Preconditioning with ß-hydroxybutyrate attenuates lung ischemia-reperfusion injury by suppressing alveolar macrophage pyroptosis through the SIRT1-FOXO3 signaling pathway.

The complex pathogenesis of lung ischemia-reperfusion injury (LIRI) was examined in a murine model, focusing on the role of pyroptosis and its exacerbation of lung injury. We specifically examined the levels and cellular localization of pyroptosis within the lung, which revealed alveolar macrophages as the primary site. The inhibition of pyroptosis by VX-765 reduced the severity of lung injury, underscoring its significant role in LIRI. Furthermore, the therapeutic potential of ß-hydroxybutyrate (ß-OHB) in ameliorating LIRI was examined. Modulation of ß-OHB levels was evaluated by ketone ester supplementation and 3-hydroxybutyrate dehydrogenase 1 (BDH-1) gene knockout, along with the manipulation of the SIRT1-FOXO3 signaling pathway using EX-527 and pCMV-SIRT1 plasmid transfection. This revealed that ß-OHB exerts lung-protective and anti-pyroptotic effects, which were mediated through the upregulation of SIRT1 and the enhancement of FOXO3 deacetylation, leading to decreased pyroptosis markers and lung injury. In addition, ß-OHB treatment of MH-S cells in vitro showed a concentration-dependent improvement in pyroptosis, linking its therapeutic benefits to specific cell mechanisms. Overall, this study highlights the significance of alveolar macrophage pyroptosis in the exacerbation of LIRI and indicates the potential of ß-OHB in mitigating injury by modulating the SIRT1-FOXO3 signaling pathway.

γ-Aminobutyric Acid-Ergic Development Contributes to the Enhancement of Electroencephalogram Slow-Delta Oscillations Under Volatile Anesthesia in Neonatal Rats.

BACKGROUND: General anesthetics (eg, propofol and volatile anesthetics) enhance the slow-delta oscillations of the cortical electroencephalogram (EEG), which partly results from the enhancement of (γ-aminobutyric acid [GABA]) γ-aminobutyric acid-ergic (GABAergic) transmission. There is a GABAergic excitatory-inhibitory shift during postnatal development. Whether general anesthetics can enhance slow-delta oscillations in the immature brain has not yet been unequivocally determined. METHODS: Perforated patch-clamp recording was used to confirm the reversal potential of GABAergic currents throughout GABAergic development in acute brain slices of neonatal rats. The power density of the electrocorticogram and the minimum alveolar concentrations (MAC) of isoflurane and/or sevoflurane were measured in P4-P21 rats. Then, the effects of bumetanide, an inhibitor of the Na + -K + -2Cl - cotransporter (NKCC1) and K + -Cl - cotransporter (KCC2) knockdown on the potency of volatile anesthetics and the power density of the EEG were determined in vivo. RESULTS: Reversal potential of GABAergic currents were gradually hyperpolarized from P4 to P21 in cortical pyramidal neurons. Bumetanide enhanced the hypnotic effects of volatile anesthetics at P5 (for MAC LORR , isoflurane: 0.63% ± 0.07% vs 0.81% ± 0.05%, 95% confidence interval [CI], -0.257 to -0.103, P < .001; sevoflurane: 1.46% ± 0.12% vs 1.66% ± 0.09%, 95% CI, -0.319 to -0.081, P < .001); while knockdown of KCC2 weakened their hypnotic effects at P21 in rats (for MAC LORR , isoflurane: 0.58% ± 0.05% to 0.77% ± 0.20%, 95% CI, 0.013-0.357, P = .003; sevoflurane: 1.17% ± 0.04% to 1.33% ± 0.04%, 95% CI, 0.078-0.244, P < .001). For cortical EEG, slow-delta oscillations were the predominant components of the EEG spectrum in neonatal rats. Isoflurane and/or sevoflurane suppressed the power density of slow-delta oscillations rather than enhancement of it until GABAergic maturity. Enhancement of slow-delta oscillations under volatile anesthetics was simulated by preinjection of bumetanide at P5 (isoflurane: slow-delta changed ratio from -0.31 ± 0.22 to 1.57 ± 1.15, 95% CI, 0.67-3.08, P = .007; sevoflurane: slow-delta changed ratio from -0.46 ± 0.25 to 0.95 ± 0.97, 95% CI, 0.38-2.45, P = .014); and suppressed by KCC2-siRNA at P21 (isoflurane: slow-delta changed ratio from 16.13 ± 5.69 to 3.98 ± 2.35, 95% CI, -18.50 to -5.80, P = .002; sevoflurane: slow-delta changed ratio from 0.13 ± 2.82 to 3.23 ± 2.49, 95% CI, 3.02-10.79, P = .003). CONCLUSIONS: Enhancement of cortical EEG slow-delta oscillations by volatile anesthetics may require mature GABAergic inhibitory transmission during neonatal development.

Risk factors for postoperative urinary retention in patients underwent surgery for benign anorectal diseases: a nested case-control study.

BACKGROUND: Postoperative urinary retention (POUR) is a common complication of anorectal surgery. This study was to determine the incidence of POUR in anorectal surgery for benign anorectal diseases, identify its risk factors, and establish a nomogram for prediction of POUR. METHODS: A nested case-control study was conducted. The clinical data of patients were collected, and the incidence of POUR was analyzed. Univariate analysis was used to identify the risk factors associated with POUR, and multivariate logistic regression analysis was used to determine independent risk factors for POUR. A nomogram for the preoperative prediction of POUR using a logistic regression model was developed (n = 609). RESULTS: The incidence of POUR after anorectal surgery for benign anorectal diseases was 19.05%. The independent risk factors for POUR were: female (P = 0.007); male with benign prostatic hyperplasia (BPH) (P = 0.001); postoperative visual analogue scale (VAS) score > 6 (P = 0.002); patient-controlled epidural analgesia (PCEA) (P = 0.016); and a surgery time > 30 min (P = 0.039). In the nomogram, BPH is the most important factor affecting the occurrence of POUR, followed by a postoperative VAS score > 6, PCEA, surgery time > 30 min, and sex has the least influence. CONCLUSION: For patients undergoing anorectal surgery for benign anorectal diseases, preventive measures can be taken to reduce the risk of POUR, taking into account the following risk factors: female or male with BPH, severe postoperative pain, PCEA, and surgery time > 30 min. Furthermore, we developed and validated an easy-to-use nomogram for preoperative prediction of POUR in anorectal surgery for benign anorectal diseases. TRIAL REGISTRATION: China Clinical Trial Registry: ChiCTR2000039684, 05/11/2020.

Long Noncoding RNA H19 Overexpression Protects against Hypoxic-Ischemic Brain Damage by Inhibiting miR-107 and Up-Regulating Vascular Endothelial Growth Factor.

Long noncoding RNAs play critical roles in cellular homeostasis, and long noncoding RNA H19 (H19) is implicated in several pathologic conditions. The putative role of H19 in the pathogenesis and progression of hypoxic-ischemic brain damage (HIBD) is not yet understood. Therefore, a series of in vivo and in vitro experiments were designed to investigate the potential roles of H19 in neuronal apoptosis and cognitive dysfunction in HIBD. H19 expression was decreased in HIBD rat models established by partial occlusion of carotid artery. H19 bound to and decreased the expression of miR-107, which also increased VEGF expression. H19 overexpression reduced neuronal apoptosis and alleviated cognitive dysfunction in HIBD rats. The up-regulation of miR-107 reversed the protective effects conferred by H19. In addition, the cell model of HIBD was established by oxygen-glucose deprivation in neuronal cells used. H19 overexpression in oxygen-glucose deprivation neurons increased B-cell lymphoma-2 and decreased B-cell lymphoma-2-associated X, total and cleaved caspase-3 expressions. Taken together, the results showed that H19 expresses at a low level in HIBD. H19 overexpression decreased miR-107 and increased VEGF expression, which resulted in repressed neuronal apoptosis and alleviated cognitive dysfunction. Thus, H19 may serve as a molecular target for translational research for HIBD therapy.

Different interventions for preventing postoperative catheter-related bladder discomfort: a systematic review and meta-analysis.

OBJECTIVE: Catheter-related bladder discomfort (CRBD) is a common complication of intraoperative urinary catheterization. Various studies have evaluated the efficacy of different interventions in postoperative CRBD. The present review was performed to assess the efficacy of these interventions. METHODS: PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) databases were systematically searched to identify randomized controlled trials (RCTs) investigating the efficacy of different drugs for the prevention of postoperative CRBD. This review evaluated the incidence and severity of CRBD after different interventions at 0, 1, 2, and 6 h postoperatively. RESULTS: Forty-five studies including 31 different drugs were analyzed. Eleven drugs were investigated in more than two RCTs, of which dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and pudendal nerve block (PNB) generally showed significantly higher efficacy than controls postoperatively. Solifenacin only showed significant efficacy compared with the control at 0 h, and intravenous lidocaine only showed significant efficacy compared with the control at 6 h. There were insufficient trials to draw conclusions regarding atropine, butylscopolamine, chlorpheniramine, clonidine, darifenacin, diphenhydramine, glycopyrrolate, intravesical bupivacaine, ketamine-haloperidol, pethidine-haloperidol, ketorolac, lidocaine-prilocaine cream, magnesium, hyoscine n-butyl bromide, oxycodone, paracetamol, parecoxib, trospium, resiniferatoxin, or amikacin. However, all but pethidine-haloperidol and chlorpheniramine showed some efficacy at various time points compared with controls. CONCLUSION: This review suggests that dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and PNB are effective in preventing postoperative CRBD. Considering the efficacy and adverse effects of all drugs, dexmedetomidine and gabapentin were ranked best.

Can cell salvage be used for resuscitation in a patient with amniotic fluid embolism and hepatic laceration? A case report.

BACKGROUND: Amniotic fluid embolism (AFE) is a rare disease that can lead to profound coagulopathy and hemorrhage, especially when combined with the laceration and bleeding of other organs. Intraoperative cell salvage (ICS) has been widely used for treating obstetric hemorrhage, but it remains unclear whether ICS can be used in the treatment of AFE. CASE PRESENTATION: We report the case of a 27-year-old woman at 39 weeks' gestation who suddenly developed severe abdominal pain, convulsions, loss of consciousness, and decreased vital signs during labor. Despite an emergency cesarean section being performed, the parturient experienced sudden cardiac arrest. Fortunately, the heart rate spontaneously recovered after effective cardiopulmonary resuscitation (CPR). Further abdominal exploration revealed right hepatic laceration with active bleeding. ICS was performed and the salvaged blood was promptly transfused back to the patient. Subsequently, the patient was diagnosed with AFE based on hypotension, hypoxia, coagulopathy, and cardiac arrest. The patient was transfused with 2899 mL salvaged blood during surgery with no adverse effects. At 60- and 90-day follow-ups, no complaints of discomfort or abnormal laboratory test results were observed in the mother or the baby. CONCLUSION: ICS was used to rescue patient with AFE, and ICS did not worsen the condition of patients with AFE. For pregnant women who received CPR, clinicians should explore the presence of hepatic laceration which can be fatal to patients.

Role of Circular RNAs in Pulmonary Fibrosis.

Pulmonary fibrosis is a chronic progressive form of interstitial lung disease, characterized by the histopathological pattern of usual interstitial pneumonia. Apart from aberrant alterations of protein-coding genes, dysregulation of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs), is crucial to the initiation and progression of pulmonary fibrosis. CircRNAs are single-stranded RNAs that form covalently closed loops without 5' caps and 3' tails. Different from canonical splicing of mRNA, they are produced from the back-splicing of precursor mRNAs and have unique biological functions, as well as potential biomedical implications. They function as important gene regulators through multiple actions, including sponging microRNAs and proteins, regulating transcription, and splicing, as well as protein-coding and translation in a cap-independent manner. This review comprehensively summarizes the alteration and functional role of circRNAs in pulmonary fibrosis, with a focus on the involvement of the circRNA in the context of cell-specific pathophysiology. In addition, we discuss the diagnostic and therapeutic potential of targeting circRNA and their regulatory pathway mediators, which may facilitate the translation of recent advances from bench to bedside in the future.

MicroRNA-22-3p alleviates spinal cord ischemia/reperfusion injury by modulating M2 macrophage polarization via IRF5.

Cell death after spinal cord ischemia/reperfusion (I/R) can occur through necrosis, apoptosis, and autophagy, resulting in changes to the immune environment. However, the molecular mechanism of this immune regulation is not clear. Accumulating evidence indicates that microRNAs (miRs) play a crucial role in the pathogenesis of spinal cord I/R injury. Here, we hypothesized miR-22-3p may be involved in spinal cord I/R injury by interacting with interferon regulatory factor (IRF) 5. Rat models of spinal cord I/R injury were established by 12-min occlusion of the aortic arch followed by 48-hr reperfusion, with L4-6 segments of spinal cord tissues collected. MiR-22-3p agomir, a lentivirus-delivered siRNA specific for IRF5, or a lentivirus expressing wild-type IRF5 was injected intrathecally to rats with I/R injury to evaluate the effects of miR-22-3p and IRF5 on hindlimb motor function. Macrophages isolated from rats were treated with miR-22-3p mimic or siRNA specific for IRF5 to evaluate their effects on macrophage polarization. The levels of IL-1ß and TNF-α in spinal cord tissues were detected by ELISA. miR-22-3p was down-regulated, whereas IRF5 was up-regulated in rat spinal cord tissues following I/R. IRF5 was a target gene of miR-22-3p and could be negatively regulated by miR-22-3p. Silencing IRF5 or over-expressing miR-22-3p relieved inflammation, elevated Tarlov score, and reduced the degree of severity of spinal cord I/R injury. Increased miR-22-3p facilitated M2 polarization of macrophages and inhibited inflammation in tissues by inhibiting IRF5, thereby attenuating spinal cord I/R injury. Taken together, these results demonstrate that increased miR-22-3p can inhibit the progression of spinal cord I/R injury by repressing IRF5 in macrophages, highlighting the discovery of a promising new target for spinal cord I/R injury treatment.

Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia-reperfusion.

Lung ischemia-reperfusion (IR) injury is a common clinical pathology associated with high mortality. Ferroptosis, a novel mode of cell death elicited by iron-dependent phospholipid peroxidation, has been implicated in ischemic events. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is one of the main enzymes in pro-ferroptotic lipid metabolism. In this study, the involvement of ferroptotic death in different durations of reperfusion was evaluated by assessing the iron content, malondialdehyde, and glutathione levels, ferroptosis-related protein expression, and mitochondria morphology. The roles of ferroptosis-specific inhibitor, liproxastin-1 (Lip-1), and ACSL4 modulation in a preventive regimen were assessed in vivo and in vitro. The hallmarks of pulmonary function, such as histological lung injury score, wet/dry ratio, and oxygenation index, were evaluated as well. Results showed that lung IR increased the tissue iron content and lipid peroxidation accumulation, along with key protein (GPX4 and ACSL4) expression alteration during reperfusion. Pretreatment with Lip-1 inhibited ferroptosis and ameliorated lung IR-induced injury in animal and cell models. In addition, administering ACSL4 inhibitor rosiglitazone before ischemia diminished the ferroptotic damage in IR-injured lung tissue, consistent with the protective effect of ACSL4 knockdown on lung epithelial cells subjected to hypoxia/reoxygenation. Thus, this study delineated that IR-induced ferroptotic cell death in lung tissue and ACSL4 were correlated with this process. Inhibition of ferroptosis and ACSL4 mitigated the ferroptotic damage in IR-induced lung injury by reducing lipid peroxidation and increasing the glutathione and GPX4 levels.

Effect of Lung Recruitment Maneuvers on Reduction of Atelectasis Determined by Lung Ultrasound in Patients More Than 60 Years Old Undergoing Laparoscopic Surgery for Colorectal Carcinoma: A Prospective Study at a Single Center.

BACKGROUND Atelectasis occurs in patients of all ages during various surgeries. Previous studies have mainly focused on perioperative atelectasis in infants. However, research on the incidence of atelectasis among elderly patients, particularly those undergoing laparoscopic surgeries, is limited. Therefore, this prospective study aimed to investigate the effect of lung recruitment maneuvers (LRMs) on the reduction of atelectasis determined by lung ultrasound in patients more than 60 years old undergoing laparoscopic surgery for colorectal carcinoma. MATERIAL AND METHODS In this evaluator-blinded clinical study, 42 patients more than 60 years old diagnosed with colorectal carcinoma were randomly grouped either into a lung recruitment maneuver (RM) group or control (C) group. All patients were scheduled for laparoscopic surgery under general anesthesia using the lung-protective ventilation strategy. Lung ultrasonography was carried out at 3 predetermined time intervals. Patients in the RM group received ultrasound-guided recruitment maneuvers once atelectasis was discovered by lung ultrasound. Scores of lung ultrasound were used for assessing the severity of lung atelectasis. RESULTS At the end of the operation, the occurrence of atelectasis was 100% in the RM group and 95% in the C group. After RMs, the frequency of atelectasis in the RM group and C group was 50% and 95%, respectively (P<0.01). Postoperative pulmonary complications were not different between the 2 groups. CONCLUSIONS At a single center, patients more than 60 years old undergoing laparoscopic surgery for colorectal carcinoma had a prevalence of lung atelectasis of 100% and although LRMs significantly reduced the incidence of pulmonary atelectasis, they did not improve postoperative pulmonary complications.

Intrathecal morphine versus transversus abdominis plane block for caesarean delivery: a systematic review and meta-analysis.

BACKGROUND: The number of caesarean deliveries has been increasing. Although intrathecal morphine (ITM) can relieve pain and is widely applied in caesarean deliveries, it is associated with many side effects. Transversus abdominis plane block (TAPB), a new analgesic technology, has also began playing a certain role after caesarean delivery, with fewer adverse effects. This study mainly compares the analgesic and adverse effects of ITM and TAPB in caesarean delivery. METHODS: We systematically searched PubMed, Cochrane Library, EMBASE, and Web of Science, for randomised controlled trials (RCTs) published before 9 October, 2020 to compare the effects of ITM and TAPB. Primary outcome of the study was the pain score at rest 24 h after caesarean delivery, whereas the secondary outcomes were the pain score at movement 24 h after operation, postoperative nausea and vomiting (PONV), itching, and morphine consumption. For the outcome assessment, we conducted a sensitivity analysis. RESULT: Six RCTs involving 563 patients and meeting the study inclusion criteria were included in this study. Results indicated no significant difference in the pain score between ITM and TAPB at 24 h of rest or movement. The sensitivity analysis results indicated that the resting pain score (95% CI = - 1.27 to - 0.28; P = 0.002) and 24-h moving pain score (95% CI = - 1.8 to - 0.07; P = 0.03) of the ITM group were lower than those of the TAPB group. The consumption of morphine in the ITM group was lower than in the TAPB group (95% CI = 1.92 to 4.87; P < 0.00001); however, in terms of adverse reactions, the incidence of pruritus (95% CI = 1.17 to 8.26; P = 0.02) and PONV (95% CI = 1.92 to 4.87, P < 0.00001) in the ITM group was higher than in the TAPB group. CONCLUSION: Parturients in the ITM and TAPB groups exhibited similar analgesic effects. However, in the sensitivity analysis performed by eliminating the studies causing heterogeneity, the ITM group was found to have superior analgesic effects compared with the TAPB group, with less morphine consumption. Differently, the TAPB group displayed less side effects such as PONV. Therefore, TAPB is still a valuable analgesia option for patients who cannot use ITM for analgesia after caesarean delivery or those having a high risk of PONV. TRIAL REGISTRATION: Registration number: Registered on Prospero with the registration number of CRD42020210135 .

Extramedullary intracardiac multiple myeloma misdiagnosed as a thrombus: a case report.

BACKGROUND: Extramedullary intracardiac multiple myeloma (MM) is extremely rare. Patients with extramedullary intracardiac MM may suffer from a poor prognosis. Experience in the diagnosis and therapy of cardiac involvement in MM is limited. Herein, we describe a 67-year-old male with extramedullary intracardiac MM who was initially misdiagnosed with a thrombus. CASE PRESENTATION: A 67-year-old male was admitted for exertional dyspnea and fatigue. The patient was diagnosed with MM one year earlier and had complete remission after chemotherapy. He was implanted with a permanent pacemaker two months prior due to sick sinus syndrome. After this admission, transthoracic echocardiography (TTE) and computed tomography (CT) confirmed the existence of a large right atrial mass extending to the superior and inferior vena cava. We initially considered the right atrial mass as a thrombus and performed surgical treatment for the patient. The surgical intervention partially relieved the obstruction of the superior and inferior vena cava and improved hemodynamics. Postoperative pathological examination of the right atrial mass suggested malignant plasmacytoma associated with MM. After recovery from the surgery, the patient received one cycle of chemotherapy. A follow-up of seven months revealed that our patient was still alive with a good general condition. CONCLUSIONS: Increasing the awareness of extramedullary intracardiac lesions in patients with MM is warranted. Our case confirmed that surgical intervention followed by adjuvant chemotherapy could improve the patient's hemodynamics and achieve remission of cardiac symptoms.

PRR34-AS1 overexpression promotes protection of propofol pretreatment against ischemia/reperfusion injury in a mouse model after total knee arthroplasty via blockade of the JAK1-dependent JAK-STAT signaling pathway.

Long noncoding RNAs have been documented to be protective against ischemia/reperfusion (I/R) injury. However, few research works have focused on the protective effects of PRR34-AS1 on I/R injury after total knee arthroplasty (TKA). The objective of the present study was to investigate the possible effect of PRR34-AS1 on I/R injury after TKA. A mouse model with I/R injury after TKA was established. The interaction between PRR34-AS1 and Janus kinase 1 (JAK1) was examined and thoroughly investigated. Next, the effects of PRR34-AS1 on the expression of apoptosis-related proteins, JAS-signal transducer and activator of transcription (STAT) signaling pathways, and inflammation-related genes, chondrocyte proliferation, and apoptosis were analyzed after gain- and loss-of-function experiments. Attenuated symptoms were observed in mice pretreated with propofol, which was evidenced by decreased positive expression rate of JAK1 protein and superoxide dismutase content along with increased malondialdehyde content and IL-10 levels. PRR34-AS1 was poorly expressed in mice with I/R injury after TKA. JAK1 was a target of PRR34-AS1. Upregulated PRR34-AS1 diminished expression of JAK1, STAT1, JAK2, and STAT3 as well as cell apoptosis, while enhancing cell proliferation in vitro. Furthermore, JAK1 silencing could reverse the suppressed cell proliferation and enhanced cell apoptosis of chondrocytes imposed by silencing PRR34-AS1. Upregulation of PRR34-AS1 can potentially relieve I/R injury after TKA in mice pretreated with propofol through inhibition of the JAS-STAT signaling pathway by targeting JAK1.

Effect of ketamine combined with lidocaine in pediatric anesthesia.

BACKGROUND: We conducted a randomized clinical trial to determine whether adjunctive lidocaine diminishes the incidence of adverse effects in pediatric patients sedated with ketamine. METHODS: This case-control study involved 586 consecutive pediatric patients necessitating anesthesia. Then systolic blood pressure, heart rate, respiratory rate, and blood oxygen saturation were observed. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), and creatinine (Cr) levels were tested. General dose of ketamine, the time of onset and duration of anesthesia and postoperative recovery, anesthesia effect, and adverse reaction were subsequently compared. High-performance liquid chromatography was employed to detect ketamine concentration at different time points after administration, and the postoperative cognition function was further evaluated. RESULTS: Intra- and post-operation, the rising degree of ALT, AST, BUN, and Cr in patients treated with ketamine was higher than those in patients treated with the ketamine-lidocaine complex. General dose of ketamine, the time of onset and duration of anesthesia, postoperative recovery time, and the incidence rate of adverse reaction in patients treated with ketamine-lidocaine complex were lower, but the concentration of ketamine was higher compared to the patients treated with ketamine. In patients treated with the ketamine-lidocaine complex, elimination half-life of ketamine was prolonged, the area under curve was increased, and the plasma clearance rate was decreased relative to those with ketamine alone. CONCLUSIONS: Ketamine combined with lidocaine may be beneficial in shortening the onset of anesthesia, promoting postoperative awake, prolonging elimination half-life, increasing area under curve, and decreasing plasma clearance rate and incidence of adverse reactions.

VEGF attenuates lung injury by inducing homing of CD133+ progenitors via VEGFR1.

Although vascular endothelial growth factor (VEGF) promotes vascular permeability and results in edema, studies have suggested it may protect the lung from inflammatory injury via poorly understood mechanisms. Using a mouse model of extracorporeal circulation (ECC), we found that levels of intravenous VEGF increased in lung tissue and inhibited inflammation, thereby attenuating lung injury. These effects could be obtained by intravenous injection or inhalation of VEGF, and they were abolished by treatment with anti-VEGF antibody. Detailed analyses using immunofluorescence and flow cytometry showed that VEGF increased the homing of CD133+ VEGFR1+ progenitors to lung tissue, and this homing could be mimicked in a dose-dependent manner by treatment with VEGF receptor 1 (VEGFR1) agonist and blocked by treatment with anti-VEGFR1 antibody. Interestingly, we found that exposing pulmonary monocytes in vitro to VEGF did not inhibit ECC-induced inflammation. Our results suggest that VEGF enters lung tissues from the circulation and that it attenuates lung injury not by directly inhibiting release of pro-inflammatory factors but by binding to VEGFR1 to recruit CD133+ progenitors. These progenitors then inhibit local inflammation.

Isoflurane Modulates Hippocampal Cornu Ammonis Pyramidal Neuron Excitability by Inhibition of Both Transient and Persistent Sodium Currents in Mice.

BACKGROUND: Volatile anesthetics inhibit presynaptic voltage-gated sodium channels to reduce neurotransmitter release, but their effects on excitatory neuron excitability by sodium current inhibition are unclear. The authors hypothesized that inhibition of transient and persistent neuronal sodium currents by the volatile anesthetic isoflurane contributes to reduced hippocampal pyramidal neuron excitability. METHODS: Whole-cell patch-clamp recordings of sodium currents of hippocampal cornu ammonis pyramidal neurons were performed in acute mouse brain slices. The actions of isoflurane on both transient and persistent sodium currents were analyzed at clinically relevant concentrations of isoflurane. RESULTS: The median inhibitory concentration of isoflurane for inhibition of transient sodium currents was 1.0 ± 0.3 mM (~3.7 minimum alveolar concentration [MAC]) from a physiologic holding potential of -70 mV. Currents from a hyperpolarized holding potential of -120 mV were minimally inhibited (median inhibitory concentration = 3.6 ± 0.7 mM, ~13.3 MAC). Isoflurane (0.55 mM; ~2 MAC) shifted the voltage-dependence of steady-state inactivation by -6.5 ± 1.0 mV (n = 11, P < 0.0001), but did not affect the voltage-dependence of activation. Isoflurane increased the time constant for sodium channel recovery from 7.5 ± 0.6 to 12.7 ± 1.3 ms (n = 13, P < 0.001). Isoflurane also reduced persistent sodium current density (median inhibitory concentration = 0.4 ± 0.1 mM, ~1.5 MAC) and resurgent currents. Isoflurane (0.55 mM; ~2 MAC) reduced action potential amplitude, and hyperpolarized resting membrane potential from -54.6 ± 2.3 to -58.7 ± 2.1 mV (n = 16, P = 0.001). CONCLUSIONS: Isoflurane at clinically relevant concentrations inhibits both transient and persistent sodium currents in hippocampal cornu ammonis pyramidal neurons. These mechanisms may contribute to reductions in both hippocampal neuron excitability and synaptic neurotransmission.

Posttreatment With the Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates One-Lung Ventilation-Induced Lung Injury in a Rabbit Model.

BACKGROUND: One-lung ventilation (OLV)-induced inflammation is a risk factor for acute lung injury that is responsible for 20% of postoperative pulmonary complications after lung resection. Inflammation is an important trigger for acute lung injury. Fatty acid amide hydrolase (FAAH) is the major enzyme that degrades the endocannabinoid arachidonoylethanolamine (AEA), an important regulator of inflammation, and its downstream metabolites such as arachidonic acid (AA) are also involved in inflammation. Importantly, AEA is also found in lung parenchyma. However, it remains unclear whether pharmacological inhibition of FAAH inhibitor using compounds such as URB937 can attenuate OLV-induced lung injury. MATERIALS AND METHODS: New Zealand white rabbits were anesthetized to establish a modified OLV-induced lung injury model. Twenty-four male rabbits were randomly divided into four groups (n = 6): TLV-S (2.5-h two-lung ventilation [TLV] + 1.5 mL/kg saline + 1-h TLV), OLV-S (2.5-h OLV + 1.5 mL/kg saline + 0.5-h OLV + 0.5-h TLV), U-OLV (1.5 mL/kg URB937 + 3.0-h OLV + 0.5-h TLV), and OLV-U (2.5-h OLV + 1.5 mL/kg URB937 + 0.5-h OLV + 0.5-h TLV). Arterial blood gases, lung wet/dry ratio, and lung injury score of the nonventilated lungs were measured. The levels of AEA, AA, prostaglandin I2 (PGI2), thromboxane A2 (TXA2), and leukotriene B4 (LTB4) in the nonventilated lung were also quantified. RESULTS: The arterial oxygenation index (PaO2/FiO2) decreased after 0.5-h OLV in the three OLV groups. The PaO2/FiO2 in the OLV-U group was better than that in the OLV-S and U-OLV groups and was accompanied with reductions in the wet/dry ratio and lung injury scores of the nonventilated lungs. The FAAH inhibitor URB937 administered not before but 2.5 h after OLV attenuated OLV-induced lung injury by increasing AEA levels and reducing the levels of downstream metabolites including AA, PGI2, TXA2, and LTB4. CONCLUSIONS: Posttreatment with the FAAH inhibitor URB937 attenuated OLV-induced lung injury in rabbits and was associated with increased AEA levels and decreased levels of AA and its downstream metabolites.

Effects of monoacylglycerol lipase inhibitor URB602 on lung ischemia-reperfusion injury in mice.

Lung ischemia-reperfusion injury (LIRI) is a common and severe postoperative pathologic complication that often occurs when the oxygen supply disrupted to the lung tissue fallowed by reperfusion period, in most cases after lung transplantation and cardiopulmonary bypass. Endocannabinoids such as 2-arachidonoylglycerol (2-AG) have very important role as regulators of inflammation. Monoacylglycerol lipase (MAGL) is the main 2-AG-degrading enzyme, and the downstream metabolites of 2-AG play a role in the inflammation. Ischemia reperfusion (IR) was induced by clamping the left pulmonary hilum for 60 min, followed by 120 min of reperfusion in male C57BL/6 mice. Effects of URB602, a MAGL inhibitor, were evaluated in a preventive or therapeutic regimen (5 min before ischemia or reperfusion, respectively). Oxygenation index, wet-to-dry weight ratio and lung injury score were analyzed. Endocannabinoids including 2-AG, anandamide (AEA) and arachidonic acid (AA) levels, metabolites such as Prostaglandin I2 (PGI2), Thromboxane B2 (TXB2) and Leukotrienes B4 (LTB4) and inflammatory markers (Interleukin 6 (IL-6) andTumor necrosis factor-α (TNF-α)) in lung tissues were measured by using mass spectrometry or ELISA analyses. We found that IR increased the wet-to-dry weight ratio of lung and lung injury score and decreased oxygenation index as compared to the sham group. Moreover, treatment with URB602 in preventive or therapeutic regimen reduced the wet-to-dry weight ratio and lung injury score while increased oxygenation index when compared with the IR group, with a more improvement in the preventive regimen group. In addition, treatment with URB602 before ischemia increased 2-AG level but decreased metabolites (AA, PGI2, TXB2, LTB4) and inflammatory markers (IL-6, TNF-α). Thus, our study demonstrated that a pretreatment with URB602 significantly reduced IR-induced lung injury and inflammation. URB602 inhibited LIRI and inflammation by increasing 2-AG level and reducing downstream metabolites from AA to PGI2, TXB2 and LTB4 in lung tissues.

α7 Nicotinic acetylcholine receptor contributes to the alleviation of lung ischemia-reperfusion injury by transient receptor potential vanilloid type 1 stimulation.

BACKGROUND: Activation of transient receptor potential vanilloid type 1 (TRPV1) decreases lung ischemia-reperfusion injury (LIRI) in rabbits and rats. Stimulation of α7 nicotinic acetylcholine receptors (α7nAChRs) protects against lung injury. Here we examined whether α7nAChRs contribute to TRPV1-mediated protection against LIRI. METHODS: Wild-type (WT) and TRPV1-knockout (KO) mice were subjected to 1-h lung ischemia by clamping left hilum, followed by 2-h reperfusion. WT or KO mice were pretreated with vehicle, TRPV1 agonist capsaicin, TRPV1 antagonist capsazepine, α7nAChR antagonist methyllycaconitine, or α7nAChR agonist PNU-282987. Arterial blood and lung tissues were obtained for blood gas, lung wet-to-dry weight ratio, interleukin (IL)1ß, IL6, tumor necrosis factor-α (TNF-α), apoptosis-related proteins (caspases, Bax, Fas), and pathologic scoring. RESULTS: Capsaicin pretreatment reduced wet-to-dry ratio, pathologic score, alveolar-arterial oxygen gradient (A-aDO2), and IL1ß, IL6, and TNFα levels in WT mice, with no effects in KO mice. This reduction was reversed by TRPV1 blockade. Furthermore, α7nAChR blockade before capsaicin exacerbated LIRI as evidenced by enhanced alveolar-arterial oxygen gradient, pathologic score, and IL1ß, IL6, and TNFα levels, while α7nAChR agonist pretreatment under TRPV1 blockade showed opposite changes. Capsaicin also decreased cleaved caspase-3, caspase-3/9, and Bax protein expression, effects abolished by TRPV1 blockade. Similarly, α7nAChR blockade diminished capsaicin-induced downregulation of apoptotic proteins, and α7nAChR activation decreased expression levels even under TRPV1 blockade. CONCLUSIONS: TRPV1 activation alleviates LIRI, partially dependent on α7nAChR activity. The α7nAChR stimulation with or without existence of TRPV1 alleviates LIRI. Thus, α7nAChR is involved in the pathway of TRPV1-mediated protection against LIRI and the specific mechanism remains to be revealed.