Correction: Duan et al. Methionine Restriction Prevents Lipopolysaccharide-Induced Acute Lung Injury via Modulating CSE/H2S Pathway. Nutrients 2022, 14, 322.

In the original publication [...].

Prophylactic Administration with Methylene Blue Improves Hemodynamic Stabilization During Obstructive Jaundice-Related Diseases' Operation: a Blinded Randomized Controlled Trial.

OBJECTIVES: Patients with obstruction jaundice are at a high risk of hypotension and need high volume of fluids and a high dose of catecholamine to maintain organ perfusion during operation procedure. All these likely contribute to high perioperative morbidity and mortality. The aim of the study is to evaluate the effects of methylene blue on the hemodynamics in patients undergoing surgeries associated with obstructive jaundice. DESIGN: A prospective, randomized, and controlled clinical study. SETTING: The enrolled patients randomly received 2 mg/kg of methylene blue in saline or saline (50 ml) before anesthesia induction. The primary outcome was the frequency and dose of noradrenaline administration to maintain mean arterial blood pressure over 65 mmHg or > 80% of baseline, and systemic vascular resistance (SVR) over 800 dyne/s/cm5 during operation. The secondary outcomes were liver and kidney functions, and ICU stay. PATIENTS: Seventy patients were enrolled in the study and randomly assigned to receive either methylene blue or control (n = 35/group). RESULTS: Fewer patients received noradrenaline in the methylene blue group when compared with the control group (13/35 vs 23/35, P = 0.017), and the noradrenaline dose administrated during operation was reduced in the methylene blue group when compared with the control group (0.32 ± 0.57 mg vs 1.787 ± 3.51 mg, P = 0.018). The blood level of creatinine, glutamic oxalacetic transaminase, and glutamic-pyruvic transaminase after the operation was reduced in the methylene blue group when compared with the control group. CONCLUSIONS: Prophylactic administration of methylene blue before operation associated with obstructive jaundice improves hemodynamic stability and short-term prognosis. QUESTION: Methylene blue use prevented refractory hypotension during cardiac surgery, sepsis, or anaphylactic shock. It is still unknown that methylene blue on the vascular hypo-tone associated with obstructive jaundice. FINDINGS: Prophylactic administration with methylene blue improved peri-operative hemodynamic stability, and hepatic and kidney function on the patients with obstructive jaundice. MEANINGS: Methylene blue is a promising and recommended drug for the patients undergoing the surgeries of relief obstructive jaundice during peri-operation management.

Remote ischemic preconditioning enhances aerobic performance by accelerating regional oxygenation and improving cardiac function during acute hypobaric hypoxia exposure.

Remote ischemic preconditioning (RIPC) may improve exercise performance. However, the influence of RIPC on aerobic performance and underlying physiological mechanisms during hypobaric hypoxia (HH) exposure remains relatively uncertain. Here, we systematically evaluated the potential performance benefits and underlying mechanisms of RIPC during HH exposure. Seventy-nine healthy participants were randomly assigned to receive sham intervention or RIPC (4 × 5 min occlusion 180 mm Hg/reperfusion 0 mm Hg, bilaterally on the upper arms) for 8 consecutive days in phases 1 (24 participants) and phase 2 (55 participants). In the phases 1, we measured the change in maximal oxygen uptake capacity (VO2max) and muscle oxygenation (SmO2) on the leg during a graded exercise test. We also measured regional cerebral oxygenation (rSO2) on the forehead. These measures and physiological variables, such as cardiovascular hemodynamic parameters and heart rate variability index, were used to evaluate the intervention effect of RIPC on the changes in bodily functions caused by HH exposure. In the phase 2, plasma protein mass spectrometry was then performed after RIPC intervention, and the results were further evaluated using ELISA tests to assess possible mechanisms. The results suggested that RIPC intervention improved VO2max (11.29%) and accelerated both the maximum (18.13%) and minimum (53%) values of SmO2 and rSO2 (6.88%) compared to sham intervention in hypobaric hypoxia exposure. Cardiovascular hemodynamic parameters (SV, SVRI, PPV% and SpMet%) and the heart rate variability index (Mean RR, Mean HR, RMSSD, pNN50, Lfnu, Hfnu, SD1, SD2/SD1, ApEn, SampEn, DFA1and DFA2) were evaluated. Protein sequence analysis showed 42 unregulated and six downregulated proteins in the plasma of the RIPC group compared to the sham group after HH exposure. Three proteins, thymosin ß4 (Tß4), heat shock protein-70 (HSP70), and heat shock protein-90 (HSP90), were significantly altered in the plasma of the RIPC group before and after HH exposure. Our data demonstrated that in acute HH exposure, RIPC mitigates the decline in VO2max and regional oxygenation, as well as physiological variables, such as cardiovascular hemodynamic parameters and the heart rate variability index, by influencing plasma Tß4, HSP70, and HSP90. These data suggest that RIPC may be beneficial for acute HH exposure.

Learning to predict in-hospital mortality risk in the intensive care unit with attention-based temporal convolution network.

BACKGROUND: Dynamic prediction of patient mortality risk in the ICU with time series data is limited due to high dimensionality, uncertainty in sampling intervals, and other issues. A new deep learning method, temporal convolution network (TCN), makes it possible to deal with complex clinical time series data in ICU. We aimed to develop and validate it to predict mortality risk using time series data from MIMIC III dataset. METHODS: A total of 21,139 records of ICU stays were analysed and 17 physiological variables from the MIMIC III dataset were used to predict mortality risk. Then we compared the model performance of the attention-based TCN with that of traditional artificial intelligence (AI) methods. RESULTS: The area under receiver operating characteristic (AUCROC) and area under precision-recall curve (AUC-PR) of attention-based TCN for predicting the mortality risk 48 h after ICU admission were 0.837 (0.824 -0.850) and 0.454, respectively. The sensitivity and specificity of attention-based TCN were 67.1% and 82.6%, respectively, compared to the traditional AI method, which had a low sensitivity (< 50%). CONCLUSIONS: The attention-based TCN model achieved better performance in the prediction of mortality risk with time series data than traditional AI methods and conventional score-based models. The attention-based TCN mortality risk model has the potential for helping decision-making for critical patients. TRIAL REGISTRATION: Data used for the prediction of mortality risk were extracted from the freely accessible MIMIC III dataset. The project was approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA). Requirement for individual patient consent was waived because the project did not impact clinical care and all protected health information was deidentified. The data were accessed via a data use agreement between PhysioNet, a National Institutes of Health-supported data repository (https://www.physionet.org/), and one of us (Yu-wen Chen, Certification Number: 28341490). All methods were carried out in accordance with the institutional guidelines and regulations.

Methionine Restriction Prevents Lipopolysaccharide-Induced Acute Lung Injury via Modulating CSE/H2S Pathway.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result in high mortality, whereas effective treatments are limited. Methionine restriction (MR) has been reported to offer various benefits against multiple pathological processes of organ injuries. However, it remains unknown whether MR has any potential therapeutic value for ALI/ARDS. The current study was set to investigate the therapeutic potential of MR on lipopolysaccharide (LPS)-induced ALI and its underlying mechanisms. We found that MR attenuated LPS-induced pulmonary edema, hemorrhage, atelectasis, and alveolar epithelial cell injuries in mice. MR upregulated cystathionine-gamma-lyase (CSE) expression and enhanced the production of hydrogen sulfide (H2S). MR also inhibited the activation of Toll-like receptors 4 (TLR4)/NF-κB/NOD-like receptor protein 3 (NLRP3), then reduced IL-1ß, IL-6, and TNF-α release and immune cell infiltration. Moreover, the protective effects of MR on LPS-induced ALI were abrogated by inhibiting CSE, whereas exogenous H2S treatment alone mimicked the protective effects of MR in Cse-/- mice after LPS administration. In conclusion, our findings showed that MR attenuated LPS-induced lung injury through CSE and H2S modulation. This work suggests that developing MR towards clinical use for ALI/ARDS patients may be a valuable strategy.

A Simple and Quick Screening Method for Intrapulmonary Vascular Dilation in Cirrhotic Patients Based on Machine Learning.

BACKGROUND AND AIMS: Screening for hepatopulmonary syndrome in cirrhotic patients is limited due to the need to perform contrast enhanced echocardiography (CEE) and arterial blood gas (ABG) analysis. We aimed to develop a simple and quick method to screen for the presence of intrapulmonary vascular dilation (IPVD) using noninvasive and easily available variables with machine learning (ML) algorithms. METHODS: Cirrhotic patients were enrolled from our hospital. All eligible patients underwent CEE, ABG analysis and physical examination. We developed a two-step model based on three ML algorithms, namely, adaptive boosting (termed AdaBoost), gradient boosting decision tree (termed GBDT) and eXtreme gradient boosting (termed Xgboost). Noninvasive variables were input in the first step (the NI model), and for the second step (the NIBG model), a combination of noninvasive variables and ABG results were used. Model performance was determined by the area under the curve of receiver operating characteristics (AUCROCs), precision, recall, F1-score and accuracy. RESULTS: A total of 193 cirrhotic patients were ultimately analyzed. The AUCROCs of the NI and NIBG models were 0.850 (0.738-0.962) and 0.867 (0.760-0.973), respectively, and both had an accuracy of 87.2%. For both negative and positive cases, the recall values of the NI and NIBG models were both 0.867 (0.760-0.973) and 0.875 (0.771-0.979), respectively, and the precisions were 0.813 (0.690-0.935) and 0.913 (0.825-1.000), respectively. CONCLUSIONS: We developed a two-step model based on ML using noninvasive variables and ABG results to screen for the presence of IPVD in cirrhotic patients. This model may partly solve the problem of limited access to CEE and ABG by a large numbers of cirrhotic patients.

Intraoperative Hypotension and Related Risk Factors for Postoperative Mortality After Noncardiac Surgery in Elderly Patients: A Retrospective Analysis Report.

BACKGROUND: Blood pressure fluctuation is very common during non-cardiac surgery in elderly. This retrospective study was to analyse whether intraoperative hypotension in elderly and other risk factors relate to the postoperative mortality. METHODS: A total of 118 cases (Observational group), who underwent noncardiac surgery in three medical centers between September 2014 and March 2017, and died in the hospital after the noncardiac surgery. With 1:2 ratio of propensity matching, 236 survival cases (Control group) were selected for comparison analyses with the death cases. Intraoperative blood pressure and perioperative parameters from both groups were collected from electronic anaesthesia charts. Data were analysed with univariate logistic regression analysis where variables with p values less than 0.05 were analysed with multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve was constructed. RESULTS: There are five risk factors related to postoperative death in elderly patients: ASA grade, COPD, emergency surgery, general anesthesia, 60 < MAP ≤ 65mmHg (OR > 1), and one factor may reduce the risk of postoperative mortality, which is PACU therapy (OR < 1). Compared with the Control group, the Observational group had a higher proportion of cerebral hernia, kidney injury and trauma (p < 0.001). The intraoperative blood transfusion volume and intraoperative blood loss volume were higher in the Observational group than the Control group (p < 0.001). The proportion of using vasoactive drugs was higher in the Observational group (p < 0.001), and there was more urine output during the operation in the Observational group (p = 0.005). CONCLUSION: The intraoperative MAP of geriatric patients lower than 65mmHg is highly related to the postoperative mortality. Elderly patients with emergency surgery, high ASA grade and a history of COPD have an increased risk of postoperative mortality. General anesthesia is a risk factor for postoperative death in elderly patients, and the PACU therapy is a protective factor to avoid postoperative death. TRIAL REGISTRATION: This study has been retrospectively registered in the Chinese Clinical Trials Registry (ChiCTR2000038912, 10/10/2020).

Effects of circadian rhythm on Narcotrend index and target-controlled infusion concentration of propofol anesthesia.

BACKGROUND: The effects of circadian rhythms on drug metabolism and efficacy are being increasingly recognized. However, the extent to which they affect general anesthesia remains unclear. This study aims to investigate the effects of circadian rhythms on anesthetic depth and the concentrations of propofol target-controlled infusion (TCI). METHODS: Sixty patients undergoing laparoscopic surgeries were sequentially assigned to four groups. Group ND (n = 15): Propofol TCI with Narcotrend monitor during the day (8:00-18:00), Group NN (n = 15): Propofol TCI with Narcotrend monitor during the night (22:00-5:00), Group CLTD (n = 15): Propofol closed-loop TCI guided by bispectral index (BIS) during the day (8:00-18:00), Group CLTN (n = 15): Propofol closed-loop TCI guided by BIS during the night (22:00-5:00). The Narcotrend index, mean arterial pressure (MAP) and heart rate (HR) were compared between group ND and NN at 7 time points, from 5 min before induction to the end of operation. The propofol TCI concentrations, MAP and HR were compared between group CLTD and CLTN at 7 time points, from 5 min after induction to the end of operation. RESULTS: The Narcotrend index, MAP, and HR in group NN were lower than those in group ND from the beginning of mechanical ventilation to the end of operation (p < 0.05). The propofol TCI concentrations in group CLTN were lower than those in group CLTD from the beginning of operation to the end of operation (p < 0.05). CONCLUSION: Circadian rhythms have a significant effect on the depth of anesthesia and drug infusion concentrations during propofol TCI. When using general anesthesia during night surgery, the propofol infusion concentration should be appropriately reduced compared to surgery during the day. TRIAL REGISTRATION: The present study was registered on the ClinicalTrials.gov website ( NCT02440269 ) and approved by the Medical Ethics Committee of Southwest Hospital of Third Military Medical University (ethics lot number: 2016 Research No. 93). All patients provided informed written consent to participate in the study.

Effects of dexmedetomidine on the function of distal organs and oxidative stress after lower limb ischaemia-reperfusion in elderly patients undergoing unilateral knee arthroplasty.

AIMS: This study aims to evaluate the effects of dexmedetomidine on organ function, inflammation response, and oxidative stress in elderly patients following iatrogenic lower limb ischaemia-reperfusion (IR) during unilateral total knee arthroplasty. METHODS: Following unilateral total knee arthroplasty, 54 elderly patients were randomized to receive either intraoperative intravenous injection of dexmedetomidine (n = 27) or equivalent volume of 0.9% saline (n = 27). Blood samples were harvested at 5 minutes before lower limb tourniquet release (baseline); and 1, 6 and 24 hours after tourniquet release. Surrogate markers of cardiac, pulmonary, hepatic and renal function, oxidative stress, inflammatory response, along with parasympathetic and sympathetic activity were recorded and analysed. RESULTS: The levels of blood xanthine oxidase, creatine kinase, lactic acid and respiratory index increased in patients following tourniquet-induced lower limb IR injury. Dexmedetomidine administration decreased the respiratory index (P = .014, P = .01, and P = .043) and the norepinephrine level (P < .001) at 1, 6 and 24 hours; and decreased the xanthine oxidase level (P = .049, P < .001) at 6 and 24 hours after tourniquet release compared with the Control group. Other measurements, including creatine kinase isoenzyme, lactate dehydrogenase, creatinine, urea nitrogen, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, malondialdehyde, interleukin-1, interleukin-6 and tumour necrosis factor-α, were not statistically significantly different between the 2 groups. CONCLUSIONS: Intraoperative dexmedetomidine administration in elderly patients dampens the deterioration in respiratory function and suppresses the oxidative stress response in elderly patients following iatrogenic lower limb IR injury.

The Effect of Mechanical Ventilation With Low Tidal Volume on Blood Loss During Laparoscopic Liver Resection: A Randomized Controlled Trial.

BACKGROUND: Control of bleeding during laparoscopic liver resection (LLR) is important for patient safety. It remains unknown what the effects of mechanical ventilation with varying tidal volumes on bleeding during LLR. Thus, this study aims to investigate whether mechanical ventilation with low tidal volume (LTV) reduces surgical bleeding during LLR. METHODS: In this prospective, randomized, and controlled clinical study, 82 patients who underwent scheduled LLR were enrolled and randomly received either mechanical ventilation with LTV group (6-8 mL/kg) along with recruitment maneuver (once/30 min) without positive end-expiratory pressure (PEEP) or conventional tidal volume (CTV; 10-12 mL/kg) during parenchymal resection. The estimated volume of blood loss during parenchymal resection and the incidence of postoperative respiratory complications were compared between 2 groups. RESULT: The estimated volume of blood loss (median [interquartile range {IQR}]) was decreased in the LTV group compared to the CTV group (301 [148, 402] vs 394 [244, 672] mL, P = .009); blood loss per cm2 of transected surface of liver (5.5 [4.1, 7.7] vs 12.2 [9.8, 14.4] mL/cm2, P < .001) and the risk of clinically significant estimated blood loss (>800 mL) were reduced in the LTV group compared to the CTV group (0/40 vs 8/40, P = .003). Blood transfusion was decreased in the LTV group compared to the CTV group (5% vs 20% of patients, P = .043). No patient in the LTV group but 2 patients in the CTV group were switched from LLR to open hepatectomy. Airway plateau pressure was lower in the LTV group compared to the CTV group (mean ± standard deviation [SD]) (12.7 ± 2.4 vs 17.5 ± 3.5 cm H2O, P = .002). CONCLUSIONS: Mechanical ventilation with LTV may reduce bleeding during laparoscopic liver surgery.

A better method for the dynamic, precise estimating of blood/haemoglobin loss based on deep learning of artificial intelligence.

BACKGROUND: Dynamic and precise estimation of blood loss (EBL) is quite important for perioperative management. To date, the Triton System, based on feature extraction technology (FET), has been applied to estimate intra-operative haemoglobin (Hb) loss but is unable to directly assess the amount of blood loss. We aimed to develop a method for the dynamic and precise EBL and estimate Hb loss (EHL) based on artificial intelligence (AI). METHODS: We collected surgical patients' non-recycled blood to generate blood-soaked sponges at a set gradient of volume. After image acquisition and preprocessing, FET and densely connected convolutional networks (DenseNet) were applied for EBL and EHL. The accuracy was evaluated using R2, the mean absolute error (MAE), the mean square error (MSE), and the Bland-Altman analysis. RESULTS: For EBL, the R2, MAE and MSE for the method based on DenseNet were 0.966 (95% CI: 0.962-0.971), 0.186 (95% CI: 0.167-0.207) and 0.096 (95% CI: 0.084-0.109), respectively. For EHL, the R2, MAE and MSE for the method based on DenseNet were 0.941 (95% CI: 0.934-0.948), 0.325 (95% CI: 0.293-0.355) and 0.284 (95% CI: 0.251-0.317), respectively. The accuracies of EBL and EHL based on DenseNet were more satisfactory than that of FET. Bland-Altman analysis revealed a bias of 0.02 ml with narrow limits of agreement (LOA) (-0.47 to 0.52 mL) and of 0.05 g with narrow LOA (-0.87 to 0.97 g) between the methods based on DenseNet and actual blood loss and Hb loss. CONCLUSIONS: We developed a simpler and more accurate AI-based method for EBL and EHL, which may be more fit for surgeries primarily using sponges and with a small to medium amount of blood loss.

Dexmedetomidine-Mediated Prevention of Renal Ischemia-Reperfusion Injury Depends in Part on Cholinergic Anti-Inflammatory Mechanisms.

BACKGROUND: Organ ischemia-reperfusion injury often induces local and systemic inflammatory responses, which in turn worsen organ injury. These inflammatory responses can be regulated by the central nervous system, particularly by the vagal nerve and nicotinic acetylcholine receptors, which are the key components of cholinergic anti-inflammatory pathway. Activation of the cholinergic anti-inflammatory pathway can suppress excessive inflammatory responses and be a potential strategy for prevention of ischemia-reperfusion injury of organs including the kidney. METHODS: Vagal nerve activity, plasma acetylcholine, catecholamine and inflammatory mediators, renal tissue injury, and cell death were measured in mice with bilateral renal ischemia/reperfusion with or without treatment with dexmedetomidine (Dex), an α2-adrenergic receptor agonist. RESULTS: Dex significantly increased the discharge frequency of the cervical vagal nerve by up to 142 Hz (mean) (P < .001), and preserved kidney gross morphology and structure and attenuated cell apoptosis after ischemia-reperfusion. Furthermore, Dex also significantly increased acetylcholine release to 135.8 pmol/L (median) when compared to that (84.7 pmol/L) in the sham group (P < .001) and reduced the levels of several inflammatory mediators induced by renal ischemia/reperfusion. All the effects were abolished by vagotomy, splenectomy, or combinative administration of atipamezole, an α2-adrenergic receptor antagonist. CONCLUSIONS: Our findings suggest that Dex provides renoprotection, at least in part, through anti-inflammatory effects of the parasympathetic nervous system activation in addition to its direct actions on α2-adrenergic receptors.

Osteopontin mediates necroptosis in lung injury after transplantation of ischaemic renal allografts in rats.

BACKGROUND: Respiratory complications after surgery are associated with morbidity and mortality. Acute lung injury can result from the systemic inflammatory response after acute kidney injury. The mechanisms behind this remote injury are not fully understood. In this study, a renal transplantation model was used to investigate remote lung injury and the underlying molecular mechanisms, especially the role of osteopontin (OPN). METHODS: In vitro, human lung epithelial cell line (A549) and monocyte/macrophage cell line (U937) were challenged with tumour necrosis factor-alpha (TNF-α) in combination with OPN. In vivo, the Fischer rat renal grafts were extracted and stored in 4°C University of Wisconsin preserving solution for up to 16 h, and transplanted into Lewis rat recipients. Lungs were harvested on Day 1 after grafting for further analysis. RESULTS: Renal engraftment was associated with pathological changes and an increase in TNF-α and interleukin-1 beta in the lung of the recipient. OPN, endoplasmic reticulum (ER) stress, and necroptosis were increased in both the recipient lung and A549 cells challenged with TNF-α. Exogenous OPN exacerbated lung injury and necroptosis. Suppression of OPN through siRNA reduced remote lung injury by mitigation of ER stress, necroptosis, and the inflammatory response. CONCLUSIONS: Renal allograft transplant triggers recipient remote lung injury, which is, in part, mediated by OPN signalling. This study may provide a molecular basis for strategies to be developed to treat such perioperative complications.

Inhibition of tyrosine kinases protects against lipopolysaccharide-induced acute lung injury by preventing nuclear export of Nrf2.

Acute Lung Injury is a common severe pathological condition that is usually caused by lipopolysaccharide (LPS) infection from bacteria. Enhanced activity of nuclear factor erythroid 2-related factor 2 (Nrf2) could attenuate LPS induced lung injury, However, it still remains unknown whether the enhanced activity of Nrf2 via suppression of Nrf2 nucleus export attenuates the LPS induced lung injury. The aim of this study is to investigate the effects of inhibitors of Fyn on the LPS-induced acute lung injury and to explore its underlying molecular mechanisms. Nrf2 localization in the cells was observed by using confocal microscopy and its transcriptional activation was measured by Electrophoretic Mobility Shift Assay and controlled genes expression levels. The lung injury severity was examined by histopathological scoring and oxidative stress level. In this study, we showed that PP2, LMB, and Nrf2 Y568A abrogated Nrf2 nuclear export and thus enhance the Nrf2 transcriptional activity. PP2 attenuated lung injury and the reduction of cells viability induced by LPS. The current study demonstrated, for the first time, that increase of expression of Nrf2 controlled protective genes via suppression of Nrf2 nucleus export could attenuate lung injury.

Argon Mitigates Impaired Wound Healing Process and Enhances Wound Healing In Vitro and In Vivo.

Diabetic foot ulcers are associated with significant morbidity and mortality, and current treatments are far from optimal. Chronic wounds in diabetes are characterised by impaired angiogenesis, leukocyte function, fibroblast proliferation, and keratinocyte migration and proliferation. Methods: We tested the effect of exposure to argon gas on endothelial cell, fibroblast, macrophage and keratinocyte cell cultures in vitro and in vivo of a streptozotocin-induced diabetic mouse model. Results: Exposure to normobaric argon gas promotes multiple steps of the wound healing process. Argon accelerated angiogenesis, associated with upregulation of pro-angiogenic Angiopoietin-1 and vascular endothelial growth factor (VEGF) signalling in vitro and in vivo. Treatment with argon enhanced expression of transforming growth factor (TGF)-ß, early recruitment of macrophages and keratinocyte proliferation. Argon had a pro-survival effect, inducing expression of cytoprotective mediators B-cell lymphoma 2 and heme oxygenase 1. Argon was able to accelerate wound closure in a diabetic mouse model. Conclusion: Together these findings indicate that argon gas may be a promising candidate for clinical use in treatment of diabetic ulcers.

A self-organized actomyosin drives multiple intercellular junction disruption and directly promotes neutrophil recruitment in lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI), with the hallmarks of vascular integrity disruption and neutrophil recruitment, is associated with high morbidity and mortality. Enhanced actomyosin assembly contributes to endothelial cell contact dysfunction. However, the roles and mechanisms of actomyosin assembly in ALI are not totally clear. We investigated the dynamic alterations and roles of actomyosin in ALI in vivo and in vitro models induced by LPS. Pulmonary levels of E-cadherin, vascular endothelial-cadherin, occludin, myosin phosphatase target subunit 1, and thymosin ß4 were decreased, and the number and activity of neutrophils and the levels of actomyosin, p-ρ-associated protein kinase, p-myosin light-chain kinase, and profilin1 were increased within 3 d after LPS administration, and then, those alterations were recovered within the next 4 d, which was consistent with the alterations of lung histology, vascular permeability, edema, and serum levels of IL-6 and TNF-α. Direct or indirect inhibition of increased F-actin or myosin assembly ameliorated the reduction of intercellular junction molecules, the activation and migration of neutrophils, and the degree of lung injury. Moreover, neutrophil activation further promoted actomyosin assembly and aggravated lung injury. Conclusively, the enhancement of self-organized actomyosin contributes to alveolar-capillary barrier disruption and neutrophil recruitment in inflammatory response, which is a potential therapeutic target for ALI.-Chen, B., Yang, Z., Yang, C., Qin, W., Gu, J., Hu, C., Chen, A., Ning, J., Yi, B., Lu, K. A self-organized actomyosin drives multiple intercellular junction disruption and directly promotes neutrophil recruitment in lipopolysaccharide-induced acute lung injury.

Dexmedetomidine attenuates lung apoptosis induced by renal ischemia-reperfusion injury through α2AR/PI3K/Akt pathway.

BACKGROUND: Acute lung injury caused by renal ischemia-reperfusion is one of the leading causes of acute kidney injury-related death. Dexmedetomidine, an α2-adrenergic agonist sedative, has been found to have protective effects against acute kidney injury and remote lung injury. We sought to determine whether dexmedetomidine can exert its anti-apoptotic effects in acute lung injury after acute kidney injury, in addition to its common anti-inflammatory effects, and to determine the underlying mechanisms. METHODS: In vivo, acute kidney injury was induced by 60 min of kidney ischemia (bilateral occlusion of renal pedicles) followed by 24 h of reperfusion. Mice received dexmedetomidine (25 µg/kg, i.p.) in the absence or presence of α2-adrenergic antagonist atipamezole (250 µg/kg, i.p.) before IR. Histological assessment of the lung was conducted by HE staining and arterial blood gases were measured. Lung apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. The expression of caspase 3 and p-Akt in lung tissue was detected by western blot. In vitro, C57BL/6J mice pulmonary microvascular endothelial cells were treated with serum from mice obtained following sham or IR. Dexmedetomidine was given before serum stimulation in cells, alone or with atipamezole or LY294002. Cell viability was assessed by CCK 8 assay. Cell apoptosis was examined by Hoechst staining and Annexin V-FITC/PI staining flow cytometry analysis. Mitochondrial membrane potential was measured by flow cytometry. The expression of p-Akt, caspase 3, Bcl-2 and Bax was measured by western blot. RESULTS: In vivo, dexmedetomidine remarkably mitigated pathohistological changes and apoptosis and significantly increased p-Akt expression in the lung. In addition, dexmedetomidine also slightly improved oxygenation in mice after IR, which can be abolished by atipamezole. In vitro, dexmedetomidine significantly inhibited IR serum-induced loss of viability and apoptosis in PMVECs. Dexmedetomidine increased p-Akt in a time- and dose-dependent manner, and down-regulated the expression of caspase 3 and Bax and up-regulated the Bcl-2 expression in PMVECs. The changes of MMP were also improved by dexmedetomidine. Whilst these effects were abolished by Atipamezole or LY294002. CONCLUSION: Our results demonstrated that dexmedetomidine attenuates lung apoptosis induced by IR, at least in part, via α2AR/PI3K/Akt pathway.

AMD3100 treatment attenuates pulmonary angiogenesis by reducing the c-kit (+) cells and its pro-angiogenic activity in CBDL rat lungs.

Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit+ cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25mg/kg/day, i.p.) or 0.9% saline for 3weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit+ cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit+ cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic-related functions of c-kit+ cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit+ cells and microvessel counts and improved arterial oxygenation within 3weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit+ cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit+ cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment.

Transforming growth factor ß plays an important role in enhancing wound healing by topical application of Povidone-iodine.

Povidone-iodine (PVI) is principally used as an antimicrobial agent. It has been found that 0.5% PVI can attenuate congestion, edema and pain induced by pressure sores. Thus this study aimed to assess the effects of 0.5% PVI on acute skin wounds. Four full-thickness excisional wounds were generated on the dorsal skin of male Sprague-Dawley rats with a 10-mm sterile punch. Two wounds were left untreated and the other two were dressed with gauze with 0.5% PVI for 1 hour per day for the first 5 days after injury. 10-mm full-thickness excisional wounds were also generated on the dorsal skin of rats treated with 10 mg/kg SB431542 and all wounds were treated with 0.5% PVI for 5 days. PVI treatment enhanced wound healing via promotion of expression of α SMA and TGF ß, neovascularization and re-epithelialization. Interleukin 6 was reduced following PVI treatment. Inhibition of TGF ß abolished the effect of PVI treatment on wound closure. These data show that topical application of 0.5% PVI could promote acute skin wound healing though increased expression of TGF ß leading to enhanced formation of granulation tissue, even in the absence of obvious infection.

Deferoxamine regulates neuroinflammation and iron homeostasis in a mouse model of postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially amongst elderly patients. Neuroinflammation and iron homeostasis are key hallmarks of several neurological disorders. In this study, we investigated the role of deferoxamine (DFO), a clinically used iron chelator, in a mouse model of surgery-induced cognitive dysfunction and assessed its neuroprotective effects on neuroinflammation, oxidative stress, and memory function. METHODS: A model of laparotomy under general anesthesia and analgesia was used to study POCD. Twelve to 14 months C57BL/6J male mice were treated with DFO, and changes in iron signaling, microglia activity, oxidative stress, inflammatory cytokines, and neurotrophic factors were assessed in the hippocampus on postoperative days 3, 7, and 14. Memory function was evaluated using fear conditioning and Morris water maze tests. BV2 microglia cells were used to test the anti-inflammatory and neuroprotective effects of DFO. RESULTS: Peripheral surgical trauma triggered changes in hippocampal iron homeostasis including ferric iron deposition, increase in hepcidin and divalent metal transporter-1, reduction in ferroportin and ferritin, and oxidative stress. Microglia activation, inflammatory cytokines, brain-derived neurotropic factor impairments, and cognitive dysfunction were found up to day 14 after surgery. Treatment with DFO significantly reduced neuroinflammation and improved cognitive decline by modulating p38 MAPK signaling, reactive oxygen species, and pro-inflammatory cytokines release. CONCLUSIONS: Iron imbalance represents a novel mechanism underlying surgery-induced neuroinflammation and cognitive decline. DFO treatment regulates neuroinflammation and microglia activity after surgery.