Publications by authors named "Tokujiro Uchida"

41 Publications

TEG6s Platelet Mapping assay for the estimation of plasma fibrinogen concentration during cardiovascular surgery: a single-center prospective observational study.

J Anesth 2021 Oct 13. Epub 2021 Oct 13.

Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Purpose: The Activator F (ActF) test on the TEG6s Platelet Mapping assay system is a means of quantifying blood viscoelasticity caused by fibrin network formation, triggered by reptilase and factor XIII, while platelets are inhibited. This unique methodology enables the measurement of blood viscoelasticity, even in highly heparinized blood. Here, we investigated whether fibrinogen concentration could be estimated using the ActF test in blood samples obtained during cardiopulmonary bypass (CPB) and after CPB in patients undergoing cardiovascular surgery.

Methods: We performed a single-center prospective observational study at a university hospital. Forty patients aged ≥ 18 years who underwent elective cardiovascular surgery with CPB were enrolled. Blood samples were drawn after the induction of anesthesia, after declamping of the aorta during CPB, and after the reversal of heparinization using protamine (after CPB). Coagulation profiles were evaluated using the Platelet Mapping assay and standard laboratory tests.

Results: There were strong correlations between the maximal amplitude of clot strength (MA) in the ActF test and fibrinogen concentration in samples drawn during CPB (R = 0.84, 95% confidence interval [CI] 0.72-0.91; P < 0.001) and after CPB (R = 0.83, 95% CI 0.70-0.91; P < 0.001). The areas under the receiver-operating characteristic curve for the ActF MA for fibrinogen concentrations < 150 mg/dL were 0.86 (95% CI 0.73-1.0) during CPB and 0.98 (95% CI 0.94-1.0) after CPB.

Conclusion: TEG6s Platelet Mapping ActF MA values strongly correlated with plasma fibrinogen concentration in highly heparinized blood during CPB and yielded highly accurate measurements of low fibrinogen concentrations.
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http://dx.doi.org/10.1007/s00540-021-03009-4DOI Listing
October 2021

Transcriptome analysis of sevoflurane exposure effects at the different brain regions.

PLoS One 2020 15;15(12):e0236771. Epub 2020 Dec 15.

Department of Systems BioMedicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Backgrounds: Sevoflurane is a most frequently used volatile anesthetics, but its molecular mechanisms of action remain unclear. We hypothesized that specific genes play regulatory roles in brain exposed to sevoflurane. Thus, we aimed to evaluate the effects of sevoflurane inhalation and identify potential regulatory genes by RNA-seq analysis.

Methods: Eight-week old mice were exposed to sevoflurane. RNA from medial prefrontal cortex, striatum, hypothalamus, and hippocampus were analysed using RNA-seq. Differently expressed genes were extracted and their gene ontology terms were analysed using Metascape. These our anesthetized mouse data and the transcriptome array data of the cerebral cortex of sleeping mice were compared. Finally, the activities of transcription factors were evaluated using a weighted parametric gene set analysis (wPGSA). JASPAR was used to confirm the existence of binding motifs in the upstream sequences of the differently expressed genes.

Results: The gene ontology term enrichment analysis result suggests that sevoflurane inhalation upregulated angiogenesis and downregulated neural differentiation in each region of brain. The comparison with the brains of sleeping mice showed that the gene expression changes were specific to anesthetized mice. Focusing on individual genes, sevoflurane induced Klf4 upregulation in all sampled parts of brain. wPGSA supported the function of KLF4 as a transcription factor, and KLF4-binding motifs were present in many regulatory regions of the differentially expressed genes.

Conclusions: Klf4 was upregulated by sevoflurane inhalation in the mouse brain. The roles of KLF4 might be key to elucidating the mechanisms of sevoflurane induced functional modification in the brain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236771PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737892PMC
January 2021

Dielectric blood coagulometry as a means of evaluating the change in thrombin generation induced by direct oral anticoagulants.

Thromb Res 2021 01 10;197:141-143. Epub 2020 Nov 10.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.thromres.2020.11.007DOI Listing
January 2021

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass in adult patients undergoing cardiac surgery.

Eur J Clin Pharmacol 2021 May 19;77(5):735-745. Epub 2020 Nov 19.

Department of Pharmacokinetics and Pharmacodynamics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Purpose: The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin.

Methods: Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated.

Results: A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (B). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed.

Conclusion: PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.
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http://dx.doi.org/10.1007/s00228-020-03045-1DOI Listing
May 2021

Severe COVID-19 Pneumonia in a 30-Year-Old Woman in the 36th Week of Pregnancy Treated with Postpartum Extracorporeal Membrane Oxygenation.

Am J Case Rep 2020 Oct 28;21:e927521. Epub 2020 Oct 28.

Trauma and Acute Critical Care Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.

BACKGROUND There are few reports of coronavirus disease 2019 (COVID-19) in pregnant women. Although coagulation dysfunction was reported to affect the severity of COVID-19, the association between pregnancy, which is usually accompanied by changes in coagulation function, and the worsening of COVID-19 is unknown. We present a case of a 30-year-old woman in the 36th week of pregnancy who was diagnosed with severe COVID-19 pneumonia and required postpartum extracorporeal membrane oxygenation (ECMO) therapy. CASE REPORT A 30-year-old, 36-weeks pregnant woman presented to our hospital and was diagnosed with severe COVID-19 pneumonia soon after she had undergone a cesarean section. Her respiratory failure could not be managed by conventional therapeutic approaches. Therefore, ECMO was administered on day 7. Controlling coagulation function to maintain ECMO therapy was challenging. Nafamostat mesylate and cryoprecipitate were administered to treat the hypercoagulative status and severe hypofibrinogenemia, respectively. Since coagulopathy and her respiratory state improved, the ECMO therapy was terminated on day 15. CONCLUSIONS We report a case of severe COVID-19 pneumonia in a pregnant woman urgently treated with ECMO in the postpartum period. Thus, this case highlights the importance of close monitoring and appropriate medical care for pregnant women with severe COVID-19 pneumonia.
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http://dx.doi.org/10.12659/AJCR.927521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603798PMC
October 2020

Comparative analysis demonstrates cell type-specific conservation of SOX9 targets between mouse and chicken.

Sci Rep 2019 08 29;9(1):12560. Epub 2019 Aug 29.

Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

SRY (sex-determining region Y)-box 9 (SOX9) is a transcription factor regulating both chondrogenesis and sex determination. Among vertebrates, SOX9's functions in chondrogenesis are well conserved, while they vary in sex determination. To investigate the conservation of SOX9's regulatory functions in chondrogenesis and gonad development among species, we performed chromatin immunoprecipitation sequencing (ChIP-seq) using developing limb buds and male gonads from embryos of two vertebrates, mouse and chicken. In both mouse and chicken, SOX9 bound to intronic and distal regions of genes more frequently in limb buds than in male gonads, while SOX9 bound to the proximal upstream regions of genes more frequently in male gonads than in limb buds. In both species, SOX palindromic repeats were identified more frequently in SOX9 binding regions in limb bud genes compared with those in male gonad genes. The conservation of SOX9 binding regions was significantly higher in limb bud genes. In addition, we combined RNA expression analysis (RNA sequencing) with the ChIP-seq results at the same stage in developing chondrocytes and Sertoli cells and determined SOX9 target genes in these cells of the two species and disclosed that SOX9 targets showed high similarity of targets in chondrocytes, but not in Sertoli cells.
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http://dx.doi.org/10.1038/s41598-019-48979-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715657PMC
August 2019

Incidence and predictive factors of hypoglycemia after pheochromocytoma resection.

Int J Urol 2019 02 22;26(2):273-277. Epub 2018 Nov 22.

Department of Urology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Objectives: To determine the incidence and preoperative risk factors of post-excisional hypoglycemia in patients undergoing pheochromocytoma resection.

Methods: Patients who underwent surgical resection of pheochromocytoma at a single institution were retrospectively enrolled in the present study. The primary end-point was the development of post-excisional hypoglycemia; that is, a serum glucose level <70 mg/dL. The serum levels of immunoreactive insulin and glucose levels during the preoperative oral glucose-tolerance test and surgery were analyzed to elucidate the mechanism of hypoglycemia.

Results: A total of 49 patients underwent surgical resection of pheochromocytoma, of which 21 patients (43%) developed post-excisional hypoglycemia. The incidence of hypoglycemia was not statistically different between patients with adrenal tumors and those with extra-adrenal tumors (18/41 [44%] vs 3/8 [38%], respectively, P = 0.73). There was no difference in the immunoreactive insulin/glucose ratio during the preoperative oral glucose-tolerance test between patients with and those without post-excisional hypoglycemia. The intraoperative immunoreactive insulin/glucose ratio was significantly higher in patients with hypoglycemia than in those without hypoglycemia. A higher 24-h urinary epinephrine level, but not norepinephrine level, was a predictive factor for post-excisional hypoglycemia.

Conclusions: Post-excisional hypoglycemia is a frequent complication of pheochromocytoma resection, irrespective of the tumor location, and might be common in patients with epinephrine-predominant tumors. All patients undergoing resection of adrenal and extra-adrenal pheochromocytoma require intensive monitoring of serum glucose levels during and after surgery.
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http://dx.doi.org/10.1111/iju.13864DOI Listing
February 2019

Effects of cardiopulmonary bypass on the disposition of cefazolin in patients undergoing cardiothoracic surgery.

Pharmacol Res Perspect 2018 12 5;6(6):e00440. Epub 2018 Nov 5.

Department of Pharmacokinetics and Pharmacodynamics Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU) Tokyo Japan.

The aim of the study was to evaluate the disposition of plasma unbound cefazolin in patients undergoing cardiothoracic surgery with cardiopulmonary bypass (CPB). Adult patients undergoing cardiothoracic surgery with CPB were enrolled in the study. Cefazolin sodium was given intravenously before skin incision (1 g) and at the beginning of CPB (2 g). Thereafter, an additional dose (1 g) was given every 4 hours. Seven to ten blood samples were collected before and during surgery. Plasma total and unbound (ultrafiltrated) cefazolin concentrations were analyzed using an HPLC-UV method. Plasma protein binding was analyzed with the Langmuir model. Twenty-seven patients (aged 70 ± 12 years, body weight 62 ± 12 kg, mean ± SD) with GFR >30 mL min completed the study. There was a significant ( < 0.001) increase in median plasma unbound fraction of cefazolin from 21% before skin incision to 45% during CPB ( < 0.001), which was accompanied by a significant ( < 0.001) reduction in median plasma albumin concentration from 36 to 27 g L. Plasma concentrations of unbound cefazolin exceeded the assumed target thresholds of 2 μg mL in all samples and of 8 μg mL in all but one of 199 samples. The increased plasma unbound fraction of cefazolin would be attributable to dilutional reduction of serum albumin at the beginning of CPB and to saturable plasma protein binding of cefazolin. These data reveal CPB may alter the plasma protein binding and possibly distribution of cefazolin. Further studies are warranted to reappraise the protocol of antimicrobial prophylaxis with cefazolin in patients undergoing surgery with CPB.
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http://dx.doi.org/10.1002/prp2.440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218359PMC
December 2018

Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes.

J Anesth 2018 02 29;32(1):120-131. Epub 2017 Dec 29.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Purpose: Propofol infusion syndrome (PRIS) is a lethal condition caused by propofol overdose. Previous studies suggest that pathophysiological mechanisms underlying PRIS involve mitochondrial dysfunction; however, these mechanisms have not been fully elucidated. This study aimed to establish an experimental model of propofol-induced cytotoxicity using cultured human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to determine the mechanisms behind propofol-induced mitochondrial dysfunction, and to evaluate the protective effects of coenzyme Q10 (CoQ10).

Methods: Human iPSC-derived cardiomyocytes were exposed to propofol (0, 2, 10, or 50 µg/ml) with or without 5 µM CoQ10. Mitochondrial function was assessed by measuring intracellular ATP, lactate concentrations in culture media, NAD/NADH ratio, and the mitochondrial membrane potential. Propofol-induced cytotoxicity was evaluated by analysis of cell viability. Expression levels of genes associated with mitochondrial energy metabolism were determined by PCR. Intracellular morphological changes were analyzed by confocal microscopy.

Results: Treatment with 50 µg/ml propofol for 48 h reduced cell viability. High concentrations of propofol (≥ 10 µg/ml) induced mitochondrial dysfunction accompanied by downregulation of gene expression of PGC-1alpha and its downstream targets (NDUFS8 and SDHB, which are involved in the respiratory chain reaction; and CPT1B, which regulates beta-oxidation). Cardiomyocytes co-treated with 5 µM CoQ10 exhibited resistance to propofol-induced toxicity through recovery of gene expression.

Conclusions: Propofol-induced cytotoxicity in human iPSC-derived cardiomyocytes may be associated with mitochondrial dysfunction via downregulation of PGC-1alpha-regulated genes associated with mitochondrial energy metabolism. Co-treatment with CoQ10 protected cardiomyocytes from propofol-induced cytotoxicity.
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http://dx.doi.org/10.1007/s00540-017-2441-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797219PMC
February 2018

Perioperative Elevation in Cell-Free DNA Levels in Patients Undergoing Cardiac Surgery: Possible Contribution of Neutrophil Extracellular Traps to Perioperative Renal Dysfunction.

Anesthesiol Res Pract 2016 2;2016:2794364. Epub 2016 Nov 2.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

. This study aimed to determine the perioperative change in serum double-strand DNA (dsDNA) as a marker potentially reflecting neutrophil extracellular trap concentration in samples from patients undergoing cardiac surgery and to analyze a relationship between serum dsDNA concentrations and perioperative renal dysfunction. . Serum dsDNA concentrations in samples that were collected during a previously conducted, prospective, multicenter, observational study were measured. Eighty patients undergoing elective cardiac surgery were studied. Serum samples were collected at baseline, immediately after surgery, and the day after surgery (POD-1). . Serum dsDNA concentration was significantly increased from baseline (median, 398 ng/mL [interquartile range, 372-475 ng/mL]) to immediately after surgery (median, 540 ng/mL [437-682 ng/mL], < 0.001), and they were reduced by POD-1 (median, 323 ng/mL [256-436 ng/mL]). The difference in serum creatinine concentration between baseline and POD-1 was correlated with dsDNA concentration on POD-1 ( = 0.61, < 0.001). . In patients undergoing cardiac surgery, serum dsDNA concentration is elevated postoperatively. Prolonged elevation in dsDNA concentration is correlated with perioperative renal dysfunction. Further large-scale studies are needed to determine the relationship between serum concentration of circulating dsDNA and perioperative renal dysfunction.
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http://dx.doi.org/10.1155/2016/2794364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110877PMC
November 2016

Polymyxin B hemoperfusion prevents acute kidney injury in sepsis model.

J Surg Res 2016 Mar 10;201(1):59-68. Epub 2015 Nov 10.

Department of Anesthesiology, Juntendo University Hospital, Tokyo, Japan.

Background: Direct hemoperfusion with a polymyxin B-immobilized column (PMX-DHP) adsorbs endotoxin and has been used for the treatment of septic shock. Yet, the mechanisms by which PMX-DHP acts on acute kidney injury are only partially understood.

Materials And Methods: Rats were anesthetized, tracheostomized, and placed on mechanical ventilation. The animals were randomized to three groups: a cecal ligation and puncture (CLP) + dummy-DHP group (n = 10), a CLP + PMX-DHP group (n = 10), and a sham group (n = 4). Four hours after CLP, a dummy-DHP or PMX-DHP was performed for 1 h. The heart rate, mean arterial pressure, arterial blood gases, and plasma concentrations of creatinine, lactate, potassium, interleukin (IL)-6, and IL-10 were measured at 0 h and 8 h. Eight hours after CLP, the kidney was harvested, and histopathologic examination was performed. The expressions of cleaved poly (ADP-ribose) polymerase (PARP) and nuclear factor (NF)-κB p65 were examined by immunohistochemistry. A terminal deoxynucleotide transferase dUTP nick-end labeling assay was performed to detect apoptotic nuclei in kidney sections.

Results: PMX-DHP maintained hemodynamics and the acid-base balance and significantly (P < 0.05) decreased the plasma concentrations of lactate, creatinine, potassium, IL-6, and IL-10 compared with dummy-DHP. PMX-DHP significantly (P < 0.001) attenuated the expressions of cleaved PARP and NF-κB p65 in renal tubular cells and renal tubular cell apoptosis compared with dummy-DHP.

Conclusions: These findings suggest that PMX-DHP may protect against acute kidney injury not only by inhibiting the NF-κB signaling pathway but also by preventing renal tubular cell apoptosis.
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http://dx.doi.org/10.1016/j.jss.2015.10.020DOI Listing
March 2016

Effects of atrial natriuretic peptide on inter-organ crosstalk among the kidney, lung, and heart in a rat model of renal ischemia-reperfusion injury.

Intensive Care Med Exp 2014 Dec 8;2(1):28. Epub 2014 Nov 8.

Department of Critical Care Medicine, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan,

Background: Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients. Renal IRI releases proinflammatory cytokines within the kidney that induce crosstalk between the kidney and other organ systems. Atrial natriuretic peptide (ANP) has anti-inflammatory as well as natriuretic effects and serves important functions as a regulator of blood pressure, fluid homeostasis, and inflammation. The objective of the present study was to elucidate whether ANP post-treatment attenuates kidney-lung-heart crosstalk in a rat model of renal IRI.

Methods: In experiment I, a rat model of unilateral renal IRI with mechanical ventilation was prepared by clamping the left renal pedicle for 30 min. Five minutes after clamping, saline or ANP (0.2 μg/kg/min) was infused. The hemodynamics, arterial blood gases, and plasma concentrations of lactate and potassium were measured at baseline and at 1, 2, and 3 h after declamping. The mRNA expression and localization of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the kidney, lung, and heart were examined. In experiment II, a rat model of bilateral renal IRI without mechanical ventilation was prepared by clamping bilateral renal pedicles for 30 min. Thirty minutes after clamping, lactated Ringer's (LR) solution or ANP (0.2 μg/kg/min) was infused. Plasma concentrations of TNF-α, IL-6, and IL-1β were determined at baseline and at 3 h after declamping.

Results: In unilateral IRI rats with mechanical ventilation, ANP inhibited the following changes induced by IRI: metabolic acidosis; pulmonary edema; increases in lactate, creatinine, and potassium; and increases in the mRNA expression of TNF-α, IL-1β, and IL-6 in the kidney and lung and IL-1β and IL-6 in the heart. It also attenuated the histological localization of TNF-α, IL-6, and nuclear factor (NF)-κB in the kidney and lung. In bilateral IRI rats without mechanical ventilation, ANP attenuated the IRI-induced increases of the plasma concentrations of potassium, IL-1β, and IL-6.

Conclusions: Renal IRI induced injury in remote organs including the lung and the contralateral kidney. ANP post-treatment ameliorated injuries in these organs by direct tissue protective effect and anti-inflammatory effects, which potentially inhibited inter-organ crosstalk.
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http://dx.doi.org/10.1186/s40635-014-0028-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513012PMC
December 2014

Interactions between rat alveolar epithelial cells and bone marrow-derived mesenchymal stem cells: an in vitro co-culture model.

Intensive Care Med Exp 2015 Dec 24;3(1):53. Epub 2015 May 24.

Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan,

Background: Bone marrow-derived mesenchymal stem cells (BMSCs) reduced the severity of acute lung injury after transplantation in multiple experimental studies, and several paracrine soluble factors secreted by the cells likely contribute to their therapeutic effect. The direct interactions between BMSCs and alveolar epithelial cells (AECs) may be an important part of their beneficial effects. Therefore, we assessed the interactions between BMSCs and AECs using a co-culture model of these two cell types from rats.

Methods: BMSCs and AECs were co-cultured using a Transwell system under the following conditions: (1) separated co-culture-AECs seeded on the insert and BMSCs in the base of the well; and (2) mixed co-culture-AECs on top of the monolayer of BMSCs on the culture insert and no cells in the base of the well. After 21 days of culture, the cells on the membrane of the culture insert were fixed and stained with antibodies against the receptor for advanced glycation end-products (RAGE), surfactant protein D (SP-D), and zona occludens protein-1, and then analyzed by confocal microscopy.

Results: In the separated co-culture condition, the phenotype of the AECs was maintained for 21 days, and cluster formation of SP-D-positive cells was induced in the AEC monolayer. We also found cluster formations of phospholipid-positive cells covered with RAGE-positive epithelial cells. In the mixed co-culture condition, the BMSCs induced alveolar-like structures covered with an epithelial cell layer. To determine the effect of keratinocyte growth factor (KGF) on this three-dimensional structure formation, we treated the mixed co-cultures with siRNA for KGF. While KGF siRNA treatment induced a significant reduction in surfactant protein transcript expression, formation of the alveolar-like structure was unaffected. We also assessed whether Gap26, a functional inhibitor of connexin-43, could mitigate the effect of the BMSCs on the AECs. However, even at 300 μM, Gap26 did not inhibit formation of the alveolar-like structure.

Conclusions: BMSCs release soluble factors that help maintain and sustain the AEC phenotype for 21 days, and direct interaction between these two cell types can induce a cyst-like, three-dimensional structure covered with AECs.
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http://dx.doi.org/10.1186/s40635-015-0053-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480799PMC
December 2015

Ketamine causes mitochondrial dysfunction in human induced pluripotent stem cell-derived neurons.

PLoS One 2015 28;10(5):e0128445. Epub 2015 May 28.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Yushima, Bunkyo-ku, Tokyo, Japan.

Purpose: Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated.

Methods: Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy.

Results: Twenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P < 0.01), 14% increase in ROS production (P < 0.01), and 81% reduction in mitochondrial membrane potential (P < 0.01), compared with untreated cells. Lower concentration of ketamine (100 μM) decreased the ATP level (22%, P < 0.01) and increased the NADH/NAD+ ratio (46%, P < 0.05) without caspase activation. Transmission electron microscopy showed enhanced mitochondrial fission and autophagocytosis at the 100 μM ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation.

Conclusions: We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128445PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447382PMC
April 2016

[How to establish and organize research activities].

Masui 2015 Jan;64(1):30-9

The goal of this article is to introduce how to establish and organize research activities. There are many questions to be answered to make our clinical levels higher and more sophisticated, and some of them may also trigger research activities. We have two options, clinical study and basic research, and combination of these two methods is an ideal way to find answers to these questions. Also, cutting edge methodologies often result in some breakthroughs in our research field. Collaboration with experts is helpful for application of these new methodologies, and it facilitates establishing network of researchers. Finally, based on results of many excellent studies (both basic and clinical), we design large scale randomized clinical trials, to verify whether these research products contribute to improvement in our clinical activity. Excellent results give some hints to a next series of studies, and in this context, reviewing and updating the achievements are also important. Organizing study groups facilitates these activities, and the Japanese Society of Anesthesiologists has recently started a project to activate research activity.
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January 2015

[Potential influence of pre and intraoperative factors on postoperative recurrence and survival in patients undergoing radical resection of esophageal cancer].

Masui 2014 Dec;63(12):1344-9

Background: Several papers report that preoperative and intraoperative factors influence postoperative recurrence of malignancy. The purpose of this study is to define which factors affect the recurrence and survival of patients after the surgical resection of the esophageal cancer.

Methods: Ninety five patients underwent complete elective resection of the esophageal cancer. All patients were without preoperative chemotherapy and radiotherapy. We extracted 12 parameters, and cox regression analyses were used to assess the relation of 12 factors and the outcomes of patients. The 12 factors included preoperative factors (age, sex, weight stage of cancer, ASA PS, serum creatinine and total bilirubin), intraoperative variables (duration of anesthesia, blood transfusion, fluid balance, hypotensive episodes) and surgical Apgar score. Hypotensive episodes were defined as the systolic pressure lower than 70 mmHg occurring from the introduction of anesthesia to the end of anesthesia.

Results: Hypotensive episodes and blood transfusion significantly affected 1 year cancer specific survival. Stage of cancer and blood transfusion affected 5 year cancer specific survival.

Conclusions: We found that intraoperative hypotension affected 1-year cancer specific survival; however, the stage of cancer affected long-term survival instead of intraoperative factors. A low 5-year survival rate in esophageal cancer may have affected this result.
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December 2014

Catecholamine release induces elevation in plasma lactate levels in patients undergoing adrenalectomy for pheochromocytoma.

J Clin Anesth 2014 Dec 18;26(8):616-22. Epub 2014 Oct 18.

Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

Study Objective: To determine the relationship between preoperative catecholamine levels and intraoperative peak plasma lactate levels in patients who underwent adrenalectomy for pheochromocytoma.

Design: Retrospective observational study.

Setting: Operating room in one university hospital.

Measurements: The records of 27 ASA physical status 1 and 2 patients who underwent adrenalectomy for pheochromocytoma were studied. Preoperative catecholamine levels and intraoperative plasma lactate levels were recorded.

Main Results: Twenty cases had high lactate levels (>2 mmol/L). Preoperative urine epinephrine levels and urine metanephrine levels showed a moderate correlation with intraoperative peak plasma lactate levels (rs = 0.475 and rs = 0.499, respectively; Spearman's rank correlation test). Receiver operating characteristic (ROC) curve analysis for preoperative urine epinephrine levels showed good performance for prediction of high lactate levels [>2 mmol/L, area under the curve (AUC) =0.800], whereas ROC for preoperative urine norepinephrine levels showed no predictive performance for high lactate levels.

Conclusions: Catecholamine release caused by surgical manipulation may be a possible cause of intraoperative transient lactic acidosis, and it should be considered as a differential diagnosis of intraoperative lactic acidosis. Intraoperative peak plasma lactate level was correlated with preoperative epinephrine-releasing activity.
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http://dx.doi.org/10.1016/j.jclinane.2014.06.005DOI Listing
December 2014

Elevated levels of angiopoietin-2 as a biomarker for respiratory failure after cardiac surgery.

J Cardiothorac Vasc Anesth 2014 Oct 11;28(5):1293-301. Epub 2014 Jul 11.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan.

Objectives: Angiopoietin-1 and angiopoietin-2 are important factors in regulating endothelial vascular permeability. This study evaluated perioperative changes in serum levels of angiopoietin-1 and -2 in patients undergoing cardiac surgery.

Design: Measurement of serum levels of angiopoietin-1 and angiopoietin-2 in samples collected during a previously conducted prospective, multicenter, observational study.

Setting: Three university hospitals.

Participants: Eighty-four adult patients undergoing cardiac surgery.

Intervention: Serum levels of angiopoietins were measured at baseline, immediately after surgery, and the day after surgery (POD-1).

Measurements And Main Results: Serum levels of angiopoietin-2 were elevated by POD-1 (median 3.3 ng/mL, interquartile range [IQR] 2.5-4.6 ng/mL) compared with baseline (median 1.6 ng/mL, IQR 1.3-2.1 ng/mL, p < 0.0001), and angiopoietin-1 levels were decreased immediately after surgery (baseline median 23.2 ng/mL, IQR 10.2-32.8 ng/mL; postoperative median 8.0 ng/mL, IQR 1.5-13.2 ng/mL, p<0.0001). Angiopoietin-2 levels on POD-1 in patients undergoing off-pump coronary artery bypass grafting were significantly lower than those in patients undergoing aortic surgery (p = 0.0009) and valve surgery (p = 0.008). Angiopoietin-2 levels on POD-1 had a predictive performance of the area under the curve (AUC) of the receiver operating characteristic curve 0.74 for mechanical ventilation>3 days. Angiopoietin-1 levels and the angiopoietin-2/angiopoietin-1 ratio showed lower predictive performance (AUC values 0.58 and 0.68, respectively).

Conclusions: Angiopoietin-2 serum levels were elevated after cardiac surgery. Elevated angiopoietin-2 had a good predictive performance for respiratory failure after cardiac surgery, perhaps reflecting the severity of lung dysfunction related to postoperative increases in vascular permeability.
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http://dx.doi.org/10.1053/j.jvca.2014.03.004DOI Listing
October 2014

Soluble isoform of the receptor for advanced glycation end products as a biomarker for postoperative respiratory failure after cardiac surgery.

PLoS One 2013 23;8(7):e70200. Epub 2013 Jul 23.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo, Japan.

Purpose: Postoperative respiratory failure is a major problem which can prolong the stay in the intensive care unit in patients undergoing cardiac surgery. We measured the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE), and we studied its association with postoperative respiratory failure.

Methods: Eighty-seven patients undergoing elective cardiac surgery were enrolled in this multicenter observational study in three university hospitals. Serum biomarker levels were measured perioperatively, and clinical data were collected for 7 days postoperatively. The duration of mechanical ventilation was studied for 28 days.

Results: Serum levels of sRAGE elevated immediately after surgery (median, 1751 pg/mL; interquartile range (IQR) 1080-3034 pg/mL) compared with the level after anesthetic induction (median, 884 pg/mL; IQR, 568-1462 pg/mL). Postoperative sRAGE levels in patients undergoing off-pump coronary artery bypass grafting (median, 1193 pg/mL; IQR 737-1869 pg/mL) were significantly lower than in patients undergoing aortic surgery (median, 1883 pg/mL; IQR, 1406-4456 pg/mL; p=0.0024) and valve surgery (median, 2302 pg/mL; IQR, 1447-3585 pg/mL; p=0.0005), and postoperative sRAGE correlated moderately with duration of cardiopulmonary bypass (rs  =0.44, p<0.0001). Receiver operating characteristic curve analysis demonstrated that postoperative sRAGE had a predictive performance with area under the curve of 0.81 (95% confidence interval 0.71-0.88) for postoperative respiratory failure, defined as prolonged mechanical ventilation >3 days. The optimum cutoff value for prediction of respiratory failure was 3656 pg/mL, with sensitivity and specificity of 62% and 91%, respectively.

Conclusions: Serum sRAGE levels elevated immediately after cardiac surgery, and the range of elevation was associated with the morbidity of postoperative respiratory failure. Early postoperative sRAGE levels appear to be linked to cardiopulmonary bypass, and may have predictive performance for postoperative respiratory failure; however, large-scale validation studies are needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070200PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720894PMC
March 2014

[A case of prolonged neuromuscular blockade possibly related to a high anti-acetylcholine receptor antibody level].

Masui 2013 Apr;62(4):445-8

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo 113-8519.

Prolonged neuromuscular blockade is a relatively common complication of general anesthesia. Some previous reports have shown that positive serum anti-acetylcholine receptor antibody (AChR Ab) might contribute to this complication. We experienced a case of a 69-year-old woman with prolonged neuromuscular blockade after laparoscopic sigmoid colectomy under general anesthesia using rocuronium. A high level of anti-AChR Ab (45 nmol x l-1) was found in postoperative examination and the patient had progressive muscle weakness for six months after the operation. Although this patient had mediastinal tumor diagnosed as thymic carcinoma two years before the operation, preoperative clinical evaluation was negative for myasthenia gravis (MG) and the tumor was in remission at the operation. These observations suggest that preoperative measurement of anti-AChR Ab level might be recommended for patients with mediastinal tumor regardless of symptoms of MG and that neuromuscular blocking agents should be administrated carefully in anti-AChR Ab positive patients under monitoring of the neuromuscular blockade.
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April 2013

Retrospective analysis of spontaneous recovery from neuromuscular blockade produced by empirical use of rocuronium.

J Anesth 2011 Dec 21;25(6):845-9. Epub 2011 Sep 21.

Department of Anesthesiology, Tokyo Medical and Dental University, Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Purpose: A train-of-four ratio (TOF ratio) of >0.9 should be the clinical cut-off to avoid residual paralysis. However, it is not rare to extubate patients without measurement of the TOF ratio, although the safe interval from the last administration of rocuronium assuring a TOF ratio of >0.9 has not been established in the daily clinical setting. In this study, to estimate the safe interval to avoid residual paralysis, we retrospectively selected patients in whom the TOF ratio was measured during remifentanil administration before extubation, and we studied the characteristics of recovery from the neuromuscular blockade produced by the empirical use of rocuronium.

Methods: Patients undergoing surgery under general anesthesia with sevoflurane and remifentanil were studied (n = 134). Rocuronium was administered at 0.7-1.0 mg/kg for tracheal intubation, and repeated bolus administration (10 mg) or continuous infusion (15-25 mg/h) was performed by the anesthesiologists in charge of the patient to maintain intraoperative paralysis. At the end of the surgery, the TOF ratio was measured, during remifentanil infusion and the contribution of clinical parameters to spontaneous recovery from the rocuronium-induced paralysis was studied by multivariate logistic regression analyses.

Results: Spontaneous recovery from rocuronium-induced paralysis within 2 h after the last administration of rocuronium varied among the patients. Multivariate logistic regression analyses showed that age (P = 0.002) and time elapsed from the last administration of rocuronium (P < 0.0001) significantly contributed to TOF recovery, and elderly patients demonstrated significantly slower recovery.

Conclusion: Because of the large variation in the recovery from rocuronium-induced paralysis, TOF-based evaluation of residual paralysis is essential to determine the appropriate indication for reversal, especially for elderly patients.
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http://dx.doi.org/10.1007/s00540-011-1229-xDOI Listing
December 2011

Reversible cerebral vasoconstriction syndrome with limb myoclonus following intravenous administration of methylergometrine.

J Anesth 2011 Jun 23;25(3):405-8. Epub 2011 Mar 23.

Department of Anesthesiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Neurological deficits associated with methylergometrine have been reported primarily as a result of reversible cerebral vasoconstriction syndromes (RCVS). RCVS are characterized by reversible multifocal vasoconstrictions of the cerebral arteries heralded by acute severe headache with or without neurological deficits. Here, we present the first case of suspected RCVS with transient limb myoclonus following the intravenous administration of methylergometrine during cesarean section. A 31-year-old woman who received slowly infused intravenous methylergometrine during a cesarean section suddenly reported severe occipital headache after 40 min, followed by apnea and unconsciousness for 8 min. A second administration of methylergometrine to treat the weakness of her uterine contractions resulted in a repeated loss of consciousness within minutes and the development of limb myoclonus. No abnormalities were detected by brain computerized tomography, magnetic resonance imaging, and electroencephalogram. She fully recovered spontaneously within 12 h. We consider that the transient limb myoclonus in our patient appeared as a result of RCVS caused by the intravenous administration of methylergometrine.
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http://dx.doi.org/10.1007/s00540-011-1122-7DOI Listing
June 2011

Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells.

Am J Physiol Lung Cell Mol Physiol 2011 Apr 21;300(4):L516-25. Epub 2011 Jan 21.

Department of Anesthesiology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 μg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.
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http://dx.doi.org/10.1152/ajplung.00118.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075094PMC
April 2011

Acute lung injury and alveolar epithelial function.

Authors:
Tokujiro Uchida

J Anesth 2011 Feb 14;25(1):152-4. Epub 2010 Dec 14.

Department of Anesthesiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

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http://dx.doi.org/10.1007/s00540-010-1063-6DOI Listing
February 2011

Cardiac arrest in the left lateral decubitus position and extracorporeal cardiopulmonary resuscitation during neurosurgery: a case report.

J Anesth 2010 Jun 20;24(3):447-51. Epub 2010 Mar 20.

Department of Intensive Care Medicine, Yokohama City Minato Red Cross Hospital, 3-12-1 Shin-yamashita, Naka-ku, Yokohama 231-8682, Japan.

Cardiopulmonary resuscitation (CPR) in the lateral position during noncardiac surgery has been described in only a few reports in the past. Here, we report a case of cardiac arrest in a 61-year-old man undergoing microvascular decompression surgery for trigeminal neuralgia in the left lateral decubitus position. During the initial 5 min of CPR, chest compression was performed in this position by two rescuers; one from the chest and the other from the back, pushing simultaneously. Because ventricular arrhythmia was refractory to conventional CPR even after placing the patient back to the supine position, extracorporeal life support was introduced in the operating room by using the femoro-femoral approach (right atrio-femoral veno-arterial bypass). This alternative CPR markedly decreased the frequency of ventricular arrhythmia. Subsequent coronary angiogram detected 99% stenosis of the right coronary artery. Ventricular arrhythmia ceased after coronary revascularization, and the patient was successfully weaned from the extracorporeal bypass circuit. The patient was discharged alive with minimal neurological impairment. We suggest that chest compression in the lateral position by two rescuers is an efficient resuscitation maneuver, and if an electrical storm is refractory to conventional CPR, extracorporeal life support should be considered in the operating-room setting.
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http://dx.doi.org/10.1007/s00540-010-0911-8DOI Listing
June 2010

[Case of anosmia which appeared after anaphylactic shock due to intravenous heparin].

Masui 2009 Aug;58(8):997-9

Department of Anesthesiology, Tokyo Medical and Dental University, School of Medicine, Tokyo 113-8510.

A patient developed anaphylactic shock after a heparin dosage during an operation to make inner shunt for chronic renal failure of Alport syndrome. The operation was canceled and the patient was admitted to the ICU with tracheal intubation. He was extubated safely on the fifth postoperative day, but he lost the sense of smell from the day after. Abnormality of the nasal mucosa was not recognized. The smell disorder improved slowly in three or four weeks. Anosmia after anaphylactic shock is very rare, but we should be careful for this complication after anaphylactic shock.
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August 2009

Elevated levels of the receptor for advanced glycation end products, a marker of alveolar epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human lungs.

Chest 2009 Feb 18;135(2):269-275. Epub 2008 Nov 18.

Department of Medicine, University of California, San Francisco, CA. Electronic address:

Background: Although alveolar epithelial injury is a major determinant of outcome in patients with acute lung injury, there is no reliable biological marker of alveolar epithelial injury. The primary objective was to determine whether elevated levels of the receptor for advanced glycation end products (RAGE), a marker of alveolar epithelial injury, reflect impaired alveolar fluid clearance (AFC) in an ex vivo perfused human lung preparation. A second objective was to determine whether levels of a marker of endothelial injury, von Willebrand factor antigen (vWF:Ag), are associated with impaired AFC.

Methods: Human lungs (N = 30) declined for transplantation by the California Transplant Donor Network were perfused at a constant pulmonary artery pressure of 12 mm Hg. Following rewarming to 36 degrees C, the lungs were inflated with a continuous positive airway pressure of 10 cm H(2)O. RAGE and vWF:Ag levels and AFC rates were then measured.

Results: The rate of AFC was inversely correlated with RAGE levels in the alveolar fluid (p < 0.005). Similarly, the concentration of RAGE in the alveolar fluid was significantly higher in lungs with submaximal AFC, defined in a prespecified analysis as
Conclusions: RAGE may be a useful biological marker of alveolar epithelial injury and impaired AFC in donor lungs prior to transplant and perhaps in patients with acute lung injury.
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http://dx.doi.org/10.1378/chest.08-0919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714162PMC
February 2009

[Acute lung injury and alveolar epithelial function].

Masui 2008 Jan;57(1):51-9

Department of Anesthesiology, Graduate School of Medicne, Tokyo Medical and Dental University, Tokyo.

Since its original definition forty years ago, acute lung injury/acute respiratory distress syndrome has been a challenging target for both clinicians and researchers. In this review, several progresses in the past decades in the area of research concerning the pathophysiology of alveolar epithelium in this syndrome are discussed. Understanding the mechanism of tissue injury and tissue repair are key points to develop new strategy for clinical evaluation of severity of this syndrome and possible therapeutic approaches in future.
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January 2008

Plasma receptor for advanced glycation end-products predicts duration of ICU stay and mechanical ventilation in patients after lung transplantation.

J Heart Lung Transplant 2007 Jul;26(7):675-80

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, California 94143-0130, USA.

Background: Primary graft dysfunction, formerly termed reperfusion pulmonary edema, is the leading cause of short-term complications after lung transplantation. New evidence shows that alveolar type I epithelial cells play an active role in alveolar fluid transport and are therefore presumed to be critical in the absorption of pulmonary edema. We tested the potential relevance of a novel marker of alveolar type I cell injury, the receptor for advanced glycation end-products (RAGE), to short-term outcomes of lung transplantation.

Methods: The study was a prospective, observational cohort study of 20 patients undergoing single lung, bilateral lung or combined heart-lung transplantation. Plasma biomarkers were measured 4 hours after allograft reperfusion.

Results: Higher plasma RAGE levels were associated with a longer duration of mechanical ventilation and longer intensive care unit length of stay, in contrast to markers of alveolar type II cell injury, endothelial injury and acute inflammation. Specifically, for every doubling in plasma RAGE levels, the duration of mechanical ventilation increased on average by 26 hours, adjusting for ischemia time (95% confidence interval [CI] 7.4 to 44.7 hours, p = 0.01). Likewise, for every doubling of plasma RAGE levels, intensive care unit length of stay increased on average by 1.8 days, again adjusting for ischemia time (95% CI 0.13 to 3.45 days p = 0.04). In contrast, the clinical diagnosis of primary graft dysfunction was not as predictive of these short-term outcomes.

Conclusions: Higher levels of plasma RAGE measured shortly after reperfusion predicted poor short-term outcomes from lung transplantation. Elevated plasma RAGE levels may have both pathogenetic and prognostic value in patients after lung transplantation.
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http://dx.doi.org/10.1016/j.healun.2007.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741136PMC
July 2007

Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats.

Am J Respir Cell Mol Biol 2007 Aug 12;37(2):186-92. Epub 2007 Apr 12.

Cardiovascular Research Institute, University of California San Francisco, HSW 825, 505 Parnassus Ave., San Francisco, CA 94143-0130, USA.

New evidence indicates that neural mechanisms can down-regulate acute inflammation. In these studies, we tested the potential role of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in a rodent model of acid-induced acute lung injury. We first determined that the alpha7 nAChR was expressed by alveolar macrophages and lung epithelial cells. Then, using an acid-induced acute lung injury mouse model, we found that nicotine, choline, and PNU-282,987 (a specific alpha7 nAChR agonist) decreased excess lung water and lung vascular permeability, and reduced protein concentration in the bronchoalveolar lavage (BAL). Deficiency of alpha7 nAChR resulted in a 2-fold increase in excess lung water and lung vascular permeability. The reduction of proinflammatory cytokines (macrophage inflammatory protein-2 and TNF-alpha) in the BAL with nicotine probably resulted from the suppression of NF-kappaB activation in alveolar macrophages. The beneficial effect of nicotine was also tested in rat model of acid-induced acute lung injury in which BAL protein and receptor for advanced glycation end products (RAGE), a marker of type I cell injury, were reduced by nicotine treatment. These results indicate that activation of alpha7 nAChR may provide a new therapeutic pathway for the treatment of acute lung injury.
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http://dx.doi.org/10.1165/rcmb.2006-0240OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976545PMC
August 2007
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