVLM has an overall comparable performance to the Ambu Aura-i mask. However, the SaCoVLM is better relative to direct intubation without the assistance of a flexible intubation scope, which reduces the device's demand.

Corrigendum: PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury.

[This corrects the article DOI: 10.3389/fimmu.2022.949217.].

Dysregulation of neutrophil death in sepsis.

Sepsis is a prevalent disease that has alarmingly high mortality rates and, for several survivors, long-term morbidity. The modern definition of sepsis is an aberrant host response to infection followed by a life-threatening organ dysfunction. Sepsis has a complicated pathophysiology and involves multiple immune and non-immune mediators. It is now believed that in the initial stages of sepsis, excessive immune system activation and cascading inflammation are usually accompanied by immunosuppression. During the pathophysiology of severe sepsis, neutrophils are crucial. Recent researches have demonstrated a clear link between the process of neutrophil cell death and the emergence of organ dysfunction in sepsis. During sepsis, spontaneous apoptosis of neutrophils is inhibited and neutrophils may undergo some other types of cell death. In this review, we describe various types of neutrophil cell death, including necrosis, apoptosis, necroptosis, pyroptosis, NETosis, and autophagy, to reveal their known effects in the development and progression of sepsis. However, the exact role and mechanisms of neutrophil cell death in sepsis have not been fully elucidated, and this remains a major challenge for future neutrophil research. We hope that this review will provide hints for researches regarding neutrophil cell death in sepsis and provide insights for clinical practitioners.

Post-cardiopulmonary bypass hypoxaemia in paediatric patients undergoing congenital heart disease surgery: risk factors, features, and postoperative pulmonary complications.

BACKGROUND: Hypoxemia after cardiopulmonary bypass (CPB) is the quantifiable manifestation of pulmonary dysfunction. This retrospective study was designed to investigate the risk factors for post-cardiopulmonary bypass hypoxaemia and the features of hypoxaemia and pulmonary complications in paediatric congenital heart disease surgery involving CPB. METHODS: Data including demographics, preoperative pulmonary or cardiac parameters, and intraoperative interventions were retrospectively collected from 318 paediatric patients who underwent radical surgery with CPB for congenital heart disease. Among them, the factors that were significant by univariate analysis were screened for multivariate Cox regression. The lowest ratio of arterial oxygen tension and the inspiratory oxygen fraction (PaO2/FiO2), hypoxaemia (PaO2/FiO2 ≤ 300) insult time, duration of hypoxaemia, extubation time, and pulmonary complications were also analysed postoperatively. RESULTS: The morbidity of post-cardiopulmonary bypass hypoxaemia was 48.4% (154/318). Months (6 < months ≤ 12, 12 < months ≤ 36 and 36 < months compared with 0 ≤ months ≤ 6: HR 0.582, 95% CI 0.388-0.873; HR 0.398, 95% CI 0.251-0.632; HR 0.336, 95% CI 0.197-0.574, respectively; p < 0.01), preoperative intracardiac right-to-left shunting (HR 1.729, 95% CI 1.200-2.493, p = 0.003) and intraoperative pleural cavity entry (HR 1.582, 95% CI 1.128-2.219, p = 0.008) were identified as independent risk factors for the development of post-cardiopulmonary bypass hypoxaemia. Most hypoxaemia cases (83.8%, 129/154) occurred within 2 h, and the rate of moderate hypoxaemia (100 < PaO2/FiO2 ≤ 200) was 60.4% (93/154). CONCLUSION: The morbidity of post-cardiopulmonary bypass hypoxaemia in paediatric congenital heart disease surgery was considerably high. Most hypoxaemia cases were moderate and occurred in the early period after CPB. Scrupulous management should be employed for younger infants or children with preoperative intracardiac right-to-left shunting or intraoperative pleural cavity entry.

Salvianolic Acid A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Neutrophil NETosis.

Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.

PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury.

Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both in vivo and in vitro. Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS.

Senkyunolide I alleviates renal Ischemia-Reperfusion injury by inhibiting oxidative stress, endoplasmic reticulum stress and apoptosis.

BACKGROUND: Ligusticum striatum DC. is traditionally used to treat ischemic diseases because of its potent effect against blood stasis and thrombosis, including various cardiovascular, cerebral and renal diseases. Senkyunolide I (SEI), which is the major active phthalide ingredient of Ligusticum striatum DC., is mainly distributed in kidney and has been shown to attenuate ischemia reperfusion injury in liver. However, the underlying effect of SEI against renal ischemia-reperfusion injury (IRI) remain unclear. METHODS: Renal ischemia reperfusion mice model was established by clamping bilateral renal pedicles. In vitro oxidative stress model was induced by H2O2. Level of blood urea nitrogen (BUN) and serum creatinine (SCr) was tested for in vivo model evaluation, while cell viability was tested using CCK8 to evaluate in vitro model. SEI solution containing 1% DMSO was injected intraperitoneally in the I/R group, while normal saline containing 1% DMSO injected in the Sham group. Reduced glutathione (GSH) solution containing 1% DMSO was used as a positive control. RESULTS: SEI protected renal function and structural integrity. It reversed the I/R-induced elevation of BUN, SCr levels and renal pathological injury. The secretion of proinflammatory cytokines including TNF-α and IL-6 was inhibited, and the renal apoptosis was attenuated by SEI. In addition, SEI played a protective role by reducing the production of reactive oxidative species (ROS), as shown by the elevated expression of antioxidant proteins including Nrf2, HO-1, NQO1, and reduced expression of endoplasmic reticulum stress (ERS) related proteins including GRP78 and CHOP. It also attenuated HK2 cell injury in an in vitro model induced by H2O2. CONCLUSIONS: SEI alleviates renal injury induced by ischemia reperfusion with anti-inflammatory, anti-endoplasmic reticulum stress, anti-oxidative and anti-apoptotic effect.

Influence of sugammadex versus neostigmine for neuromuscular block reversal on the incidence of postoperative pulmonary complications: a meta-analysis of randomized controlled trials.

BACKGROUND: The influence of sugammadex for reversal of neuromuscular block (NMB) on postoperative pulmonary complications (PPCs), compared with neostigmine, remains to be determined. We performed a meta-analysis of randomized controlled trials (RCTs) to compare the incidence of PPCs between patients who received sugammadex versus neostigmine. METHODS: Relevant studies were obtained by searching the PubMed, Embase, and Cochrane Library databases. A random effects model incorporating the potential heterogeneity was used to pool the results. RESULTS: Fourteen RCTs including 1478 adult patients who underwent surgeries with general anesthesia were included, and of these, 753 received sugammadex and 725 received neostigmine for reversal of NMB. The pooled results showed that sugammadex was associated with a lower risk of overall PPCs compared to neostigmine (odds ratio [OR]: 0.62, 95% confidence interval [CI]: 0.43-0.89, p = 0.01; I2 = 0%). This finding remained consistent after exclusion of two studies with potential overlapping events (OR: 0.58, 95% CI: 0.36-0.96, p = 0.03; I2=9%). Stratified analyses according to the categories of PPCs showed that sugammadex was associated with a significantly lower risk of postoperative respiratory failure (OR: 0.60, 95% CI: 0.38-0.97, p = 0.04; I2 = 0%) but not of postoperative pulmonary infection (OR: 0.79, p = 0.71), atelectasis (OR: 0.78, p = 0.33), or pneumothorax (OR: 0.87, p = 0.79). CONCLUSIONS: Compared with neostigmine, the use of sugammadex for reversal of NMB was associated with a lower risk of PPCs, mainly due to a lower incidence of postoperative respiratory failure with the use of sugammadex.

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis.

PD-L1 is a ligand for PD-1, and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. In this study, PD-L1 expression correlated negatively with rates of apoptosis in human neutrophils harvested from patients with sepsis. Coimmunoprecipitation assays on control neutrophils challenged with interferon-γ and LPS showed that PD-L1 complexes with the p85 subunit of phosphatidyl 3-kinase (PI3K) to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared with wild-type animals, PD-L1-deficient animals presented lower levels of plasma tumor necrosis factor-α and interleukin-6 (IL-6) and higher levels of IL-10 after CLP, and reduced 7-day mortality in CLP PD-L1-knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.

Mechanism of Mitophagy and Its Role in Sepsis Induced Organ Dysfunction: A Review.

Autophagy, an evolutionarily conserved process, plays an important role in maintaining cellular homeostasis under physiological and pathophysiological conditions. It is widely believed that mitochondria influence the development of disease by regulating cellular metabolism. When challenged by different stimuli, mitochondria may experience morphological disorders and functional abnormalities, leading to a selective form of autophagy-mitophagy, which can clear damaged mitochondria to promote mitochondrial quality control. Sepsis is a complex global problem with multiple organ dysfunction, often accompanied by manifold mitochondrial damage. Recent studies have shown that autophagy can regulate both innate and acquired immune processes to protect against organ dysfunction in sepsis. Sepsis-induced mitochondrial dysfunction may play a pathophysiological role in the initiation and progression of sepsis-induced organ failure. Mitophagy is reported to be beneficial for sepsis by eliminating disabled mitochondria and maintaining homeostasis to protect against organ failure. In this review, we summarize the recent findings and mechanisms of mitophagy and its involvement in septic organ dysfunction as a potential therapeutic target.

Dexmedetomidine reduces the incidence of postoperative delirium after cardiac surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: The role of dexmedetomidine in preventing postoperative delirium (POD) after cardiac surgery remains controversial because of several recent trials with negative results. We aimed to perform an updated meta-analysis of randomized controlled trials (RCTs) to clarify this controversy. METHODS: RCTs investigating the perioperative administration of dexmedetomidine in cardiac surgery were retrieved from PubMed, Web of Science, and the Cochrane library until August,27,2020. Two researchers independently screened the literature, collected the data and evaluated the bias risk of the included studies. The meta-analysis was performed with the RevMan 5.3. RESULTS: A total of 15 studies including 2813 patients were included in the study. A pooled result showed that dexmedetomidine could reduce the risk of POD in adult population underwent cardiac surgery (OR 0.56, 95%CI 0.36-0.89, P = 0.0004, I2 = 64%). The subgroup analysis demonstrated that the protective effect of dexmedetomidine was only present in the patients injected with dexmedetomidine after surgery but not from the start of surgery, in the adult patients without specific age limitation but not in the elderly, and in the studies in comparison with other sedatives but not with placebo. There were no statistical differences when analyzing the secondary outcomes including hypotension (OR 1.13; 95% CI 0.54-2.37, P < 0.00001, I2 = 85%), bradycardia (OR 1.72; 95% CI 0.84-3.53, P = 0.04, I2 = 58%) and atrial fibrillation (OR 0.87; 95% CI 0.70-1.08, P = 0.43, I2 = 0). CONCLUSIONS: Dexmedetomidine can reduce the incidence of POD compared to other sedatives and opioids after cardiac surgery in adult patients. The proper population and timing for perioperative use of dexmedetomidine after cardiac surgery remain to be further investigated.