Inhaled Pro-Efferocytic Nanozymes Promote Resolution of Acute Lung Injury.

Acute lung injury (ALI) is a significant contributor to the morbidity and mortality of sepsis. Characterized by uncontrolled inflammation and excessive inflammatory cells infiltration in lung, ALI has been exacerbated by impaired efferocytosis (clearance of apoptotic cells by macrophages). Through specific receptor recognition and activation of downstream signaling, efferocytic macrophages promote resolution of inflammation by efficiently engulfing dying cells, avoiding the consequent release of cellular inflammatory contents. Here, inspired by the intrinsic recovery mechanism of efferocytosis, an apoptotic cell membrane (ACM) coated antioxidant nanozyme (AOzyme) is engineered, thus obtaining an inhalable pro-efferocytic nanozyme (AOzyme@ACM). Notably, AOzyme@ACM can efficiently increase apoptotic cell removal by combing enhanced macrophages recognition of "eat me" signals through apoptotic body mimicking and scavenge of intracellular excessive reactive oxygen species (ROS), a significant barrier for efferocytosis. AOzyme@ACM can significantly inhibit inflammatory response, promote pro-resolving (M2) phenotype transition of macrophage, and alleviate ALI in endotoxemia mice compared with AOzyme group. By addressing the critical factor in the pathogenesis of sepsis-related ALI through restoring efferocytosis activity, the ACM-based antioxidant nanozyme in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury.

BACKGROUND: Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear. METHODS: Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mϕ) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved. RESULTS: Exosomes released by TNF-α-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor κB (NF-κB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions. CONCLUSIONS: The present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.

Driving Pressure-Guided Individualized Positive End-Expiratory Pressure in Abdominal Surgery: A Randomized Controlled Trial.

BACKGROUND: The optimal positive end-expiratory pressure (PEEP) to prevent postoperative pulmonary complications (PPCs) remains unclear. Recent evidence showed that driving pressure was closely related to PPCs. In this study, we tested the hypothesis that an individualized PEEP guided by minimum driving pressure during abdominal surgery would reduce the incidence of PPCs. METHODS: This single-centered, randomized controlled trial included a total of 148 patients scheduled for open upper abdominal surgery. Patients were randomly assigned to receive an individualized PEEP guided by minimum driving pressure or an empiric fixed PEEP of 6 cm H2O. The primary outcome was the incidence of clinically significant PPCs within the first 7 days after surgery, using a χ2 test. Secondary outcomes were the severity of PPCs, the area of atelectasis, and pleural effusion. Other outcomes, such as the incidence of different types of PPCs (including hypoxemia, atelectasis, pleural effusion, dyspnea, pneumonia, pneumothorax, and acute respiratory distress syndrome), intensive care unit (ICU) admission rate, length of hospital stay, and 30-day mortality were also explored. RESULTS: The median value of PEEP in the individualized group was 10 cm H2O. The incidence of clinically significant PPCs was significantly lower in the individualized PEEP group compared with that in the fixed PEEP group (26 of 67 [38.8%] vs 42 of 67 [62.7%], relative risk = 0.619, 95% confidence intervals, 0.435-0.881; P = .006). The overall severity of PPCs and the area of atelectasis were also significantly diminished in the individualized PEEP group. Higher respiratory compliance during surgery and improved intra- and postoperative oxygenation was observed in the individualized group. No significant differences were found in other outcomes between the 2 groups, such as ICU admission rate or 30-day mortality. CONCLUSIONS: The application of individualized PEEP based on minimum driving pressure may effectively decrease the severity of atelectasis, improve oxygenation, and reduce the incidence of clinically significant PPCs after open upper abdominal surgery.

Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock.

BACKGROUND: Platelets have been demonstrated to be potent activators of neutrophil extracellular trap (NET) formation during sepsis. However, the mediators and molecular pathways involved in human platelet-mediated NET generation remain poorly defined. Circulating plasma exosomes mostly originating from platelets may induce vascular apoptosis and myocardial dysfunction during sepsis; however, their role in NET formation remains unclear. This study aimed to detect whether platelet-derived exosomes could promote NET formation during septic shock and determine the potential mechanisms involved. METHODS: Polymorphonuclear neutrophils (PMNs) were cocultured with exosomes isolated from the plasma of healthy controls and septic shock patients or the supernatant of human platelets stimulated ex vivo with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). A lethal cecal ligation and puncture (CLP) mouse model was used to mimic sepsis in vivo; then, NET formation and molecular pathways were detected. RESULTS: NET components (dsDNA and MPO-DNA complexes) were significantly increased in response to treatment with septic shock patient-derived exosomes and correlated positively with disease severity and outcome. In the animal CLP model, platelet depletion reduced plasma exosome concentration, NET formation, and lung injury. Mechanistic studies demonstrated that exosomal high-mobility group protein 1 (HMGB1) and/or miR-15b-5p and miR-378a-3p induced NET formation through the Akt/mTOR autophagy pathway. Furthermore, the results suggested that IκB kinase (IKK) controls platelet-derived exosome secretion in septic shock. CONCLUSIONS: Platelet-derived exosomes promote excessive NET formation in sepsis and subsequent organ injury. This finding suggests a previously unidentified role of platelet-derived exosomes in sepsis and may lead to new therapeutic approaches.

Intraoperative monitoring of nociception for opioid administration: a meta-analysis of randomized controlled trials.

INTRODUCTION: Under-dosage or over-dosage of intraoperative analgesia can cause harm to patients. Many studies have demonstrated the clinical advantages of nociception monitoring tools, but with some conflicting results. To clarify the issue, this meta-analysis compared the effects of Analgesia Nociception Index (ANI), Surgical Pleth Index (SPI), and pupillometry monitoring methods with those of analgesia management practices of intraoperative opioid administration. EVIDENCE ACQUISITION: A comprehensive literature search was conducted to identify clinical trials that compared the effect of monitoring of nociception-antinociception balance (versus clinical signs) on intraoperative opioid administration. Meta-analysis was performed for intraoperative opioid administration, postoperative pain and rescue opioid consumption separately using fixed-effects model and random effects model. In addition, a subgroup analysis was also performed to determine the effects of age, study quality, anesthesia regimen, and nociception monitoring devices on intraoperative opioid administration. EVIDENCE ANALYSIS: Ten studies that used ANI, SPI, or pupillometry for intraoperative opioid guidance were identified. As a principle finding, nociception measurement-guided analgesia reduced intraoperative opioid consumption compared with conventional analgesia. In adults, SPI-guided intraoperative opioid administration was lower than conventional analgesia, whereas the difference between ANI-guided analgesia and standard clinical care was not statistically significant. Furthermore, in adults, anesthetized with sevoflurane, nociception monitoring decreased intraoperative analgesia doses. CONCLUSIONS: Nociception monitoring devices seem to have an advantage over standard clinical practice on intraoperative management of analgesia during general anesthesia. Future research should focus on identifying appropriate indicators to objectively assess the degree of pain in children and perform large-scale multicenter trials to prove clinical advantages of nociception measurements during propofol anesthesia.

Aging-related Atg5 defect impairs neutrophil extracellular traps formation.

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.

Preemptive analgesia effects of ketamine in patients undergoing surgery. A meta-analysis.

PURPOSE: To evaluate the preemptive analgesia effects of ketamine for postoperative pain. METHODS: PubMed, EMBASE and Cochrane Library were searched to identify randomized controlled trials (RCTs) involved in ketamine for preemptive analgesic up to March 2013. The relative risk (RR) or mean difference (MD) as well as the confounding 95% confidence interval (CI) were calculated by the Revman 5.0 software. RESULTS: A total of five studies including 266 patients were included in this meta-analysis. Overall, ketamine could reduce the postoperative morphine consumption and significantly prolong the time to first analgesic (p < 0.00001, MD = 0.91, 95% CI: 0.56 to 1.26). However, there was no significant difference in indicators of nausea and vomiting (p = 0.87, RR = 1.04, 95% CI: 0.67 to 1.60), surgical time (p = 0.41, MD = -2.13, 95% CI: -7.21 to 2.95) and anesthetic time (p = 0.53, MD = -1.54, 95% CI: -6.34 to -3.26) between ketamine and control group. CONCLUSIONS: Ketamine was able to accomplish some preemptive analgesic effects of reducing postoperative morphine consumption and prolonging the time to first analgesic. Meanwhile, ketamine was as safe as physiological saline in side effects of nausea and vomiting.

Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner.

Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 µM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 µM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

Preemptive analgesia effects of Ketamine in patients undergoing surgery. A meta-analysis

PURPOSE: To evaluate the preemptive analgesia effects of ketamine for postoperative pain. METHODS: PubMed, EMBASE and Cochrane Library were searched to identify randomized controlled trials (RCTs) involved in ketamine for preemptive analgesic up to March 2013. The relative risk (RR) or mean difference (MD) as well as the confounding 95% confidence interval (CI) were calculated by the Revman 5.0 software. RESULTS: A total of five studies including 266 patients were included in this meta-analysis. Overall, ketamine could reduce the postoperative morphine consumption and significantly prolong the time to first analgesic (p < 0.00001, MD = 0.91, 95% CI: 0.56 to 1.26). However, there was no significant difference in indicators of nausea and vomiting (p = 0.87, RR = 1.04, 95% CI: 0.67 to 1.60), surgical time (p = 0.41, MD = -2.13, 95% CI: -7.21 to 2.95) and anesthetic time (p = 0.53, MD = -1.54, 95% CI: -6.34 to -3.26) between ketamine and control group. CONCLUSIONS: Ketamine was able to accomplish some preemptive analgesic effects of reducing postoperative morphine consumption and prolonging the time to first analgesic. Meanwhile, ketamine was as safe as physiological saline in side effects of nausea and vomiting. .

Competitive inhibition of the nondepolarizing muscle relaxant rocuronium on nicotinic acetylcholine receptor channels in the rat superior cervical ganglia.

A number of case reports now indicate that rocuronium can induce a number of serious side effects. We hypothesized that these side effects might be mediated by the inhibition of nicotinic acetylcholine receptors (nAChRs) at superior cervical ganglion (SCG) neurons. Conventional patch clamp recordings were used to study the effects of rocuronium on nAChR currents from enzymatically dissociated rat SCG neurons. We found that ACh induced a peak transient inward current in rat SCG neurons. Additionally, rocuronium suppressed the peak ACh-evoked currents in rat SCG neurons in a concentration-dependent and competitive manner, and it increased the extent of desensitization of nAChRs. The inhibitory rate of rocuronium on nAChR currents did not change significantly at membrane potentials between -70 and -20 mV, suggesting that this inhibition was voltage independent. Lastly, rocuronium preapplication enhanced its inhibitory effect, indicating that this drug might prefer to act on the closed state of nAChR channels. In conclusion, rocuronium, at clinically relevant concentrations, directly inhibits nAChRs at the SCG by interacting with both opened and closed states. This inhibition is competitive, dose dependent, and voltage independent. Blockade of synaptic transmission in the sympathetic ganglia by rocuronium might have potentially inhibitory effects on the cardiovascular system.

Prophylactic midazolam and clonidine for emergence from agitation in children after emergence from sevoflurane anesthesia: a meta-analysis.

BACKGROUND: Emergence agitation (EA) after emergence from sevoflurane anesthesia is a common phenomenon in children. The efficacy of prophylactic midazolam or clonidine in preventing EA is controversial. OBJECTIVE: We performed a meta-analysis of clinical trials of the 2 drugs to evaluate their ability to prevent EA in pediatric patients after emergence from sevoflurane anesthesia. METHODS: A comprehensive literature search was conducted to identify clinical trials that observed the effect of midazolam and clonidine on preventing EA in children after their emergence from sevoflurane anesthesia. All data were examined using the Mantel-Haenszel model to calculate the pooled odds ratio (OR) and 95% CI. I(2) was used to assess heterogeneity. Subgroup analysis was used to assess the effects of preoperative analgesics, routes of administration, and dose, and funnel plots were used to check publication bias. RESULTS: After a comprehensive literature search, we found 12 papers that met the criteria for inclusion in this analysis, with a total of 447 children in the midazolam group and 767 children in the clonidine group. We found that both midazolam and clonidine decreased the incidence of EA (OR = 0.45 [95% CI, 0.29-0.70], P = 0.0004, I(2) = 46%; and OR = 0.24 [95% CI, 0.13-0.43], P < 0.00001, I(2) = 48%, respectively). Subgroup analysis indicated that preoperative analgesia may decrease the effect of midazolam against EA, whereas for clonidine, neither the route of administration (intravenous or caudal) nor the dose affected the results. Funnel plots did not detect publication bias in the midazolam group, but a bias was detected in the clonidine group. CONCLUSIONS: This meta-analysis suggests that prophylactic administration of midazolam or clonidine could significantly decrease the incidence of sevoflurane-induced EA in pediatric patients.