Connexin32 gap junction channels deliver miR155-3p to mediate pyroptosis in renal ischemia-reperfusion injury.

OBJECTIVES: To explore whether the gap junction (GJ) composed by connexin32(Cx32) mediated pyroptosis in renal ischemia-reperfusion(I/R) injury via transmitting miR155-3p, with aim to provide new strategies for the prevention and treatment of acute kidney injury (AKI) after renal I/R. METHODS: 8-10 weeks of male C57BL/ 6 wild-type mice and Cx32 knockdown mice were divided into two groups respectively: control group and renal I/R group. MCC950 (50 mg/kg. ip.) was used to inhibit NLRP3 in vivo. Human kidney tubular epithelial cells (HK - 2) and rat kidney tubular epithelial cells (NRK-52E) were divided into high-density group and low-density group, and treated with hypoxia reoxygenation (H/R) to mimic I/R. The siRNA and plasmid of Cx32, mimic and inhibitor of miR155-3p were transfected into HK - 2 cells respectively. Kidney pathological and functional injuries were measured. Western Blot and immunofluorescent staining were used to observe the expression of NLRP3, GSDMD, GSDMD-N, IL - 18, and mature IL-18. The secretion of IL-18 and IL-1ß in serum, kidney tissue and cells supernatant were detected by enzyme-linked immuno sorbent assay (ELISA) kit, and the expression of NLPR3 and miR155-3p were detected by RT-qPCR and fluorescence in situ hybridization (FISH). RESULTS: Tubular pyroptosis were found to promote AKI after I/R in vivo and Cx32-GJ regulated pyroptosis by affecting the expression of miR155-3p after renal I/R injury. In vitro, H/R could lead to pyroptosis in HK-2 and NRK-52E cells. When the GJ channels were not formed, and Cx32 was inhibited or knockdown, the expression of miR155-3p was significantly reduced and the pyroptosis was obviously inhibited, leading to the reduction of injury and the increase of survival rate. Moreover, regulating the level of miR155-3p could affect survival rate and pyroptosis in vitro after H/R. CONCLUSIONS: The GJ channels composed of Cx32 regulated tubular pyroptosis in renal I/R injury by transmitting miR155-3p. Inhibition of Cx32 could reduce the level of miR155-3p further to inhibit pyroptosis, leading to alleviation of renal I/R injury which provided a new strategy for preventing the occurrence of AKI. Video Abstract.

Intravenous Lidocaine Alleviates the Pain of Propofol Injection by Local Anesthetic and Central Analgesic Effects.

Objective: Lidocaine alleviates propofol injection pain. However, whether lidocaine works through a local anesthetic effect at the site of intravenous injection or through a systemic effect on the central nervous system remains unknown. This study aimed to determine the pain-alleviating mechanism of lidocaine. Design: A randomized controlled study. Setting: A gastroscopy facility. Methods: The study was divided into two parts. Part 1 involved 717 patients who were randomly assigned into five groups. Groups PR, RL20, and RL40 received normal saline or saline containing 20 or 40 mg of lidocaine, injected via the vein on the right hand. Groups LL20 and LL40 received 20 or 40 mg of lidocaine, injected via the vein on the left hand. Part 2 involved 378 patients who were randomly assigned into five groups. Groups RL40, RL1.2, and RL1.5 received 40 mg, 1.2 mg/kg, and 1.5 mg/kg of lidocaine, injected via the vein on the right hand. Groups LL1.2 and LL1.5 received 1.2 or 1.5 mg/kg of lidocaine, injected via the vein on the left hand. All received 2 mg/kg of propofol via the vein on the right hand two minutes later. Injection pain and patient satisfaction were recorded. Results: The incidence of pain of group RL40 was lower than that of group PR. The incidence of pain of group LL1.2 was higher than that of other groups. Conclusions: A dosage of 40 mg lidocaine is an appropriate dosage to alleviate propofol injection pain within the same vein. Lidocaine reduces propofol injection pain through both a local anesthetic effect and a central analgesic effect when the dosage reaches 1.5 mg/kg.

Propofol attenuated acute kidney injury after orthotopic liver transplantation via inhibiting gap junction composed of connexin 32.

BACKGROUND: Postliver transplantation acute kidney injury (AKI) severely affects patient survival, whereas the mechanism is unclear and effective therapy is lacking. The authors postulated that reperfusion induced enhancement of connexin32 (Cx32) gap junction plays a critical role in mediating postliver transplantation AKI and that pretreatment/precondition 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 Cx32 inhibitor, 2-aminoethoxydiphenyl borate or propofol (50 mg/kg) (n = 8 per group). Also, kidney tubular epithelial (NRK-52E) cells were subjected to hypoxia-reoxygenation and the function of Cx32 was manipulated by three distinct mechanisms: cell culture in different density; pretreatment with Cx32 inhibitors or enhancer; Cx32 gene knock-down (n = 4 to 5). RESULTS: AOLT resulted in significant increases of renal Cx32 protein expression and gap junction, which were coincident with increases in oxidative stress and impairment in renal function and tissue injury as compared to sham group. Similarly, hypoxia-reoxygenation resulted in significant cellular injury manifested as reduced cell growth and increased lactate dehydrogenase release, which was significantly attenuated by Cx32 gene knock-down but exacerbated by Cx32 enhancement. Propofol inhibited Cx32 function and attenuated post-AOLT AKI. In NRK-52E cells, propofol reduced posthypoxic reactive oxygen species production and attenuated cellular injury, and the cellular protective effects of propofol were reinforced by Cx32 inhibition but cancelled by Cx32 enhancement. CONCLUSION: Cx32 plays a critical role in AOLT-induced AKI and that inhibition of Cx32 function may represent a new and major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-AOLT AKI.

Ulinastatin prevents acute lung injury led by liver transplantation.

BACKGROUND: Little is known regarding the effect of ulinastatin (UTI) on acute lung injury (ALI) induced by orthotopic liver transplantation. This study aims to investigate the protective effect of UTI on ALI induced by orthotopic autologous liver transplantation (OALT) in a rat model and to explore the potential underlying mechanism. MATERIALS AND METHODS: Rats were randomly allocated into the following four groups (n = 8 each): (i) sham control group (group sham); (ii) model group (underwent OALT) (group model); (iii) low-dose UTI-treated group (group u1), with UTI (50 U/g) administered intravenously both before the portal vein was occluded and after liver reperfusion started; and (iv) high-dose UTI-treated group (group uh), with UTI (100 U/g) given in the same way as group ul. The lung pathologic parameters, lung water content, and levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD) activity, RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1), and peroxiredoxin-2 (Prx-2) were assessed 8 h after OALT was performed. RESULTS: According to histology, there was severe damage in the lung of group model accompanied by increases in the TNF-α, IL-1ß, IL-6, and MDA levels and decreases in SOD activity and the expression of RBCK1 and Prx-2. UTI treatment significantly reduced the pathologic scores, lung water content, and TNF-α, IL-1ß, IL-6, and MDA levels while restoring the SOD activity and expression of RBCK1 and Prx-2. Furthermore, compared with group u1, treatment with a high dose of UTI resulted in a better protective effect on the lung when assessed by the TNF-α, IL-1ß, IL-6, and MDA levels and SOD activity. CONCLUSIONS: UTI dose-dependently attenuates ALI that is induced by OALT in this rat model, which is mainly due to the suppression of the inflammatory response and oxidant stress, which may, in turn, be mediated by the upregulation of RBCK1 and Prx-2 expression.

In Vivo Evaluation of the Ameliorating Effects of Small-Volume Resuscitation with Four Different Fluids on Endotoxemia-Induced Kidney Injury.

Acute kidney injury associated with renal hypoperfusion is a frequent and severe complication during sepsis. Fluid resuscitation is the main therapy. However, heart failure is usually lethal for those patients receiving large volumes of fluids. We compared the effects of small-volume resuscitation using four different treatment regimens, involving saline, hypertonic saline (HTS), hydroxyethyl starch (HES), or hypertonic saline hydroxyethyl starch (HSH), on the kidneys of rats treated with lipopolysaccharide (LPS) to induce endotoxemia. LPS injection caused reduced and progressively deteriorated systemic (arterial blood pressure) and renal hemodynamics (renal blood flow and renal vascular resistance index) over time. This deterioration was accompanied by marked renal functional and pathological injury, as well as an oxidative and inflammatory response, manifesting as increased levels of tumor necrosis factor-α, nitric oxide, and malondialdehyde and decreased activity of superoxide dismutase. Small-volume perfusion with saline failed to improve renal and systemic circulation. However, small-volume perfusion with HES and HSH greatly improved the above parameters, while HTS only transiently improved systemic and renal hemodynamics with obvious renal injury. Therefore, single small-volume resuscitation with HES and HSH could be valid therapeutic approaches to ameliorate kidney injury induced by endotoxemia, while HTS transiently delays injury and saline shows no protective effects.

Pivotal role of mast cell carboxypeptidase A in mediating protection against small intestinal ischemia-reperfusion injury in rats after ischemic preconditioning.

AIM OF THE STUDY: Mast cell (MC) degranulation contributes to the protection mediated by ischemic preconditioning (IPC); however, the precise mechanisms underlying this protection remain largely unknown. Mast cell carboxypeptidase A (MC-CPA) is released solely from MCs and plays a critical role in degrading toxins and endothelin 1 (ET-1). The present study sought to explore whether MC-CPA is involved in the process of IPC in a rodent model of small intestinal ischemia reperfusion (IIR) injury. MATERIALS AND METHODS: IIR injuries were induced in Sprague-Dawley rats by clamping the superior mesenteric artery for 60 min followed by reperfusion for 2 h. One cycle of 10 min intestinal ischemia and 10 min of reperfusion was used in the IPC group, and the MC stabilizer cromolyn sodium and MC potato carboxypeptidase inhibitor were administered before the start of IPC. At the end of experiment, intestine tissue was obtained for assays of the MC-CPA3, tumor necrosis factor-α, interleukin-6, and ET-1 contents and myeloperoxidase activities. Intestinal histologic injury scores and MC degranulation were assessed. Apoptosis indices and cleaved caspase- 3 protein expressions were quantified. RESULTS: IIR resulted in severe injury, as evidenced by significant increases in injury scores and MC-CPA3, tumor necrosis factor-α, interleukin-6, and ET-1 contents that were accompanied with concomitant elevations in cleaved caspase 3 expression, apoptosis indices, and myeloperoxidase activities. IPC induced a significant increase in MC-CPA3, induced MC degranulation, and attenuated IIR injury by downregulating IIR-induced biochemical changes, whereas cromolyn sodium and potato carboxypeptidase inhibitor abolished the IPC-mediated changes. CONCLUSIONS: These data suggest that IPC protected against IIR injury via the MC degranulation-mediated release of MC-CPA.

Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.

Background: Obesity and type 2 diabetes mellitus (DM) contribute to a higher mortality rate in patients with septic acute kidney injury (AKI) during sepsis. Reactive oxygen species (ROS) is the major injury factor for sepsis. This study was aimed at exploring the potential therapeutic drug for septic AKI targeting on ROS. Methods: A murine septic AKI model was established in both wild-type and high-fat diet-fed (HFD) mice. NADPH oxidase inhibitor Vas2870 was used in vivo to explore the role of NADPH oxidase in ROS release in septic AKI in diabetic mice. Ferrostatin-1 was administered to investigate the role of ferroptosis in ROS accumulation during NADPH oxidase activating in septic AKI in diabetic mice. Results: Compared to chow diet-fed mice, HFD diabetic mice which were subjected to LPS exhibited aggravated renal function (blood urea nitrogen, creatinine clearance, and serum cystatin C) and oxidative stress (malondialdehyde, 4-HNE, ROS, 8-OHdG, and NADPH oxidase), thus resulting in a higher mortality rate. Septic renal injury was significantly attenuated by the ferroptosis inhibitor Fer-1 in HFD-challenged mice. Furthermore, ferroptosis accumulation and related protein expression (ASCL4, FTH1, and GPX4) were altered by LPS stimulation in HFD-challenged mice and suppressed by NADPH oxidase inhibition via Vas2870 in vivo. In summary, NADPH inhibition restored septic renal function from injury by suppressing ferroptosis accumulation in HFD-challenged mice. Conclusion: These results suggest that targeting NADPH-mediated ROS release and ferroptosis accumulation is a novel therapeutic strategy to protect the kidney from septic injury in patients with obesity and type 2 DM.

Comparison of the Analgesic Effects of Intravenous Infusion of Dexmedetomidine Versus Bilateral Superficial Cervical Plexus Block After Thyroidectomy: A Randomized Controlled Trial.

OBJECTIVES: Dexmedetomidine (DEX) is widely used in clinical practice because of its safety and effectiveness. Superficial cervical plexus block (SCPB) can reduce pain in thyroid surgery. The objective of this study was to investigated whether intravenous DEX has an equivalent analgesic effect and patients' satisfaction to SCPB for thyroid surgery. MATERIALS AND METHODS: Ninety patients who had been scheduled for thyroidectomy under general anesthesia with endotracheal intubation were randomly divided into 3 groups. Group D: DEX was administered intravenously at an initial dose of 1 µg/kg over 10 minutes; then induction and endotracheal intubation performed, and then a continuous intravenous infusion of DEX was administered at a rate of 0.4 µg/kg/h until 30 minutes before the end of surgery. Group B: ultrasound-guided bilateral SCPB was performed, with 10 mL of 0.375% ropivacaine injected on each side. Group C: intravenous saline was administered at the same rate and dose as in group D. Patients' perioperative status, visual analog scale scores, complications and patients' satisfaction were recorded. RESULTS: The pain at rest at 1 hour after extubation and the movement-evoked pain within 24 hours after extubation were significantly lower in groups D and B than in group C. Patients' satisfaction was significantly higher in groups D and B than in group C. There was no difference in pain at rest, movement-evoked pain and patients' satisfaction between group D and B. CONCLUSIONS: Perioperative intravenous infusion of DEX can effectively reduce wound pain after thyroidectomy, and the analgesic effect is equivalent to that of bilateral SCPB.

The use of virtual reality to reduce stress among night-shift anesthesiologists: study protocol for a crossover trial.

BACKGROUND: Because of the lack of anesthesia workforce, anesthesiologists are forced to work overtime and more night shifts, which can disturb their biological rhythm and cause severe stress and depression, potentially leading to negative and even devastating outcomes for both themselves and patients. Virtual reality (VR), a new method to reduce stress and pain for patients, has been widely used in biomedical fields. The purpose of this study is to evaluate the potential effectiveness of VR technology in reducing stress among night-shift anesthesiologists. METHODS: In this randomized controlled, crossover, single-center clinical trial, a total of 30 anesthesiologists will be enrolled and randomized in a 1:1 allocation to either the VR immersion group (intervention group) or the routine night-shift group (control group) with a washout of 1 week. Anesthesiologists in the intervention group will undergo VR immersion twice, while anesthesiologists in the control group will not watch VR videos during the night shift. The primary outcome will be the difference in the NASA Task Load Index (NASA-TLX) score between the two groups. Secondary outcomes will include the Chinese Perceived Stress Scale (CPSS), perceived stress scores (visual analogue scale (VAS)), and Multidimensional Fatigue Inventory (MFI-20) scores; levels of satisfaction among the participants; incidence of arrhythmia; and incidence of chest tightness, headache, and palpitations. DISCUSSION: It is unknown whether the use of VR technology during the night shift can reduce stress among anesthesiologists. With the widespread use of VR technology, a positive result in this trial could spur hospitals to apply VR technology to reduce stress among night-shift doctors in every department and provide a relatively relaxed working environment. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000031025 . Registered on 21 March 2020.

Aerosol inhalation of a hydrogen-rich solution restored septic renal function.

Sepsis-related acute kidney injury (AKI) is known to be caused by inflammation. We explored the renal protective effects of aerosol inhalation of a hydrogen-rich solution (HRS; hydrogen gas dissolved to saturation in saline) in a mouse model of septic AKI. Septic AKI was induced through 18 hours of cecal ligation and puncture. AKI occurred during the early stage of sepsis, as evidenced by increased blood urea nitrogen and serum creatinine levels, pathological changes, renal fibrosis and renal tubular epithelial cell apoptosis, accompanied by macrophage infiltration and M1 macrophage-associated pro-inflammatory cytokine (Il-6 and Tnf-α) generation in renal tissues. Aerosol inhalation of the HRS increased anti-inflammatory cytokine (Il-4 and Il-13) mRNA levels in renal tissues and promoted macrophage polarization to the M2 type, which generated additional anti-inflammatory cytokines (Il-10 and Tgf-ß). Ultimately, aerosol inhalation of HRS protected the kidneys and increased survival among septic mice. HRS was confirmed to promote M2 macrophage polarization in lipopolysaccharide-stimulated RAW 264.7 cells. The TGF-ß1 receptor inhibitor SB-431542 partly reversed the effects of HRS on renal function, fibrosis, tubular epithelial cell apoptosis and senescence in mice. Thus, HRS aerosol inhalation appears highly useful for renal protection and inflammation reduction in septic AKI.

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.

Corrigendum to "Propofol Attenuates Small Intestinal Ischemia Reperfusion Injury through Inhibiting NADPH Oxidase Mediated Mast Cell Activation".

[This corrects the article DOI: 10.1155/2015/167014.].

Changes of nitric oxide and endothelin, thromboxane A2 and prostaglandin in cirrhotic patients undergoing liver transplantation.

AIM: To investigate the perioperative changes of nitric oxide (NO) and endothelin (ET), thromboxane A2 (TXA2) and prostaglandin (PGI2) during liver transplantation in end-stage liver disease patients. METHODS: Twenty-seven patients with end-stage cirrhosis undergoing liver transplantation were enrolled in this prospective study. Blood samples were obtained from superior vena at five different surgical stages. Plasma concentrations of nitrate and nitrite were determined to reflect plasma NO levels. Plasma levels of ET-1,6-keto-PGF1 alpha and thromboxane B2 (TXB2), the latter two being stable metabolites of PGI2 and TXA2 respectively, were measured. RESULTS: The NO level decreased significantly after vascular cross-clamping and increased significantly at 30 min after reperfusion. While the ET levels at 30 min after clamping and after reperfusion were significantly elevated. The ratio of NO/ET decreased significantly at 30 min after vascular cross-clamping and at the end of surgery. The PGI2 level and the TXA2 during liver transplantation were significantly higher than the baseline level, but the ratio of TXA2/PGI2 decreased significantly at 30 min after clamping. CONCLUSION: NO/ET and TXA2/PGI2 change during liver transplantation. Although the precise mechanism remains unknown, they may play a role in the pathobiology of a variety of liver transplant-relevant processes.

[Change in mixed venous oxygen saturation in patients in perioperative periods of orthotopic liver transplantation and its clinical implication].

OBJECTIVE: To observe the changes in mixed venous oxygen saturation(SvO(2))during perioperative periods of orthotopic liver transplantation (OLT), and explore its clinical significances. METHODS: Twenty patients in terminal stage of hepatic cirrhosis were scheduled for OLT under combined general anesthesia. Vigilance monitor (Edwards, USA) was employed to monitor perioperative SvO(2), oxygen delivery (DO(2)), oxygen consumption(VO(2)), oxygen extraction rate (ERO(2)) and body temperature, cardiac output (CO), and mean arterial blood pressure (MAP). RESULTS: Compared with the preoperative stage, SvO(2) elevated during 15 minutes of anhepatic stage (P<0.05), but decreased significantly during 30 minutes compared to that during 15 minutes of anhepatic stage. Then it was elevated significantly at 30 minutes after the reperfusion of the graft and at the end of operation (all P<0.05). Both DO(2) and VO(2) were decreased significantly during the anhepatic phase (both P<0.05), and increased significantly after graft reperfusion (all P<0.05); ERO(2) increased significantly after graft reperfusion (P<0.05). The level of SvO(2) was correlated with VO(2) significantly at each stage (all P<0.05), but not with DO(2) and hemoglobin (all P<0.05). SvO(2) was correlated well with CO before operation (P<0.05), but not at the other time points (all P>0.05). CONCLUSION: Monitoring SvO(2) continually is of clinical significance in patients during OLT.

Dexmedetomidine improves gastrointestinal motility after laparoscopic resection of colorectal cancer: A randomized clinical trial.

BACKGROUND: To investigate the effects of intraoperative application of dexmedetomidine (Dex) on early gastrointestinal motility after laparoscopic resection of colorectal cancer. METHODS: In this prospective, randomized double-blind investigation, 60 patients who underwent laparoscopic resection of colorectal cancer were randomly allocated to receive Dex (DEX group, n = 30) or saline (CON group, n = 30). In the DEX group, Dex was loaded (1 µg/kg) before anesthesia induction and was infused (0.3 µg/kg/h) during surgery. Time to postoperative first flatus (FFL) and first feces (FFE), and time to regular diet were recorded. Serum diamine oxidase (DAO) activity and intestinal fatty acid-binding protein (I-FABP) were detected. RESULTS: Both the time to the FFL (44.41 ±â€Š4.51 hours vs 61.03 ±â€Š5.16 hours, P = 0.02) and the time to the FFE (60.67 ±â€Š4.94 hours vs 82.50 ±â€Š6.88 hours, P = 0.014) were significantly shorter in the DEX group than the CON group. Furthermore, the time to regular diet of the DEX group was shorter than that of the CON group (76.15 ±â€Š4.11 hours vs 91.50 ±â€Š5.70 hours, P = 0.037). Both DAO and I-FABP increased significantly from beginning of surgery to postoperative day 1 in the CON group (2.49 ±â€Š0.41 ng/mL vs 4.48 ±â€Š0.94 ng/mL for DAO, P = 0.028, 1.32 ±â€Š0.09 ng/mL vs 2.17 ±â€Š0.12 ng/mL for I-FABP, P = 0.045, respectively), whereas no significant change was observed in the DEX group. Furthermore, patients in the DEX group had stable hemodynamics and shorter hospital stay than those in the CON group. CONCLUSION: Dex administration intraoperatively benefits recovery of gastrointestinal motility function after laparoscopic resection of colorectal cancer with stable hemodynamics during surgery though further studies are needed to explore the mechanisms of Dex on gastrointestinal motility.

[Changes in hemodynamics and nitric oxide/endothelin-1 during liver transplantation in patients with cirrhosis].

OBJECTIVE: To study the systemic and pulmonary hemodynamic changes of patients with cirrhosis during liver transplantation and evaluate the role of nitric oxide (NO) and endothelin-1(ET-1). METHODS: Twenty-four patients with cirrhosis at terminal stage underwent modifying piggy-back liver transplantation. Hemodynamic parameters including cardiac index (CI), arterial blood pressure (ABP) and pulmonary arterial pressure (PAP) were monitored continuously. NO and ET-1 levels were measured by radioimmunoassay. Blood samples were obtained from superior vena cava at induction of anesthesia (T1), 10 minutes before vascular cross clamping (T2), 30 minutes after vascular cross clamping (T3), 30 minutes after reperfusion of the new liver (T4), and at the end of surgery (T5). RESULTS: (1) Mean arterial blood pressure (MABP) lowered significantly in the early stage of anhepatic period and neohepatic period (P<0.05 or P<0.01). (2) Central venous pressure (CVP), mean pulmonary arterial pressure (MPAP) and pulmonary arterial wedge pressure (PAWP) lowered significantly during anhepatic period. They rose significantly after graft reperfusion, and remained at a high level with respect to the baseline level (P<0.05). (3) CI declined significantly during anhepatic period and increased 10 minutes after reperfusion of new liver. (4) Systemic vascular resistance index and pulmonary vascular resistance index increased during anhepatic period and were higher than the baseline level 15 minutes after reperfusion. SVRI was lower than baseline level 30 minutes after reperfusion. (5) Compared with the baseline level, NO decreased significantly after vascular cross-clamping and elevated 30 minutes after reperfusion. ET levels were significant elevated 30 minutes after clamping and after reperfusion (P<0.05). CONCLUSION: Significant hemodynamic changes occur in patients with cirrhosis during liver transplantation, and pulmonary hypertension develops during neohepatic period. The role of elevated contents of NO and ET-1 after reperfusion needs further study.

[Changes in pulmonary gas exchange and intrapulmonary shunt during orthotopic liver transplantation with non-venovenous bypass].

OBJECTIVE: To study the changes in pulmonary gas exchange and intrapulmonary shunt during orthotopic liver transplantation (OLT) with non-venovenous bypass. METHODS: Nineteen American Society of Anesthesiologists (ASA) III-IV patients (male 17, female 2) with terminal liver diseases were enrolled for study. Their age ranged from 25-67 years. Anesthesia was induced with midazolam 0.05 mg/kg, propofol 0.5-1.0 mg/kg, fentanyl 4 microg/kg, with vecuronium 0.1 mg/kg, and it was maintained with isoflurane inhalation, fentanyl and vecuronium. All patients were mechanically ventilated with 100% O(2) during operation. After induction of anesthesia, Swan-Ganz catheter was inserted via right internal jugular vein. Cardiac output (CO), mixed venous oxygen saturation and core venous temperature were continuously monitored with continuous cardiac output monitor, and electrocardiogram (ECG), central venous pressure (CVP), pulmonary arterial wedge pressure (PAWP), pulse oxygen saturation (SpO(2)) and end-tidal carbon dioxide tension (P(ET)CO(2)) were also continuously monitored during operation. Radial artery was cannulated for continuous direct blood pressure monitoring. Arterial and mixed venous blood samples were taken after induction of anaesthesia, and partial pressure of oxygen (PaO(2)), partial pressure of carbon dioxide (PaCO(2)), and cardiac index(CI) were determined after induction of anaesthesia, 30 minutes before anhepatic stage, 30 minutes during anhepatic stage, 30 minutes during neohepatic stage and at the end of operation. Alveolar-arterial oxygen partial pressure difference (P(A-a)O(2)) and intrapulmonary shunt (Qs/Qt) were calculated according to the standard formula. RESULTS: After induction of anaesthesia, when the inspired oxygen flow (FiO(2)) was 1.00, PaO(2) was only (385.0+/-56.4) mm Hg (1 mm Hg=0.133 kPa), P(A-a)O(2) and Qs/Qt were all higher than normal values. There were no significant changes 30 minutes before anhepatic stage as compared with that after induction of anaesthesia. CO, CI and Qs/Qt were decreased significantly during anhepatic stage compared with that after induction of anaesthesia. PaO(2), PaCO(2), CO and CI were increased and P(A-a)O(2) decreased significantly, but there were no significant changes in Qs/Qt 30 minutes during neohepatic stage. CI and CO increased and Qs/Qt decreased significantly at the end of operation, but there were no significant difference in PaO(2), PaCO(2) and P(A-a)O(2). CONCLUSION: There are obvious changes in pulmonary gas exchange and intrapulmonary shunt during OLT with non-veno-venous bypass.

[Changes in oxygen metabolism in hepatitis B gravis in peri-operative stages of orthotopic liver transplantation].

OBJECTIVE: To investigate the changes in oxygen metabolism in peri-operative stages in hepatitis B gravis and non-hepatitis B gravis undergoing orthotopic liver transplantation (OLT). METHODS: Twelve patients undergoing OLT for hepatitis B gravis (experimental group) and 10 patients without hepatitis B gravis (control group) were enrolled for study. Anesthesia was induced by propofol, fentanyl and vecuronium bromide, and maintained with isoflurane. Arterial catheter was inserted into the left radial artery. Swan-Ganz catheter was inserted through the right internal jugular vein. Arterial partial pressure of oxygen (PaO(2)), mixed venous partial pressure of oxygen (PvO(2)), arterial oxygen content (CaO(2)), mixed venous oxygen content (CvO(2)), arterial-venous oxygen content difference (Ca-vO(2)), oxygen delivery (DO(2)), index of oxygen delivery (DO(2)I), oxygen consumption (VO(2)), index of oxygen consumption (VO(2)I), index of oxygen extract (O(2)EI), oxygen extract rate (O(2)ER) were determined before skin incision (T1), 10 minutes before anhepatic phase (T2), 25 minutes after liver was removed (anhepatic phase, T3), 30 minutes in neohapitic phase (T4), and the end of operation (T5). RESULTS: (1) In the experimental group, PvO(2) increased, Ca-vO(2) decreased, DO(2) and VO(2) showed no change, and O(2)EI and O(2)ER decreased in T2. In preanhepatic period, PvO(2) increased, Ca-vO(2) decreased, DO(2) and VO(2) did not change. In anhepatic period, DO(2), DO(2)I, VO(2) and VO(2)I decreased obviously, DO(2) decreased by 43%, while VO(2) decreased by 21%, and O(2)ER increased obviously. In reperfusion period, PaO(2) and PvO(2) increased, CaO(2) and Ca-vO(2) decreased, DO(2) and DO(2)I increased, VO(2) and VO(2)I recovered to base level. After termination of operation, PvO(2), DO(2), DO(2)I were still high. (2) In the control group: PvO(2) increased, O(2)EI and O(2)ER decreased, but no significant changes were found in DO(2) and VO(2) in T2. DO(2), DO(2)I, VO(2), and VO(2)I all decreased in T3, while DO(2) reduced by 25% and VO(2) reduced by 12%. In T4, PvO(2), DO(2) and DO(2)I all increased, while Ca-vO(2), VO(2) and VO(2)I reached the pre-operative levels in T4. DO(2) and DO(2)I levels were higher than those of pre-operation in T5. CONCLUSION: The decrease in DO(2) is more obvious than VO(2) in anhepatic period during OLT in hepatitis B gravis patients. In neohepatic period, DO(2) increases while VO(2) returns to base level.

Changes in the Concentrations of Mediators of Inflammation and Oxidative Stress in Exhaled Breath Condensate During Liver Transplantation and Their Relations With Postoperative ARDS.

BACKGROUND: Oxidative stress and inflammatory responses are thought to be involved in the pathogenesis of ARDS, which is one of the most serious complications of orthotopic liver transplantation (OLT). The collection of exhaled breath condensate (EBC) is a noninvasive method for obtaining clinical samples from the lungs. However, the changes of mediators of inflammation and oxidative stress in EBC remain unclear. Therefore, the aim of this study was to investigate the changes of mediators in EBC from OLT subjects and the relations between these mediators and ARDS. METHODS: The levels of mediators of oxidative stress (superoxide dismutase [SOD], malondialdehyde [MDA], H2O2, NO, and 8-iso-prostaglandin F2α) and of inflammatory factors (tumor necrosis factor-α[TNF-α], interleukin [IL]-8, and IL-10) were measured in EBC and serum samples collected from 28 subjects before OLT surgery and at 2 and 4 h after the anhepatic phase. The diagnostic value for ARDS until the 3 days following transplantation was evaluated. RESULTS: Eighteen subjects developed ARDS after OLT. The concentrations of TNF-α, IL-8, MDA, NO, H2O2, and 8-iso-prostaglandin F2α were much higher in the ARDS group than in the control group, whereas the levels of IL-10 and SOD were lower in the ARDS group than in the control group. The serum levels of mediators of oxidative stress or inflammation were closely related to EBC levels. Receiver operating characteristic analysis showed that areas under the curves for MDA, NO, H2O2, 8-iso-prostaglandin F2α, TNF-α, IL-8, SOD, and IL-10 were 0.88, 0.88, 0.78, 0.84, 0.84, 0.94, 0.81, and 0.84 at 2 h after graft reperfusion and 0.98, 0.88, 0.92, 0.79, 0.95, 0.83, 0.88, and 0.97 at 4 h after graft reperfusion. CONCLUSIONS: EBC analysis is a noninvasive method for detecting mediators of inflammation and oxidative stress from the lungs. This method could be used to predict the higher incidence of ARDS induced by OLT.

Propofol pretreatment attenuates remote kidney injury induced by orthotopic liver autotransplantation, which is correlated with the activation of Nrf2 in rats.

Nuclear factor erythroid 2­related factor 2 (Nrf2) is a critical regulator of the cellular­defense response in protection against oxidative injury. Several studies have demonstrated that propofol ameliorates ischemia/reperfusion injury in a number of organs. However, whether propofol exerts renal protection against liver transplantation via Nrf2 activation remains to be elucidated. The aim of the present study was to investigate the effects of orthotopic liver autotransplantation (OLAT) on renal Nrf2 expression and to determine whether propofol protects against kidney injury induced by OLAT via Nrf2 activation. A total of 24 male Sprague Dawley rats were randomly divided into four groups: sham surgery + normal saline (sham group); OLAT + normal saline (OLAT group); OLAT + propofol 50 mg/kg (L­Prop group) and OLAT + propofol 100 mg/kg (H­Prop group). Normal saline and propofol were administered for 3 consecutive days through an intraperitoneal injection prior to surgery. Kidney pathology, blood urea nitrogen (BUN), creatinine (Cr), superoxide anion (O2•­), hydroxyl radical (·OH), maleic dialdehyde (MDA) and expression levels of Nrf2, Kelch­like ECH­associated protein 1 (Keap1), heme oxygenase­1 (HO­1) and NADP quinine oxidoreductase 1 (NQO1) were assessed 8 h after OLAT. It was demonstrated that OLAT induced remote kidney damage. Pretreatment with propofol significantly ameliorated renal pathology and abrogated the increase of the Cr and BUN concentrations, O2•­ and ·OH activities, and MDA levels induced by OLAT. In the H­Prop group, Keap1 expression in the cytoplasm was decreased and Nrf2 expression in the nucleus was upregulated, accompanied by an increase of HO­1 and NQO1 expression. The present results suggest that propofol pretreatment exerted renal protection against OLAT, with the upregulation of nuclear Nrf2 expression as a potential mechanism.