Upconversion-Mediated Optogenetics for the Treatment of Surgery-Induced Postoperative Neurocognitive Dysfunction.

Perioperative neurocognitive disorder (PND) is a common complication in surgical patients. While many interventions to prevent PND have been studied, the availability of treatment methods is limited. Thus, it is crucial to delve into the mechanisms of PND, pinpoint therapeutic targets, and develop effective treatment approaches. In this study, reduced dorsal tenia tecta (DTT) neuronal activity was found to be associated with tibial fracture surgery-induced PND, indicating that a neuronal excitation-inhibition (E-I) imbalance could contribute to PND. Optogenetics in the DTT brain region was conducted using upconversion nanoparticles (UCNPs) with the ability to convert 808 nm near-infrared light to visible wavelengths, which triggered the activation of excitatory neurons with minimal damage in the DTT brain region, thus improving cognitive impairment symptoms in the PND model. Moreover, this noninvasive intervention to modulate E-I imbalance showed a positive influence on mouse behavior in the Morris water maze test, which demonstrates that UCNP-mediated optogenetics is a promising tool for the treatment of neurological imbalance disorders.

Bilevel positive airway pressure ventilation in patients susceptible to hypoxemia during procedural sedation for colonoscopy: a prospective randomized controlled study.

BACKGROUND AND AIMS: Hypoxemia is one of the most common adverse events during colonoscopy, particularly among patients who are diagnosed with obstructive sleep apnea (OSA) or are overweight. Consequently, the objective of this study was to evaluate the effectiveness of bilevel positive airway pressure (BPAP) ventilation for patients with high-risk hypoxemia during colonoscopy with sedation. METHODS: In this trial, 127 patients who met the eligibility criteria were randomly assigned to the BPAP oxygen group and nasal cannula (NC) group. The primary endpoint was the incidence of hypoxemia. RESULTS: Compared with the use of NC, BPAP ventilation exhibited a significant reduction in the incidence of hypoxemia, decreasing it from 23.8% to 6.3% (absolute risk difference, 17.5%; 95% confidence interval, 5.4-29.6; P = .006). Importantly, BPAP ventilation prevented the occurrence of severe hypoxemia (9.5% vs 0%; absolute risk difference, 9.5%; 95% confidence interval, 2.3-16.7; P = .035). In addition, the BPAP group required fewer airway interventions (P < .05). CONCLUSIONS: In individuals with OSA or overweight status, the use of BPAP ventilation during colonoscopy significantly reduced the incidence of hypoxemia. (Clinical trial registration number: ChiCTR2300073193.).

A Cyclodextrin-Based pH-Responsive MicroRNA Delivery Platform Targeting Polarization of M1 to M2 Macrophages for Sepsis Therapy.

The mortality rate of sepsis remains high despite improvements in the diagnosis and treatment of sepsis using symptomatic and supportive therapies, such as anti-infection therapy and fluid resuscitation. Nucleic acid-based drugs have therapeutic potential, although their poor stability and low delivery efficiency have hindered their widespread use. Herein, it is confirmed that miR-223 can polarize proinflammation M1 macrophages to anti-inflammation M2 macrophages. A pH-sensitive nano-drug delivery system comprising ß-cyclodextrin-poly(2-(diisopropylamino)ethyl methacrylate)/distearoyl phosphoethanolamine-polyethylene glycol (ß-CD-PDPA/DSPE-PEG) is synthesized and developed to target M1 macrophages and miR-223 is encapsulated into nanoparticles (NPs) for sepsis treatment. NPs/miR-223 demonstrated in vitro pH responsiveness with favorable biosafety, stability, and high delivery efficiency. In vivo studies demonstrate that NPs/miR-223 are preferentially accumulated and retained in the inflammation site, thereby reducing inflammation and improving the survival rate of mice with sepsis while exhibiting ideal biosafety. Mechanically, NPs/miR-223 regulates macrophage polarization by targeting Pknox1 and inhibiting the activation of the NF-κB signaling pathway, thereby achieving an anti-inflammatory effect. Collectively, it is demonstrated that the miRNA delivery vector described here provides a new approach for sepsis treatment and accelerates the advancement of nucleic acid drug therapy.

Protective role of nitric oxide donors on endothelium in ischemia-reperfusion injury: a meta-analysis of randomized controlled trials.

BACKGROUND: Decreased bioavailability of nitric oxide (NO) under hypoxic conditions can lead to endothelial dysfunction. NO supplementation may protect endothelial function in ischemia-reperfusion (IR) injury. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to verify the protective effect of NO donors on endothelium in IR injury. METHODS: Medline, Embase, Cochrane Library, and Web of Science databases were searched from inception to April 1, 2023. The specific inclusion criteria were as follows: (1) RCTs; (2) trials comparing NO donors with placebo control groups; and (3) trials reporting the effects of these interventions on vascular endothelial functional outcomes in IR injury. Random-effects models were used to assess pooled effect sizes, which were expressed as standardized mean differences (SMD). RESULTS: Seven studies satisfied the inclusion criteria and consisted of a total of 149 participants. NO donors were protective of endothelial function in IR injury (SMD: - 1.60; 95% confidence interval [CI]: - 2.33, - 0.88, P < 0.0001; heterogeneity [I2 = 66%, P = 0.001]). Results of the subgroup analysis showed the following: absence of protective effect of NO donor use following ischemia on endothelial function in IR injury - 1.78 (95% CI: - 2.50, - 1.07) and loss of protective effect on endothelial function after prolonged NO donor use - 0.89 (95% CI: - 2.06, 0.28). CONCLUSION: The short-period use of NO donors before the onset of ischemia can protect endothelial function in IR injury.

Bilevel positive airway pressure for gastroscopy with sedation in patients at risk of hypoxemia: A prospective randomized controlled study.

STUDY OBJECTIVE: Hypoxemia is one of the most frequent adverse events during sedated gastroscopy, and there is still no effective means to prevent and cure it. Therefore, we conducted this randomized trial to confirm our hypothesis that, compared with the nasal cannula group, bilevel positive airway pressure (BPAP) would decrease the incidence of hypoxemia in patients with obstructive sleep apnea (OSA) or overweight status undergoing gastroscopy. DESIGN: In a single-center, prospective, randomized controlled clinical trial, 80 patients aged 18-65 years and with OSA or overweight status who underwent gastroscopy with sedation were randomly assigned to two groups: the nasal cannula and BPAP groups. The primary outcome was the incidence of hypoxemia (75% < peripheral oxygen saturation [SpO2] < 90% for >5 sand <60 s). MAIN RESULTS: Compared to the nasal cannula group, BPAP therapy significantly decreased the incidence of hypoxemia from 40.0% to 2.5% (absolute risk difference [ARD], 37.5% [95% confidence interval (CI), 21.6 to 53.4], p < 0.001), decreased subclinical respiratory depression from 52.5% to 22.5% (ARD, 30.0% [95% CI, 9.8 to 50.2], p = 0.006), and decreased severe hypoxemia from 17.5% to 0% (ARD, 17.5% [95% CI, 5.7 to 29.3], p = 0.006). The BPAP intervention also decreased the total propofol dosage and operation time and improved anesthesiologist's satisfaction. CONCLUSION: BPAP therapy significantly decreased the incidence of hypoxemia in patients with OSA or overweight status who underwent gastroscopy.

PI3K/AKT activation attenuates acute kidney injury following liver transplantation by inducing FoxO3a nuclear export and deacetylation.

AIMS: Acute kidney injury (AKI) is a severe complication of autologous orthotopic liver transplantation (AOLT). Apoptosis has been shown to be involved in renal ischemia/reperfusion, and the PI3K/AKT signaling pathway is involved in numerous cell processes, including promoting cell survival and inhibiting apoptosis. We aimed to verify whether the PI3K/AKT signaling pathway participates in the development of post-AOLT AKI. METHODS: Male Sprague-Dawley rats underwent AOLT with or without treatment with insulin-like growth factor-1 (IGF-1, a PI3K/AKT activator) and LY294002 (a PI3K/AKT inhibitor; n = 8/group). NRK-52E cells (rat renal tubular epithelial cell line) were subjected to hypoxia-re-oxygenation to mimic renal cell I/R injury in vitro, and confirm whether silencing information regulator 1 (SIRT1) mediated the protective effects of PI3K/AKT by deacetylating forkhead protein O3a (FoxO3a). KEY FINDINGS: During the reperfusion stage, kidney injury peaked at 8 h after reperfusion, then gradually recovered, which was consistent with the dynamic changes in apoptosis and the protein expressions of Bcl-2 interacting mediator of cell death (Bim), Fas ligand (FasL), and nuclear FoxO3a AKT phosphorylation and nuclear SIRT1 protein expression were also upregulated. IGF-1 application decreased Bim, FasL, and nuclear FoxO3a protein expressions, and protected against apoptosis and AKI. In NRK-52E cells, IGF-1 upregulated nuclear SIRT1 expression, reduced FoxO3a acetylation, downregulated Bim and FasL protein expressions, and attenuated apoptosis and AKI; these effects were reversed by SIRT1 blocking. CONCLUSION: The activation of the PI3K/AKT signaling pathway not only induced FoxO3a nuclear export but also deacetylation through upregulating nuclear SIRT1 expression to attenuate post-AOLT AKI.

Long non-coding RNA review and implications in acute lung inflammation.

Acute lung inflammatory diseases severely affect the patients' recovery and outcomes worldwide. Unregulated acute inflammatory response is fundamentally central to acute lung inflammation including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To limit the potentially deleterious effects of acute lung inflammation, complex transcriptional and posttranscriptional regulatory networks have been explored, which often involves long noncoding RNAs (lncRNA). LncRNAs are RNAs that longer than 200 nucleotides, functioning as scaffolds or decoys in the cytoplasm or nucleus. By now, lncRNAs have been found to join in all major cellular processes including cell proliferation, metabolism, stress response or death. Extensive advance over the last decade furthermore indicated a fundamental role of lncRNAs in acute lung inflammation. This article reviews and summarizes the current knowledge on lncRNA in acute lung inflammatory response.

Pain management after ambulatory surgery: a prospective, multicenter, randomized, double-blinded parallel controlled trial comparing nalbuphine and tramadol.

BACKGROUND: Postoperative pain in ambulatory surgery is a multifactorial issue affecting patient satisfaction, time of discharge, and rehospitalization. This study evaluated the efficacy and safety of nalbuphine for the treatment of postoperative pain after ambulatory surgery, relative to tramadol. METHODS: This multi-center, randomized, double blind, and controlled study was conducted at 10 centers. In accordance with the inclusion criteria, 492 ambulatory surgery patients were recruited. These patients had moderate to severe pain after ambulatory surgery, with a visual analogue scale (VAS) score > 3 cm. They were randomly divided into an experimental (n = 248) or control (n = 244) group and treated for analgesia with 0.2 mg/kg of nalbuphine or 2 mg/kg of tramadol, respectively. VAS scores, adverse events, and vital signs of the patients were recorded before administration (baseline; T1); and 30 min (T2), 2 h (T3), 4 h (T4), and 6 h (T5) after administration of analgesia. A decrease in pain intensity of more than 25% compared with the baseline was used as an indicator of analgesic efficacy. The experimental and control groups were compared with regard to this indicator of efficacy at each timepoint. RESULTS: The VAS scores of the experimental and control groups were statistically comparable at timepoints T1-T4. At T5, the VAS scores of the experimental group were significantly lower than that of the control. The pain intensity was significantly higher in the experimental group compared with the control at T2 and T3. Adverse events and vital signs were similar for the two groups at each timepoint. CONCLUSIONS: Nalbuphine can provide effective and safe pain relief in patients after ambulatory surgery. TRIAL REGISTRATION: The registration number is ChiCTR-IOR-16010032 , the date of registration was 2016-11-28.

Effects of Connexin 32-Mediated Lung Inflammation Resolution During Liver Ischemia Reperfusion.

BACKGROUND: Hepatic ischemia reperfusion (HIR) leads to a lung inflammatory response and subsequent pulmonary barrier dysfunction. The gap junction communication protein connexin 32 (Cx32), which is widely expressed in the lungs, participates in intercellular signaling. This study determined whether the communication protein Cx32 could affect pulmonary inflammation caused by HIR. METHODS: Mice were randomly allocated into four groups (n = 8/group): (i) Cx32+/+ sham group; (ii) Cx32+/+ HIR model group; (iii) Cx32-/- sham group; and (iv) Cx32-/- HIR model group. Twenty-four hours after surgery, lung tissues were collected for bright field microscopy, western blot (Cx32, JAK2, p-JAK2, STAT3, p-STAT3), and immunofluorescence (ZO-1, 8-OHDG) analyses. The collected bronchoalveolar fluid was tested for levels of interleukin-6 (IL-6), matrix metalloproteinase 12 (MMP-12), and antitrypsin (α1-AT). Lung mmu-miR-26a/b expression was detected using a PCR assay. RESULTS: Increased expression of Cx32 mRNA and protein was noted in the lungs after HIR. Cx32 deletion significantly aggravated pulmonary function from acute lung injury induced by HIR. In addition, Cx32 deletion decreased the protein level of ZO-1 (pulmonary function) and increased the level of the oxidative stress marker 8-OHDG in the lungs. Moreover, in the Cx32-/- HIR model group, the levels of IL-6 and MMP-12 in bronchoalveolar lavage fluid were significantly increased leading to activation of the JAK2/STAT3 pathway, and decreased α1-AT levels. Furthermore, we found mmu-miR-26a/b was significantly downregulated in the Cx32-/- HIR model group. CONCLUSION: HIR leads to acute lung inflammatory injury. Cx32 deletion aggravates hepatic-derived lung inflammation, partly through blocking the transferring of mmu-miR-26a/b and leading to IL-6-related JAK2/STAT3 pathway activation.

Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation.

Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague-Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

Intravenous Anesthetic Protects Hepatocyte from Reactive Oxygen Species-Induced Cellular Apoptosis during Liver Transplantation In Vivo.

BACKGROUND: Liver transplantation leads to liver ischemia/reperfusion (I/R) injury, resulting in early graft dysfunction and failure. Exacerbations of oxidative stress and inflammatory response are key processes in the development of liver I/R injury. Intravenous anesthetic propofol potent effects on free radical scavenging and protects livers against I/R injury. However, the role and mechanism of propofol-mediated hepatic protection in liver transplantation is poorly understood. The aim of this study was to evaluate the role of propofol postconditioning in the liver I/R injury after liver transplantation. METHODS: Forty-eight rats were randomly divided into six groups: rats receiving either sham operation or orthotopic autologous liver transplantation (OALT) in the absence or presence of propofol (high dose and low dose) postconditioning or intralipid control or VAS2870 (Nox2 special inhibitor). Eight hours after OALT or sham operation, parameters of organ injury, oxidative stress, inflammation, and NADPH-associated proteins were assessed. RESULTS: After OALT, severe liver pathological injury was observed that was associated with increases of serum AST and ALT, which were attenuated by propofol postconditioning. In addition, especially high dose of propofol postconditioning reduced TNF-α, IL-1ß, IL-6, TLR4, and NF-κB inflammatory pathway, accompanied with decrease of neutrophil elastase activity, MPO activity, 8-isoprotane, p47phox and gp91phox protein expressions, and increase of SOD activity. Inhibition of Nox2 by VAS2870 conferred similar protective effects in liver transplantation. CONCLUSION: Liver transplantation leads to severe inflammation and oxidative stress with NADPH oxidase activation. Propofol postconditioning reduces liver I/R injury after liver transplantation partly via inhibiting NADPH oxidase Nox2 and the subsequent inflammation and oxidative stress.

Pharmacokinetic Analysis of Propofol Target-Controlled Infusion Models in Chinese Patients with Hepatic Insufficiency.

BACKGROUND Effects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency. MATERIAL AND METHODS We assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 µg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software. RESULTS In the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained. CONCLUSIONS Propofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.

Retrospective Comparative Study on Postoperative Pulmonary Complications After Orthotopic Liver Transplantation Using the Melbourne Group Scale (MGS-2) Diagnostic Criteria.

BACKGROUND Postoperative pulmonary complications (PPCs) after orthotopic liver transplantation (OLT) are associated with poor postoperative survival. However, there are no standard criteria for diagnosis of PPCs. This retrospective study aimed to explore the reliability of the Melbourne Group Scale version 2 (MGS-2) for determining PPCs after OLT. MATERIAL AND METHODS A total of 121 patients were divided into 3 groups. In the PPC and non-PPC groups, PPCs were determined to be present or absent in accordance with both the MGS-2 and the conventional broad criteria for diagnosis of PPCs; in the potential-PPC group, PPCs were determined to be present only in accordance with the conventional broad criteria. The perioperative risk factors for PPCs and prognosis of patients in potential-PPC group were all compared with non-PPC groups and PPC groups. RESULTS The preoperative characteristics of patients in the potential-PPC group were similar to those in non-PPC group. The length of intensive care unit stay (2.26±0.22 vs. 4.75±0.47 days; P=0.017), duration of hospitalization (33.33±1.70 vs. 48.78±2.53 days; P<0.001), and treatment cost (28.01±1.78 vs. 38.35±1.85×10 000 yuan; P=0.018) were significantly less in the potential-PPC group than in the PPC group. Furthermore, in accordance with the MGS-2 criteria for diagnosis of PPCs, patients with PPCs showed poorer overall survival rates than those without (P=0.038). CONCLUSIONS The MGS-2 appears to be a more suitable and reliable tool for diagnosis of PPCs and to identify the post-OLT patients with poorer perioperative characteristics and prognosis.

The differential expression of novel circular RNAs in an acute lung injury rat model caused by smoke inhalation.

Acute lung injury caused by smoke inhalation is a common severe clinical syndrome. This study aimed to investigate the potential expression of circular RNAs during acute lung injury triggered by smoke inhalation. The acute lung injury rat model was established with smoke inhalation from a self-made smoke generator. The occurrence of acute lung injury was validated by an analysis of the bronchoalveolar lavage fluid and hematoxylin-eosin (HE) staining of lung tissues. Next-generation sequencing and quantitative PCR were performed to identify the differentially expressed circular RNAs associated with acute lung injury that was caused by smoke inhalation. The circular form of the identified RNAs was finally verified by multiple RT-PCR-based assays. The bronchoalveolar lavage fluid (BALF) and lung tissue analysis showed that smoke inhalation successfully induced acute injury in rats, as evidenced by the significantly altered cell numbers, including macrophages, neutrophils, and red blood cells, disrupted cell lining, and increased levels of interleukin-1ß, tumor necrosis factor-alpha, and IL-8 in lung tissues. Ten significantly differentially expressed circular RNAs were identified with next-generation sequencing and RT-PCR. The circular form of these RNAs was verified by multiple RT-PCR-based assays. In conclusion, the identified circular RNAs were prevalently and differentially expressed in rat lungs after acute lung injury caused by smoke inhalation.

SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction.

BACKGROUND: Postoperative acute lung injury (ALI) is a severe complication after liver transplantation, which severely affects postoperative patients' survival. The underlying mechanism is largely unknown and effective treatment limited. We explored the role of serpin protease inhibitor B1 (SERPINB1), a potent inhibitor of neutrophil serine proteases, in ALI in liver transplantation and its interplay with signal transducer and activator of transcription 3 (STAT3) and heme oxygenase-1 (HO-1). METHODS: Sprague-Dawley rats underwent orthotopic autologous liver transplantation (OALT) were treated with recombinant SB1 (rSB1) in the absence or presence of STAT3 specific inhibitor, WP1066. Then SB1-siRNA was used to knockdown endogenous SERPINB1. Also, alveolar epithelial cells RLE-6TN and BEAS-2B were exposed to TNF-α without or with SERPINB1 and the roles of STAT3 and HO-1 were examined by respective gene knockdown. Finally, rats were treated with ERK1/2 inhibitor U0126, p38 MAPK inhibitor SB20358, or JNK inhibitor SP600125 after rSB1 pretreatment and then subjected to OALT. RESULTS: OALT resulted in increased pulmonary inflammation and oxidative stress, accompanied by severe lung injury that was coincident with increased pulmonary SERPINB1, HO-1, and STAT3. SERPINB1 gene knockdown increased post-OALT lung injury and pulmonary inflammation. rSB1 administration dose-dependently reduced post-OALT lung injury and decreased pulmonary inflammation and oxidative stress with concomitant enhanced HO-1 and STAT3 protein expression. These protective effects of SERPINB1 were abolished by STAT3 inhibition. Similarly, in RLE-6TN cells and BEAS-2B cells, TNF-α induced cell injury and increased HO-1 and STAT3. SERPINB1 further increased HO-1 and STAT3 protein expression and attenuated TNF-α-induced cellular oxidative stress, apoptotic cells, and mitochondria damage, which were cancelled by STAT3 or HO-1 gene knockdown. Furthermore, these SERPINB1-mediated STAT3/HO-1 activation and pulmonary protective effects were abolished by inhibition of ERK1/2 but not p38 MAPK or JNK. CONCLUSIONS: SERPINB1 decreased inflammation, ameliorated oxidative stress in the lung, and attenuated ALI in rats with OALT by activating HO-1 and it does so through STAT3 and it does so by activating ERK1/2.

Propofol attenuated liver transplantation-induced acute lung injury via connexin43 gap junction inhibition.

BACKGROUND: Postoperative acute lung injury (ALI) is a severe complication after liver transplantation, which influences patient survival rate obviously. However, its mechanisms are unclear and effective therapies are still lacking. The current study focused on effects of propofol on liver transplantation-induced ALI and whether its underlying mechanism was relative with connexin43 (Cx43) alternation. The authors postulated that endotoxin induced enhancement of Cx43 gap junction (GJ) plays a critical role in mediating post liver transplantation ALI and that pretreatment with the anesthetic propofol, known to inhibit gap junction, can confer effective protection. METHODS: Male Sprague-Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx43 inhibitor, enanthol (0.1 mg/kg) and propofol (50 mg/kg), a commonly used anesthetic in clinical anesthesia. In vitro study, BEAS-2B cells, a kind of lung epithelial cell line expressing Cx43, exposed to lipopolysaccharide (LPS), which mainly contributed to ALI. Function of Cx43 GJ was regulated by Cx43 specific inhibitors, gap26 (300 µM) or enhancer, retinoic acid (10 µM) and two specific siRNAs. RESULTS: Compared with the sham group, AOLT results in ALI obviously with plasma endotoxin increase. Cx43 inhibition decreased ALI through inflammatory reaction reduction. In vitro studies, LPS-induced BEAS-2B cells damage was attenuated by Cx43 function inhibition, but amplified by enhancement. Another important finding was propofol reduced Cx43 function and protected against LPS-mediated BEAS-2B cells damage or AOLT-induced ALI, mechanisms of which were also associated with inflammatory reaction decrease. CONCLUSION: Cx43 plays a vital role in liver transplantation-induced ALI. Propofol decreased Cx43 function and protected against ALI in vivo and in vitro. This finding provide a new basis for targeted intervention of organ protection in liver transplantation, even in other kinds of operations.

Alpha7 nicotinic acetylcholine receptor activation attenuated intestine-derived acute lung injury.

BACKGROUND: Intestinal ischemia-reperfusion (IIR) could lead to acute lung injury, associated with severe alveolar epithelial cells inflammatory and oxidative injury. Alpha7 nicotinic acetylcholine receptor (α7nAChR) is an essential component of the cholinergic anti-inflammatory pathway. The aim of this study was to investigate the important role of α7nAChR on the lung subjected to IIR. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into four groups (n = 8 in each): sham group (group S), model group (group M), α7nAChR agonist PNU-282987-treated group (group PNU), and specific α7nAChR antagonist methyllycaconitine-treated group (group MLA). Intestinal IR damage was induced by clamping the superior mesenteric artery for 75 min, followed by a 120-min reperfusion. All rats were killed at 2 h after release of the clamps. The histologic examination of lungs was made, and lung water content was detected. Expression levels of malondialdehyde, tumor necrosis factor alpha, interleukin-6, and superoxide dismutase activity of the lungs were detected. Additionally, expression level of toll-like receptor (TLR)4 and nuclear factor-kappaB (NF-κB p65) in the nucleus of lung tissue and apoptosis-related protein (Bax, Bcl-2, and cleaved-caspase3) were detected using Western blot. RESULTS: Lungs were damaged after intestine IR, manifested by higher lung water content, histologic score, concentrations of interleukin-6, tumor necrosis factor alpha, and malondialdehyde of group M than those of group S, accompanied with decreased superoxide dismutase activity (P < 0.05). PNU treatment could significantly improve the pulmonary function of rats subjected to IIR. These effects of activation of α7nAChR were associated with suppression of TLR4/NF-κB pathway and subsequent reduction of apoptosis-related protein. However, MLA treatment aggravated lung injury. CONCLUSIONS: α7nAChR plays a role in acute lung injury induced by IIR via attenuating lung oxidative stress and inflammation through suppression of TLR4/NF-κB pathway, resulting in reduction of apoptosis in the lung.