BACKGROUND:AI is rapidly transforming medical practice, with emerging applications in perioperative care and anesthesiology. However, the clinical implementation of AI-assisted decision-making systems in anesthetic management remains challenging and requires comprehensive evaluation. OBJECTIVE:This study aimed to assess the performance and clinical applicability of an AI-assisted decision support system (ZW-AA-001) for general anesthesia management by comparing its decisions with those of experienced anesthesiologists across 6 medical centers. METHODS:A multicenter retrospective study was conducted using perioperative data from 1008 patients who underwent elective noncardiac surgeries under total intravenous anesthesia. The AI system's recommendations for anesthetic and hemodynamic medication adjustments were compared with anesthesiologists' decisions. Key outcomes included decision concordance rates, temporal performance, and consistency across centers. Advanced statistical methods, including prevalence-adjusted and bias-adjusted κ (PABAK) and Gwet's first-order agreement coefficient (AC1), were used to evaluate agreement metrics. RESULTS:The study included 1008 patients, with a median age of 50 (IQR 37-59) years and female predominance (619/1008, 61.4%). During anesthesia maintenance, the AI system demonstrated moderate overall decision agreement with anesthesiologists (73.3%, 95% CI 72.4%-74.3%). Analysis of center-specific data revealed generally consistent performance across all 6 centers. For propofol management, high concordance was observed in dosage adjustment decisions (91.1%, 95% CI 90.4%-91.8%), though fair agreement was found in adjustment direction (68.6%, 95% CI 67.3%-69.8%). The AI system showed significantly faster decision-making time compared to anesthesiologists for the adjustment of propofol (pseudomedian difference -77.5, 95% CI -79.5 to -75.5 seconds; P<.001). Although esmolol-related decisions showed a numerically higher concordance of 71.4%, this was not statistically significant (PABAK=0.429; P=.21; AC1=0.622; P=.09). Decisions for atropine, ephedrine, and urapidil demonstrated substantially lower agreement (17.4%-29.8%). The AI system recommended hemodynamic interventions more frequently than anesthesiologists across all medications. CONCLUSIONS:The AI-assisted decision support system demonstrated varying levels of concordance with anesthesiologists in managing surgery, with the highest agreement observed in propofol administration. However, the system's lower agreement in hemodynamic medication management highlights the need for further optimization and validation. These findings underscore the potential of AI systems to enhance anesthetic decision-making, improve efficiency, and address workforce challenges in anesthesiology. Future research should focus on expanding the system's capabilities, validating its performance in prospective clinical trials, and ensuring its integration into diverse clinical settings.

Anxiety is a highly prevalent and disabling comorbidity in autism spectrum disorder (ASD), but its neurobiological mechanisms remain poorly understood. The basolateral amygdala (BLA) is critically involved in anxiety processing, yet the synaptic substrates linking ASD gene mutations to BLA dysfunction are not fully defined. Here, we evaluated anxiety-like behaviors in male Shank3b knockout (Shank3b-/-) mice using open field, elevated plus maze, and light-dark transition tests. Molecular alterations in the BLA were assessed by qPCR and Western blotting, and whole-cell patch-clamp recordings were performed to examine synaptic transmission and intrinsic excitability of BLA pyramidal neurons. Shank3b-/- mice exhibited robust anxiety-like behaviors across multiple behavioral paradigms. In the BLA, expression of the GABAA receptor α2 subunit (GABRA2) was significantly reduced, accompanied by decreased levels of NMDA receptor subunits (GluN2A and GluN2B). Electrophysiological recordings revealed a marked reduction in inhibitory synaptic transmission, as evidenced by decreased frequency and amplitude of spontaneous inhibitory postsynaptic currents, whereas excitatory transmission remained largely unchanged, resulting in a significantly elevated excitation/inhibition (E/I) ratio. In addition, BLA pyramidal neurons displayed increased intrinsic excitability, characterized by a depolarized resting membrane potential and enhanced action potential firing. Collectively, these findings identify impaired GABAergic transmission associated with reduced GABRA2 expression as a key mechanism underlying E/I imbalance and heightened neuronal excitability in the BLA of Shank3b-deficient mice, which likely contributes to ASD-related anxiety-like behaviors. These results identify GABAA receptor signaling as a promising therapeutic target for pharmacological intervention in ASD-related anxiety.

Neuropathic pain (NP), characterized by its complex pathophysiological mechanisms, has long posed a formidable therapeutic challenge. The burden of NP is further exacerbated by the increasing prevalence of chronic diseases. Emerging evidence highlights the pivotal role of gut microbiota in modulating immune responses, offering novel insights into NP pathogenesis. This review explores recent advancements in understanding how gut microbiota-derived metabolites - including short-chain fatty acids (SCFAs), bile acids, and tryptophan derivatives - regulate immune processes that influence neuroinflammation and nociceptive signaling. We focus on key immune mediators, including macrophages, microglia, T cells, and astrocytes, elucidating their involvement in microbiota-driven immune regulation via pathways such as TLR4/NF-κB signaling, histone deacetylase (HDAC) inhibition, and aryl hydrocarbon receptor (AhR) activation. Additionally, we examine emerging evidence of sex-specific immune mechanisms in NP. Despite promising preclinical findings on microbiota-targeted therapies, such as probiotics and fecal microbiota transplantation, translational challenges, such as microbiota heterogeneity and sex-specific responses, necessitate further investigation. This review aims to bridge microbiology, neuroimmunology, and pain research, offering a multidimensional perspective and actionable insights for the future management of NP.

While N-methyl-d-aspartate receptor (NMDAR) hypofunction has been suggested as a hallmark of schizophrenia, the role of subunit-specific dysregulation such as GluN2A overexpression remains poorly understood. The present study comprehensively investigated the impact of GluN2A overexpression on behavioral phenotypes, cognitive functions, and synaptic plasticity in transgenic mice with forebrain-specific overexpression of the GluN2A subunit (GluN2A-TG). Behavioral assessments revealed schizophrenia-like phenotypes, including prolonged stereotypic movement duration, impaired sensorimotor gating, reduced social interaction, and diminished nest-building activity in GluN2A-TG mice. Consistently, GluN2A-TG mice exhibited not only deficits in spatial working memory and olfactory working memory but also impaired associative learning. In addition, both long-term potentiation and long-term depression were significantly attenuated in the prefrontal cortex (PFC) of GluN2A-TG mice. Furthermore, electrophysiological analysis of NMDAR-mediated excitatory postsynaptic currents in PFC neurons revealed altered kinetics characterized by a faster decay time and significantly increased amplitude in GluN2A-TG mice. Collectively, these findings suggest that GluN2A overexpression may induce schizophrenia-like phenotypes via impairing NMDAR-dependent long-term synaptic plasticity in the PFC, likely due to altered NMDAR subunit composition leading to disrupted calcium signaling dynamics. These results provide critical insights into the pathological role of GluN2A in schizophrenia.

Sepsis‑induced abnormalities in brain function or sepsis‑associated encephalopathy (SAE) can manifest as cognitive dysfunction and other neuropsychiatric symptoms; however, the underlying mechanisms remain unclear. The aim of the present study was to elucidate the possible effects and mechanism of capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, on the pathological features of SAE. A model of SAE in C57BL/6 mice was generated using cecal ligation and puncture (CLP). Capsaicin (1 mg/kg) was injected subcutaneously before surgery. Cognitive function in mice was evaluated using the novel object recognition test (NORT) and Morris water maze (MWM). Immunofluorescence staining, ELISA, western blotting and transmission electron microscopy were performed to detect the degree of microglial activation (ionized calcium‑binding adapter molecule 1), proinflammatory cytokine levels (TNF‑α), autophagy and apoptosis‑related protein expression, and autophagosomes. Autophagic flux was monitored using the LC3‑GFP‑mCherry fluorescent reporter. Compared with that in the sham group mice, the expression levels of TRPV1 were significantly reduced in the hippocampal tissue of mice with sepsis. Mice with sepsis also exhibited cognitive dysfunction. Notably, a single administration of capsaicin reduced the mortality rate, but did not improve cognitive function in mice with sepsis. Furthermore, repeated administration of capsaicin was revealed to enhance the recognition index of novel objects among mice with sepsis, to reduce the latency to locate the platform and to augment the duration of mouse platform quadrant movements, according to the NORT and MWM tasks. Increased microglial activation, release of proinflammatory cytokines and expression levels of apoptosis‑related proteins were all observed in mice with CLP‑induced sepsis, as was brain tissue destruction in the hippocampal regions. By contrast, capsaicin treatment ameliorated CLP‑induced microglial activation, inflammation, neuronal apoptosis (cleaved caspase 3 expression increased) and brain tissue destruction. Furthermore, application of capsaicin increased the expression levels of LC3, reduced the expression of p62 and elevated autophagic flux compared with those in the CLP group. Finally, treatment with capsaicin effectively enhanced the levels of Bcl‑2‑interacting protein 3 (BNIP3) and BNIP3‑like (NIX) expression. These findings suggested that capsaicin may be considered a potential drug for the treatment of SAE, and BNIP3/NIX‑mediated mitophagy may be involved in this process.

General anesthesia combined with peripheral nerve blocks has become a common anesthesia regimen for knee replacement surgery. Its association with high-risk isolated distal deep venous thrombosis (IDDVT) remains uncertain. In this cohort study, we obtained consecutive data from the electronic inpatient records of Shenzhen Second People’s Hospital, including adults who underwent knee arthroplasty from 1 September 2019 to 31 August 2021. The primary outcome was the incidence of high-risk IDDVT. We compared the outcomes in patients who received general anesthesia combined with nerve blocks with those in patients who received neuraxial anesthesia without nerve blocks, using a multivariable regression model with inverse probability weighting according to the propensity score. Of the 848 patients who underwent knee arthroplasty, 330 were excluded because they lacked thrombus testing or had received other types of anesthesia. Of the remaining 518 patients, 267/518 (52 ChiCTR2200057006 ), first submitted 25 February 2022.

Neuropathic pain (NP) is characterized by its complex and multifactorial nature and limited responses to opioid therapy; NP is associated with risks of drug resistance, addiction, difficulty in treatment cessation, and psychological disorders. Emerging research on gut microbiota and their metabolites has demonstrated their effectiveness in alleviating NP and augmenting opioid-based pain management, concurrently mitigating the adverse effects of opioids. This review addresses the following key points: (1) the current advances in gut microbiota research and the challenges in using opioids to treat NP, (2) the reciprocal effects and benefits of gut microbiota on NP, and (3) the interaction between opioids with gut microbiota, as well as the benefits of gut microbiota in opioid-based treatment of NP. Through various intricate mechanisms, gut microbiota influences the onset and progression of NP, ultimately enhancing the efficacy of opioids in the management of NP. These insights pave the way for further pragmatic clinical research, ultimately enhancing the efficacy of opioid-based pain management.

Studies have suggested that microglial IL-6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to STAT3 and contribute to IL-6-mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t-STAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, GLUT3, and TREM2 were assessed by Western blot. IL-6 promoter activity and IL-6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL-6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3Ser727 phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL-6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL-6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.

新型冠状病毒感染（曾称为新型冠状病毒肺炎），是一种传播迅速、对人类生存危害极大的传染病，其在老年群体中的危重患者比例要远高于其他年龄段群体。近期国家管控政策将其调整为"乙类乙管"后 [1]，感染人数迅速增加。新型冠状病毒感染后约有8%的患者出现肺炎表现 [2]，重症和危重患者所占感染人数的百分比虽然很低（据报道2022年2~6月份上海地区奥密克戎BA.2感染者发生重症、危重症风险仅为0.27%） [3]，但是由于当下总体感染总数已达中国总人口数量的一半以上，所以重症、危重症患者的绝对数不容低估。鉴于在已知危重患者中，死亡患者多为老年人，多伴随各类基础性疾病，且病毒主要损伤肺及肾、心、脑等重要脏器；而终末期直接致死的主要表现为肺功能严重损害（俗称"白肺"），所以救治的重点理应从处理肺部损伤入手。

Background Sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction, long-term cognitive impairment, and increased morbidity and mortality. The current treatment for SAE is mainly symptomatic; the lack of specific treatment options and a poor understanding of the underlying mechanism of disease are responsible for poor patient outcomes. Fgr is a member of the Src family of tyrosine kinases and is involved in the innate immune response, hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. This study investigated the protection provided by an Fgr kinase inhibitor in SAE and the underlying mechanism(s) of action. Methods A cecal ligation and puncture (CLP)-induced mouse sepsis model was established. Mice were treated with or without an Fgr inhibitor and a PGC-1α inhibitor/activator. An open field test, a novel object recognition test, and an elevated plus maze were used to assess neurobehavioral changes in the mice. Western blotting and immunofluorescence were used to measure protein expression, and mRNA levels were measured using quantitative PCR (qPCR). An enzyme-linked immunosorbent assay was performed to quantify inflammatory cytokines. Mitochondrial membrane potential and morphology were measured by JC-1, electron microscopy, and the MitoTracker Deep Red probe. Oxidative stress and mitochondrial dysfunction were analyzed. In addition, the regulatory effect of Fgr on sirtuin 1 (SIRT1) was assessed. Results CLP-induced sepsis increased the expression of Fgr in the hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, the survival rate, cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Moreover, Fgr interacted with SIRT1 and reduced its activity and expression. In addition, activation of SIRT1/PGC-1α promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation of SIRT1/PGC-1α counteracted the benefits of the Fgr inhibitor. Conclusions To our knowledge, this is the first report of Fgr kinase inhibition markedly ameliorating SAE through activation of the SIRT1/PGC-1α pathway, and this may be a promising therapeutic target for SAE. Graphical Abstract

Background Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces antinociception via glycolysis and mitochondria-related pathways is still unclear. Methods Right hind paw inflammatory pain in mice was induced by intraplantar injection of Freund’s Complete Adjuvant (FCA). Von Frey test was then used to measure the paw withdrawal threshold. The detection of glycolysis and mitochondrial pathway-related proteins and IL-8 were determined by Western blot and ELISA. The potential interaction between Dexa and fructose-1,6-bisphosphate (FBP, a PKM2 activator) was examined by simulation predictions using molecular docking. Results Intrathecal administration of Dexa (20 µg/20 µL) had an obvious analgesic effect in FCA-treated mice, which was counteracted by the glycolysis inhibitor 2-deoxyglucose (2-DG, 5 mg/20 µL) or the mitochondria-related pathway inhibitor oligomycin complex (Oligo, 5 µg/20 µL). In the glycolysis pathway, Dexa decreased GLUT3 and had no impact on HIF-1α expression during FCA-induced inflammation. Additionally, Dexa further increased the PKM2 level, accompanied by the formation of hydrogen bonds between Dexa and the PKM2 activator fructose-1,6-bisphosphate (FBP). In the mitochondrial pathway, Dexa downregulated the expression of Mfn2 protein but not the PGC-1α and SIRT-1 levels in the spinal cord. Moreover, both 2-DG and Oligo decreased Mfn2 expression. Finally, IL-8 level was reduced by the single or combined administration of Dexa, 2-DG, and Oligo. Conclusion Dexa attenuated IL-8 expression via glycolysis and mitochondrial pathway-related proteins, thus mediating the analgesic effect during inflammatory pain.

Recent observation demonstrated that prolonged anesthesia modifies brain synaptic architecture in all ages, including adult. Propofol is the most commonly utilized anesthetics at clinic. Whether repeated administration of propofol modulates cognitive impairment in adults and changes synaptic plasticity remains, however, to be explored. In this study, we first discovered that repeated and prolonged exposure to propofol-induced cognitive impairment in adult rodents. Then, we examined the property of hippocampal primary neurons and slices after propofol treatment in mice, including synaptic protein profile, dendritic spine density, as well as synaptic transmission. We found the distinctive change of the F-box only protein 22 (FBXO22), an F-box E3 ligase, during this process and further explored its role. Knockdown experiments showed the downregulation of FBXO22 restored the changes by propofol treatment on hippocampal primary neurons and attenuated propofol-induced hippocampal dependent cognitive dysfunction. Our results showed that FBXO22 is involved in the regulation of repeated propofol treatment induced changes of synaptic plasticity and cognitive dysfunction in adult mice. Repeated propofol treatment leads to cognitive dysfunction by regulating FBXO22 in adult rodents.

This study aimed to investigate the effects of sevoflurane combined with propofol on oxidative stress, inflammatory response and cellular immunity in patients with one-lung ventilation in thoracoscopic lobectomy. Sixty patients with lung cancer who underwent thoracoscopic lobectomy with one-lung ventilation were divided into sevoflurane, propofol and sevoflurane+propofol groups, 20 cases in each group, which received the sevoflurane, propofol and sevoflurane combined with propofol for anesthesia maintenance, respectively. During the surgery, compared with sevoflurane or propofol group, in sevoflurane+propofol group the respiratory mechanical, hemodynamic and blood gas indexes were obviously improved, the serum malondialdehyde, tumor necrosis factor-a and interleukin-6 levels were significantly decreased, and the serum superoxide dismutase level was significantly increased. After surgery, compared with sevoflurane or propofol group, in sevoflurane+propofol group the CD3+ cell percentage and CD4+/CD8+ ratio were significantly increased. This indicates that, compared with single use of sevoflurane or propofol, sevoflurane combined with propofol can effectively reduce the oxidative stress, inflammatory response and immunosuppression in patients with one-lung ventilation in thoracoscopic lobectomy, thus exerting a better lung protective effect.

This perspective discusses the short-term tasks and long-term objectives of Chinese Anesthesiology clinical practices proposed by the Chinese Association of Anesthesiologists under the leadership of Dr. Buwei Yu and his colleagues and alliances.

AIMS:Propofol, the most commonly used intravenous anesthetic, is known for its protective effect in various human and animal disease models such as post-traumatic stress disease (PTSD). However, it still needs efforts to clarify the effect of propofol on fear memory extinction and the relevant mechanisms.METHODS:Fear memory extinction was examined in PTSD mice model. Thirty-six mice were randomly divided into three groups: a shock + propofol group (sh + Pro), shock + normal saline group (sh + NS), and sham group. The mice were treated with propofol (150 mg/kg) or normal saline (of the same volume) intraperitoneally 30 min after the conditioning. These mice's behavior was analysed with contextual test, sucrose preference test (SPT) and Morris water maze (MWM). Additionally, the synaptic plasticity of the hippocampus was examined by long-term potentiation (LTP) and long-term depression (LTD).KEY FINDINGS:Compared with the sham group, the sh + NS group showed increased freezing time and depressive behavior, meanwhile the sh + Pro group showed minor behavioral changes. What's more, we found that propofol rescued the impaired long-term potentiation (LTP) and long-term depression (LTD) in hippocampus of PTSD mice. All these suggest that propofol can accelerate fear memory extinction and change synaptic plasticity of PTSD mice.SIGNIFICANCE:The study proved that propofol can protect the mice from PTSD by reserving synaptic plasticity and brought a new insight into PTSD treatment indicating that propofol maybe a potential cure for PTSD.

Background and Aim. Interleukin-6 (IL-6) modulates neurons–glia crosstalk and subsequently triggers hyperalgesia. This study is aimed at investigating whether the interaction between protein kinase C epsilon (PKCε) and signal transducer and activator of transcription 3 (STAT3) mediated IL-6-induced hyperalgesia and neurocyte activation. Methods. A rat hyperalgesia model was induced using an intraplantar injection of Freund’s complete adjuvant (FCA) or an intrathecal injection of IL-6. Mechanical allodynia was evaluated using von Frey filament tests after intrathecal injections of T-5224 (c-Fos/AP-1 inhibitor), minocycline (Mino, a specific microglia inhibitor), L-2-aminoadipic acid (LAA, an astroglial toxin), PKCε inhibitor peptide, APTSTAT3-9R (STAT3 inhibitor), or anti-IL-6 antibody. The c-Fos, GFAP, Iba-1, PKCε, STAT3, pSTAT3Tyr705 and pSTAT3Ser727, and IL-6 expression at the spinal cord level was assessed by Western blot analysis. The interactive effects of PKCε and STAT3 were determined using immunofluorescence staining and immunoprecipitation in vivo and in vitro. Interleukin-6 promoter activity was examined using luciferase assays. Results. T-5224, Mino, and LAA attenuated FCA- or IL-6-mediated inflammatory pain, with a decrease in c-Fos, GFAP, Iba-1, PKCε, and IL-6 expression. PKCε inhibitor peptide and APTSTAT3-9R reversed FCA-induced nociceptive behavior, while decreasing pSTAT3Ser727, IL-6, c-Fos, GFAP, and Iba-1 expression and PKCε and STAT3 coexpression. Interleukin-6 promoter activity increased in the presence of PKCε and STAT3. The interaction with PKCε increased on phosphorylating STAT3 at Ser727 but not at Tyr705. Conclusion. STAT3 phosphorylation at Ser 727 and the interaction with PKCε contribute to hyperalgesia via the IL-6-mediated signaling pathway, thus regulating neuron–glia crosstalk during inflammatory pain.

湿化高流量鼻导管通气(humidified high flow nasal cannula,HFNC)是一种新型无创呼吸通气治疗技术,近年来该技术在呼吸科和重症医学科得到较多应用和报道.HFNC可为围术期低氧血症呼吸治疗、麻醉预充氧、日间手术麻醉供氧、PACU拔管后的序贯氧疗及门诊内镜诊疗麻醉中的呼吸支持等提供一项新的选择,但对危重症患者不能一概而论.要掌握HFNC的适应证和禁忌证,要加强临床监测,注意改变患者供氧模式的时机,在围术期精确使用HFNC需要科学的、充足的临床研究来支撑,探讨其临床应用价值,麻醉科医师在此领域大有可为.

Background Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI. Methods Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model. Results Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β3 or β5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown β3 integrin significantly decreased survival in ALI mice. Notably, knockdown of β5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice. Conclusion These findings support the β3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.

BACKGROUND:Postoperative pain management has increasingly become a public health problem worldwide. Psychological factors can be considered as independent risk factors for the intensity of postoperative pain and the occurrence of postoperative chronic pain.OBJECTIVES:As stress events could facilitate NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in the central nervous system, we aimed to explore the role of perioperative NLRP3-mediated neuroinflammation in the exacerbation of incisional hyperalgesia in stressed rats.STUDY DESIGN:Experimental trial in rats.SETTING:Department of Anesthesiology, Shanghai, China.METHODS:All animal experimental procedures were approved by the Animal Care and Use Committee of Shanghai Jiaotong University School of Medicine. This study was conducted in rat models of chronic restraint stress and hind paw incision model. Serum corticosterone level measurement and emotion-related behavioral tests were used to confirm that chronic restraint stress can cause depression-like behavior in rats. Pain behavior after surgery was assessed by withdrawal response to von Frey filament application. Immunofluorescence staining and  the Western blot test were used to evaluate the protein level of NLRP3, IL-1beta, C-fos in the basolateral amygdala (BLA) and GluN2B-containing N-methyl-D-aspartate (NMDA) receptors (GluN2B) expression in the central nucleus of the amygdala (CeA), respectively. Intra-BLA cannulation and microinjection of an NLRP3 specific inhibitor--MCC950 (0.5 µL, 2 µg/µL) were applied to the stressed rats for 4 days perioperatively to explore whether the stress-induced postoperative hyperalgesia and GluN2B expression in CeA can be altered.RESULTS:The results showed that chronic restraint stress exposure led to depressive behavior in rats. Moreover, chronic restraint stress exposure increased NLRP3 and interleukin 1 beta (IL-1beta) expression in the basolateral amygdala (BLA), as well as exacerbated postoperative hyperalgesia and prolonged the recovery time of postoperative pain. Meanwhile, GluN2B expression in the CeA of the stressed group was higher than that of the control incision group. Inhibition of NLRP3 reversed the exacerbation of postoperative hyperalgesia by stress exposure, and down-regulated GluN2B expression in the CeA.LIMITATIONS:The upstream mechanism by which NLRP3 is elevated in stressed rats was not explored.CONCLUSION:These findings suggest that chronic restraint stress may influence postoperative hyperalgesia and NLRP3-mediated neuroinflammation, which may in turn contribute to stress-induced postoperative pain exacerbation.

N-methyl-d-aspartic acid receptor (NMDAR)-dependent synaptic plasticity at the thalamus-lateral amygdala (T-LA) synapses is related to acquisition and extinction of auditory fear memory. However, the roles of the NMDAR GluN2A subunit in acquisition and extinction of auditory fear memory as well as synaptic plasticity at T-LA synapses remain unclear. Here, using electrophysiologic, molecular biological techniques and behavioral methods, we found that the forebrain specific GluN2A overexpression transgenic (TG) mice exhibited normal acquisition but impaired extinction of auditory fear memory. In addition, in vitro electrophysiological data showed normal basal synaptic transmission and NMDAR-dependent long-term potentiation (LTP) at T-LA synapses, but deficit in NMDAR-dependent long-term depression (LTD) at T-LA synapses in GluN2A TG mice. Consistent with the reduced NMDAR-dependent LTD, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization was also weakened during NMDAR-dependent LTD in GluN2A TG mice. Taken together, our findings for the first time indicate that GluN2A overexpression impairs extinction of auditory fear memory and NMDAR-dependent LTD at T-LA synapses, which further confirms the close relationship between NMDAR-dependent LTD and fear extinction.