Macrophage-mediated regulation of catecholamines in sympathetic neural remodeling after myocardial infarction.

Sympathetic neural remodeling, which involves the inflammatory response, plays an important role in ventricular arrhythmias (VAs) after myocardial infarction (MI). Adrenergic receptors on macrophages potentially modulate the inflammatory response. We hypothesized that the increased level of catecholamines activates macrophages and regulates sympathetic neural remodeling after MI. We treated MI mice with either clodronate or metoprolol for 5 days following coronary artery ligation. Mice without treatment after MI and sham-operation mice served as the positive control and negative control, respectively. The norepinephrine levels in plasma and the peri-infarct myocardium increased by almost two-fold in the MI mice compared with the sham-operation mice. Both in vivo and ex vivo electrophysiology examinations showed that the vulnerability to VAs induced by MI was alleviated by macrophage depletion with clodronate and ß1-adrenergic blockade with metoprolol, which was in line with circulating and peri-infarct norepinephrine levels, sympathetic reinnervation, and the expression of nerve growth factor (NGF) 7 days after surgery. To further verify the interaction between catecholamines and macrophages, we preconditioned lipopolysaccharide-stimulated RAW 264.7 cells using epinephrine or epinephrine with selective adrenergic antagonists. The expression and release of inflammatory factors including NGF were enhanced by epinephrine. This effect was inhibited by metoprolol but not by other subtype antagonists. Our data suggested that the increased level of catecholamines, traditionally known as positive inotropes secreted from sympathetic nerve endings, might regulate cardiac sympathetic neural remodeling through ß1-adrenergic receptors on macrophages, subsequently inducing VAs after MI.

Clinical outcomes and anesthetic management of pregnancies with placenta previa and suspicion for placenta accreta undergoing intraoperative abdominal aortic balloon occlusion during cesarean section.

BACKGROUND: This retrospective study aimed to compare the clinical outcomes of parturients with placenta previa (PP) and placenta accreta (PA) according to their severity, when they were managed with intraoperative abdominal aortic balloon occlusion (IAABO) during cesarean section. METHODS: We retrospectively examined 57 cases of PP and suspicion for PA in which IAABO was performed during cesarean section between April 2014 and June 2016. Based on preoperative examination and clinical risk factors, patients were divided into the low suspicion PA group and the high suspicion PA group. We compared the demographic characteristics, methods of anesthesia, intra- and postoperative parameters, and maternal and neonatal outcomes. RESULTS: The two groups showed similar demographic characteristics and intraoperative outcomes. Four women underwent cesarean hysterectomy. Eight neonates were admitted to the neonatal intensive care unit and three did not survive. Neonatal Apgar scores were significantly higher in the low suspicion PA group. Eight patients experienced postoperative femoral artery thrombosis and one patient complicated hematoma in the front wall of the common femoral artery. Patients who received neuraxial anesthesia showed significantly lower intraoperative blood loss, lower intraoperative, postoperative and total blood transfusion and shorter surgery than patients who received general anesthesia. CONCLUSIONS: Our data suggested that the severity of aberrant placental position does not affect intraoperative blood loss during a cesarean section while the IAABO is performed. We propose that neuraxial anesthesia is preferred for conducting these surgeries without contraindications.

Intraoperative Implantation of Temporary Endocardial Pacing Catheter During Thoracoscopic Redo Tricuspid Surgery.

BACKGROUND: The placement of a temporary epicardial pacing wire is a challenge during a minimally invasive redo cardiac operation. The aim of this study is to assess the application of temporary endocardial pacing in patients who underwent minimally invasive redo tricuspid surgery. METHODS: Perioperative data of consecutive patients who underwent thoracoscopic redo tricuspid surgery were collected. All the tricuspid surgeries and combined procedures were performed under peripheral cardiopulmonary bypass without aortic cross-clamping. A sheath was introduced into the right jugular vein beside the percutaneous superior vena cava cannula and a temporary endocardial pacing catheter was guided into the right ventricle via the sheath prior to the right atrial closure. The pacemaker was connected and run as needed during or after operation. RESULTS: A total of 33 patients who underwent thoracoscopic redo tricuspid surgery were enrolled. Symptomatic tricuspid valve regurgitation (93.9%) and tricuspid valvular prosthesis obstruction (6.1%) after previous cardiac operations were noted as indications for a redo surgery. The mean time from previous cardiac operation to this time redo surgery was 13.3±6.4years. Isolated tricuspid valve replacement was performed in 18 patients (54.5%) and tricuspid valve plasty combined with or without mitral valve replacement was performed in 15 patients (45.5%). A temporary endocardial pacing catheter was successfully placed in the right ventricle for all patients with good sensing and pacing. No temporary pacing related complications occurred from insertion to removal of pacing catheter in the patients. CONCLUSIONS: This application of temporary endocardial pacing provided a safe and effective substitute for epicardial pacing in patients who underwent minimally invasive redo tricuspid surgery.

A randomized comparison of pediatric-sized Streamlined Liner of Pharyngeal Airway and Laryngeal Mask Airway-Unique in paralyzed children.

BACKGROUND: The pediatric-sized Streamlined Liner of Pharyngeal Airway (SLIPA) is a new supraglottic airway device for children. AIMS: The aim of this study was to compare the clinical performance of the pediatric-sized SLIPA with the Laryngeal Mask Airway-Unique in paralyzed children under positive pressure-controlled ventilation (PCV). METHODS: One hundred children, aged 2 months to 12 years with American Society of Anesthesiologists physical status I-II were enrolled and randomly allocated to the SLIPA group or the Laryngeal Mask Airway-Unique group (50 patients in each group). The primary outcome variable was oropharyngeal leak pressure. Other outcome variables were first insertion success rate, insertion time, minor airway interventions required for successful insertion, intraoperative dislodgement, ventilatory data, and perioperative complications. RESULTS: The insertion characteristics, ventilation data, and perioperative complications were comparable between the two groups. The leak pressure of the SLIPA was significantly higher than that of the Laryngeal Mask Airway-Unique [median (IQR): 25 (22-30) cm H2O vs. 21 (19-26) cm H2O, respectively; mean ± sd: 25.3 ± 4.6 cm H2O vs. 22.6 ± 4.8 cm H2O, respectively; P = 0.006]. The incidence of intraoperative dislodgment was significantly lower in the SLIPA group than in the Laryngeal Mask Airway-Unique group (0 vs. 6 patients, respectively; P = 0.027). CONCLUSIONS: In conclusion, both the SLIPA and the Laryngeal Mask Airway-Unique can be used effectively without severe complications in paralyzed children. Additionally, the SLIPA provides a better airway seal and better intraoperative position stability than the Laryngeal Mask Airway-Unique.

Effect of intraoperative and/or postoperative esketamine administration on preventing postpartum depression: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the impact of intraoperative and/or postoperative esketamine application on the prevention of postpartum depression (PPD). PubMed, Embase, and Web of Science were thoroughly searched for eligible randomized controlled trials (RCTs) regarding the application of esketamine for postnatal depression prevention. Nine RCTs including 1277 participants were involved in the final analysis. It was found that intraoperative and/or postoperative administration of esketamine significantly reduced the PPD incidence and the Edinburgh Postnatal Depression Scores in the early postoperative period. Meanwhile, esketamine lowered the occurrence of postoperative nausea and vomiting with no influence on other psychiatric symptoms.

A novel method for SLIPA™ size selection, for adult patients, on the basis of chamber length.

PURPOSE: Nowadays the size of the streamlined liner of the pharynx airway (SLIPA™) is selected by matching the width of the thyroid cartilage of the patient to the widest dimension of the SLIPA™. The objective of this work was to improve the method of selection by matching the distance between the otobasion inferius and the most inferior margin of the cricoid cartilage (O-C) to the length of the SLIPA™ chamber. METHODS: 100 patients (ASAI-II) scheduled to undergo operations under general anesthesia were randomly divided into two groups, group A (size selected by matching O-C with SLIPA™ chamber length, n = 50) and group B (size selected by matching the width of the thyroid cartilage with the widest dimension of the SLIPA™, n = 50). We measured the distance between the nasopharynx and the interarytenoid fold (N-I) and investigated the correlation between O-C and N-I at the neutral head position. Number of attempts, insertion time, blood on the device, leakage, and the need to change sizes were assessed. RESULTS: A positive correlation (r = 0.68, p < 0.05) was detected between N-I and O-C. Leakage was observed in 6 % (n = 3) of group A patients and in 20 % (n = 10) of group B patients (p < 0.05). CONCLUSION: Compared with the classic size-selection method, matching the width of the thyroid cartilage with that of the SLIPA™, the size-selection method of matching SLIPA™ chamber length to O-C for adult patients is more accurate.

Efficacy and safety of ciprofol versus propofol for the induction of anesthesia in adult patients: a multicenter phase 2a clinical trial.

BACKGROUND: Ciprofol is a novel 2, 6-disubstituted phenolic derivative anesthetic that binds to the gamma-aminobutyric acid-A receptor. AIM: To determine the equally potent dose of ciprofol compared with propofol as an induction agent for general anesthesia in patients undergoing selective surgery, and to assess its safety. METHOD: A total of 109 patients undergoing selective non-emergency, non-cardiothoracic or non-neurosurgical surgery requiring tracheal intubation for general anesthesia were enrolled. Ten patients per group were assigned to ciprofol-0.3, 0.4 and 0.5 mg/kg, and propofol-2.0 or 2.5 mg/kg groups, respectively to receive an intravenous bolus dose. An additional 20 patients were enrolled in the ciprofol-0.3, 0.5 or propofol-2.0 mg/kg groups. The primary outcome was the success rate of induction defined as a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) ≤ 1 after the initial bolus dose. The secondary outcomes included the time to reach MOAA/S ≤ 1, the time to loss of the eyelash reflex, the incidences and severity of adverse events (AEs). RESULTS: The success rates were 100% for all 5 groups. The mean time to MOAA/S ≤ 1 and the time to loss of the eyelash reflex were not different among the 5 groups, regardless of whether a top-up dose was needed. There were no significant differences in the incidences and severity of AEs in the dose ranges investigated of ciprofol vs. propofol. CONCLUSION: The efficacy and safety of a single bolus dose of ciprofol-0.5 mg/kg for the general anesthesia induction in selective surgery patients was comparable to that of propofol-2.0 mg/kg. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03698617, retrospectively registered.

[Effect of Penehyclidine hydrochloride in systemic inflammatory response syndrome caused by cardiopulmonary bypass].

OBJECTIVE: To investigate whether Penehyclidine hydrochloride has effect on the inflammatory process and leukocytes in cardiac surgery patients undergoing cardiopulmonary bypass. METHODS: 40 rheumatic heart disease patients undergoing CPB were randomly divided into Penehyclidine hydrochloride (P) group and control (C) group (20 patients in each group). In group P, intravenous drip of 0.01 mg/kg of Penehyclidine hydrochloride injection was given before anesthesia, and 0. 015 mg/kg of Penehyclidine hydrochloride was added into initial volume of CPB. While in control group, 0.9% NaCl solution was given instead of injection as a placebo. Blood samples were taken before anesthesia (T0), 30 min after CPB (T1), 10 min after aortic off-clamping (T2) and 2 hours when CPB was over (T3). Interleukin-6 (IL-6), tumornecross alpha (TNF-alpha) levels were detected by ELISA. The morbility of pneumonia and SIRS caused by CPB was also evaluated. RESULTS: At T2 and T3, the IL-6 level was higher than T0 and T1 both in group C and group P (P < 0.05). At T2 and T3, the IL-6 level in group C was higher than that of group P (P < 0.05). The TNF-alpha level at T3 was lower than at T1 and T2 in group P (P < 0.05). There was no significant difference between group P and group C at each time point (P > 0.05). The morbility of pneumonia and SIRS was higher in group C (P < 0.05). CONCLUSION: Penehyclidine hydrochloride can decrease the levels of proinflamnlatory cytokines in plasma and therefore attenuate the morbility of pneumonia and SIRS caused by CPB.

Efficacy and Safety of HSK3486 for Anesthesia/Sedation in Patients Undergoing Fiberoptic Bronchoscopy: A Multicenter, Double-Blind, Propofol-Controlled, Randomized, Phase 3 Study.

BACKGROUND: Fiberoptic bronchoscopy is a complex procedure with the need for sufficient patient anesthesia/sedation while maintaining safety. This trial aimed to evaluate the efficacy, safety, and pharmacokinetics of HSK3486 during fiberoptic bronchoscopy. METHODS: This multicenter, double-blind, randomized, non-inferiority, parallel-group phase 3 trial was conducted in patients who underwent fiberoptic bronchoscopy. Patients randomly received HSK3486 0.4 mg/kg (N = 134) or propofol 2.0 mg/kg (N = 133). The primary efficacy endpoint was the successful rate of fiberoptic bronchoscopy, and secondary efficacy endpoints included successful induction of anesthesia/sedation, duration, time to being fully alert, and time to patient discharge. Safety assessments and drug concentrations were also measured. RESULTS: A total of 267 patients completed fiberoptic bronchoscopy, with a success rate of 100% and a 95% confidence interval of - 2.8 to 2.8% for the difference between the groups, which met the predesigned criteria of > - 8%, confirming the non-inferiority of anesthesia/sedation produced by HSK3486 compared to propofol. Among the secondary efficacy endpoints, only time to full alertness (median 8.50 vs. 6.00 min, P = 0.012) and time to discharge (median 13.00 vs. 9.87 min, P = 0.002) were slightly longer in the HSK3486 group. The incidence of adverse events was significant lower in the HSK3486 group (52.6 vs. 76.5%, P < 0.001) mainly because of less pain on injection (4.4 vs. 39.4%, P < 0.001) compared to the propofol group. HSK3486 had a similar terminal elimination half-life as propofol. CONCLUSIONS: HSK3486 exhibited non-inferiority anesthesia/sedation compared to propofol in patients undergoing fiberoptic bronchoscopy, and had a good safety profile with a lower incidence of pain on injection. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04111159, registered on 1 October 2019.

Lack of Macrophage Migration Inhibitory Factor Reduces Susceptibility to Ventricular Arrhythmias During the Acute Phase of Myocardial Infarction.

BACKGROUND: Macrophages are involved in inflammatory responses and play a crucial role in aggravating ventricular arrhythmias (VAs) after myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) participates in inflammatory responses during acute MI. In the present study, we hypothesized that knockout (KO) of MIF may prevent VAs during the acute phase of MI by inhibiting macrophage-derived pro-inflammatory mediators. METHODS AND RESULTS: We demonstrated that MIF-KO mice in a mouse model of MI exhibited a significant decrease in susceptibility to VAs both in vivo (84.6% vs 40.7%, P < 0.05) and ex vivo (86.7% vs 40.0%, P < 0.05) at day 3 after MI compared with that in wild-type (WT) mice. Both WT and MIF-KO mice presented similar left ventricular contractility, peri-infarct myocardial fibrosis and sympathetic reinnervation, and circulating and local norepinephrine levels during the acute phase of MI. Meanwhile, MIF-KO mice had inhibited macrophage aggregation, alleviated connexin 43 (Cx43) redistribution, and reduced level of pro-inflammatory mediators, including tumor necrosis factor-α and interleukin-1ß (P < 0.05) at day 3 after MI. The differences in susceptibility to VAs, expression of pro-inflammatory mediators, and Cx43 redistribution after MI between WT and MIF-KO mice disappeared by macrophage depletion with clodronate liposomes in both groups. Furthermore, the pro-inflammatory activity of cultured peritoneal macrophages was inhibited by MIF deficiency and recovered with replenishment of exogenous MIF in vitro. CONCLUSION: In conclusion, we found that lack of MIF reduced the susceptibility to VAs in mouse heart during the acute phase of MI by inhibiting pro-inflammatory activity of macrophages and improving gap-junction and electrical remodeling.

A systematic review and meta-analysis of different mask ventilation schemes on management of general anesthesia in patients with respiratory failure.

BACKGROUND: Difficulty in mask ventilation is one of the more dangerous factors in general anesthesia. The traditional mask has some problems, such as air leakage and facial skin compression injury. The head cover is a new interactive non-invasive ventilation (NIV) model. NIV studies comparing hoods and masks have all been single-center and small-sample randomized trials, and extensive clinical studies are lacking. METHODS: We conducted a computerized search in the databases of PubMed, Embase, Medline, Chinese Biomedical Literature (CBM), and others for randomized controlled trials (RCTs) on the effect of hoods and masks on patients with respiratory failure published since their establishment to March 2021. The quality of the included literature was assessed using the Cochrane Systematic Review Manual, and the data was analyzed using Review Manager 5.3 to assess the risk of bias. RESULTS: A total of 9 articles were included, involving 462 patients, with 233 patients in the hood group and 229 patients in the face mask group. The results of meta-analysis showed the comparative endotracheal intubation rate of the hood group and the mask group [odds ratio (OR) =0.26; 95% confidence interval (CI): 0.14 to 0.47; Z=4.48; P<0.00001], the complications rate (OR =0.54; 95% CI: 0.31 to 0.97; Z=2.08; P=0.04) was statistically considerable, although there was no considerable difference in in-hospital mortality (OR =0.56; 95% CI: 0.28 to 1.14; Z=1.59; P=0.11). DISCUSSION: NIV with a hood can reduce the rate of endotracheal intubation and the incidence of related complications in patients with acute respiratory failure (ARF), which has considerable advantages in contrast to the traditional mask.

Long-Term High-Altitude Exposure Does Not Increase the Incidence of Atrial Fibrillation Associated with Organic Heart Diseases.

Wang, Man, Mengxue Liu, Jia Huang, Dan Fan, Shengzhong Liu, Tao Yu, Keli Huang, Xinchuan Wei, and Qian Lei. Long-term high-altitude exposure does not increase the incidence of atrial fibrillation associated with organic heart diseases. High Alt Med Biol. 22:285-292, 2021. Background: Atrial fibrillation (AF) is one of the most common arrhythmias and is associated with several complications following cardiac surgery. However, the differences in the incidence of AF associated with organic heart diseases between highland and lowland populations have not been comprehensively studied. Methods: In this retrospective study, a total of 2,316 highland and lowland patients who underwent cardiac surgery between January 2013 and December 2018 in a single center were enrolled. According to the altitude of residence, patients were divided into high-altitude (>1,500 m) and low-altitude (<1,500 m) groups. A propensity score matching analysis was performed to estimate the association of lifetime high-altitude exposure with AF. Results: Among the enrolled patients, 239 (10.9%) were from a high-altitude plateau, while 1,946 (89.1%) were from a low-altitude area. There were statistical differences in age, gender, European System for Cardiac Operative Risk Evaluation, and other factors, between the two groups (p < 0.05). According to the propensity score, 237 patients in the high-altitude group were successfully matched to 237 patients in the low-altitude group without significant difference in baseline data (p > 0.05). Among the matched patients, 125 patients (26.4%) suffered from AF, with 66 (27.8%) in the high-altitude group and 59 (24.9%) in the low-altitude group. The incidence of AF was statistically similar between the two groups and not significantly influenced by long-term high-altitude exposure (odds ratio 1.07; 95% confidence interval 0.71-1.60, p > 0.05). Conclusion: Long-term high-altitude exposure did not significantly increase the occurrence of AF in patients with organic heart diseases. Clinical Trial No. ChiCTR1900028612.

Anesthesia of a high-altitude area inhabitant who underwent aortic dissection emergency surgery in a low-altitude area.

Heart surgery in patients from high-altitude areas is more challenging than usual. Few studies have been published on this issue, and none of them have discussed the effect of an altitude change (from high to low altitude) on a patient's physiology or its effects on a patient's perioperative management. Here, we present the case of a 46-year-old man who was a long-time resident of Tibetan area in Sichuan (altitude >3000 m) who underwent Stanford type A aortic dissection emergency surgery on the plain. Anesthetic management occurred through monitoring of the bispectral index (BIS) and transesophageal echocardiography (TEE), and we used a relatively loose fluid hydration strategy. The surgery was performed using cardiopulmonary bypass (CPB), deep hypothermia (DH), and selective antegrade cerebral perfusion. The most prominent anesthesia challenges for these patients are physiological changes due to habitation in an high-altitude environment (chronic hypoxemia), which can cause hyperhemoglobinemia, polycythemia, hypercoagulable blood, and even pulmonary hypertension, cor pulmonale, or congestive heart failure. Optimized perioperative management and close cooperation among the entire cardiac medical team were the key factors in the successful management of this rare case.

A review of the mechanism of the central analgesic effect of lidocaine.

Lidocaine, as the only local anesthetic approved for intravenous administration in the clinic, can relieve neuropathic pain, hyperalgesia, and complex regional pain syndrome. Intravenous injection of lidocaine during surgery is considered as an effective strategy to control postoperative pain, but the mechanism of its analgesic effect has not been fully elucidated. This paper intends to review recent studies on the mechanism of the analgesic effect of lidocaine. To the end, we conducted an electronic search of the PubMed database. The search period was from 5 years before June 2019. Lidocaine was used as the search term. A total of 659 documents were obtained, we included 17 articles. These articles combined with the 34 articles found by hand searching made up the 51 articles that were ultimately included. We reviewed the analgesic mechanism of lidocaine in the central nervous system.

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility.

Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (µ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1ß and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (µ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the ß-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the ß-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that ß-arrestin-2 acts as a functional component of the TLR4 pathway.

Kappa Opioid Receptor on Pulmonary Macrophages and Immune Function.

BACKGROUND: Respiratory failure significantly increases mortality in critically ill patients. While opioids are often used during the perioperative period and in critically ill situations, little is known about how opioids are involved in pulmonary immune function and the inflammatory response. There is currently no clear information on the role of the kappa opioid receptor (KOR) in pulmonary inflammation. Here we evaluate whether KORs are involved in the modulation of lung macrophages by the use of selective KOR agonists in lipopolysaccharide (LPS) activated alveolar macrophages. METHOD: The inflammatory response in rat NR8383 macrophages was induced by stimulation with LPS (100 ng/ml) at different time-points. The effects of the KOR agonists Salvinorin A (SA) and U50488 on inflammatory factors such as nitrite, TNF-α, IL-1ß, iNOS and COX-2 were investigated. Nor-binaltorphimine, a selective KOR antagonist, was used to investigate the specific role of KOR. RESULTS: Stimulation of NR8383 cells with LPS (100 ng/ml) significantly increased the level of TNF-α at 1h, 2h and 6h compared to un-stimulated cells. SA attenuated the inflammatory response by reducing the levels of TNF-α and IL-1ß after LPS treatment. SA co-treatment reduced the elevated levels of NO induced by LPS and also alleviated the over-expression of iNOS and COX-2 within 2 hours after LPS activation, and such effects can be partially blocked by KOR antagonist, nor-binaltorphimine. Similar results from U50488 were observed. CONCLUSION: Our results indicate that KORs may play a critical role in the modulation of the pulmonary inflammatory process by their activation in macrophages. Selective KOR agonists exert their anti-inflammatory effects acutely on lung macrophages, within 1-2 hours of LPS-stimulated inflammation in vitro.

Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats.

The incidence of subarachnoid hemorrhage (SAH) and hazard ratio of death increase with age. Overactivation of microglia contributes to brain damage. This study aimed to investigate the effects of A3 adenosine receptors (A3R) activation on neurofunction and microglial phenotype polarization in the context of SAH in aged rats. The A3R agonist (CI-IB-MECA) and antagonist (MRS1523) were used in the SAH model. Microglia were cultured to mimic SAH in the presence or absence of CI-IB-MECA and/or siRNA for A3R. The neurofunction and status of the microglial phenotype were evaluated. The P38 inhibitor SB202190 and the STAT6 inhibitor AS1517499 were used to explore the signaling pathway. The results showed that SAH induced microglia to polarize to the M(LPS) phenotype both in vivo and in vitro. CI-IB-MECA distinctly skewed microglia towards the M(IL-4) phenotype and ameliorated neurological dysfunction, along with the downregulation of inflammatory cytokines. Knockdown of A3R or inhibition of P38 and/or STAT6 weakened the effects of CI-IB-MECA on microglial phenotypic shifting. Collectively, our findings suggest that activation of A3R exerted anti-inflammatory and neuroprotective effects by regulating microglial phenotype polarization through P38/STAT6 pathway and indicated that A3R agonists may be a promising therapeutic options for the treatment of brain injury after SAH.