Language：English   Publishing type：Research paper (scientific journal)  

Adverse effects of morphine on locomotor function after moderate to severe spinal cord injury (SCI) have been reported; however, the effects after mild SCI without damage of lumbar α-motoneurons have not been investigated. We investigated the effects of lumbar intrathecal morphine on locomotor function after mild thoracic SCI and the involvement of classic opioid receptor activation. A mild thoracic contusive SCI was induced in adult rats at the T9-T10 spine level under sevoflurane anesthesia. We evaluated the effects of single doses of intrathecal morphine and selective μ-, δ-, and κ-opioid receptor agonists, continuous infusion of intrathecal morphine for 72 hours, and administration of physiological saline on locomotor function and muscle tone in the hindlimbs. The numbers of damaged and total α-motoneurons in the lumbar spinal cord were also investigated. Single doses of morphine aggravated residual locomotor function after SCI but did not affect functional recovery. Single doses of morphine and μ- and δ-opioid receptor agonists significantly aggravated residual locomotor function with increases in muscle tone after SCI, and the effects of the drugs were reversed by naloxone. In contrast, continuous infusion of morphine led to persistent decline in locomotor function with increased muscle tone, which was not reversed by naloxone, but did not increase the number of damaged lumbar α-motoneurons. These results indicate that a single dose of morphine at an analgesic dose transiently increases muscle tone of the hindlimbs via activation of spinal μ- and δ- opioid receptors, resulting in further deterioration of locomotor function in the acute phase of mild SCI. Our results also suggest that an increased dose of morphine with prolonged administration leads to persistent decline in locomotor function with increased muscle tone via mechanisms other than direct activation of classical opioid receptors. Morphine should be used cautiously even after mild SCI.

DOI： 10.1371/journal.pone.0273095

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Anaphylaxis caused by a catheter itself used for endovascular surgery is rare, and a method for detection of a causative catheter has not been established. We report a case of catheter-induced anaphylaxis in which the causative catheter was successfully detected. CASE PRESENTATION: A 47-year-old male underwent neuroendovascular surgery. During surgery, blood pressure suddenly dropped and the level of tryptase indicated the occurrence of anaphylaxis. There were 24 candidate agents for the cause of anaphylaxis including 8 catheters. We performed the basophil activation test by directly mixing the catheter with blood. One catheter coated with a hyaluronic acid product showed a positive reaction, and we confirmed the result by a modified skin test using an elution solution of the catheter. Later, we successfully completed the neuroendovascular surgery without the catheter. CONCLUSIONS: The methods used in this case can be useful for the detection of the causative agent in catheter-induced anaphylaxis.

DOI： 10.1186/s40981-021-00463-7

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Although chronic local inflammation in deeper tissues after skin wound healing might produce chronification of acute postsurgical pain, its mechanisms have not been fully elucidated. We hypothesized that muscle injury and severe inflammation would prolong acute postsurgical pain by its central nervous system mechanisms. MAIN METHODS: After approval of the Animal Care Committee, experiments were performed in Male Sprague-Dawley rats weighing 250-300 g. Plantar incision and plantar incision combined with cryoinjury of the plantar flexor digitorum brevis muscle were made in the plantar incision group and muscle injury group, respectively. Pain-related behaviors were assessed, and inflammatory cells were isolated from injured muscle and analyzed by flow cytometry. Spinal microglial activation was assessed with Iba-1 staining. KEY FINDINGS: Mechanical hyperalgesia from day 5 to day 8 and spontaneous pain-related behavior from day 3 to day 7 were significantly greater in the muscle injury group than in the plantar incision group (P < 0.05), whereas there was no significant difference between the two groups in thermal hyperalgesia. In the muscle injury group, the number of inflammatory cells on day 4 was significantly larger and spinal Iba-1 expression levels on days 4 and 7 were significantly higher than those in the plantar incision group (P < 0.05). SIGNIFICANCE: Surgical injury in deep tissues accompanying severe muscle inflammation induced prolonged postsurgical pain in the healing wound of the skin not by the persistence of muscle inflammation but by a central mechanism involving microglial activation at the level of the spinal cord.

DOI： 10.1016/j.lfs.2021.119389

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Since the first case of coronavirus disease 2019 (COVID-19) was reported in Japan in January 2020, the COVID-19 pandemic has brought about a significant change in people's lives. Although the COVID-19 pandemic is expected to have had an impact on the work of anesthesiologists, the specific impact has been largely unreported. We hypothesized that the number of general anesthesia (GA) cases has decreased due to the COVID-19 pandemic. To test this hypothesis, we conducted a retrospective survey at 34 facilities in Japan as a part of the Japanese Epidemiologic Study for Perioperative Anaphylaxis. The results showed that the number of GA cases had significantly decreased, particularly in May 2020, under the government's declaration of a state of emergency. The decline in GA caseload had not fully recovered by July 2020. Furthermore, there were regional differences in the decline in the number of GA cases. The impact of the COVID-19 pandemic on the work of anesthesiologists was greater in prefectures where there were more COVID-19 patients and where the state of emergency was declared earlier. Our study suggested a region-dependent decrease in the number of GA cases due to the COVID-19 pandemic.

DOI： 10.1155/2021/8144794

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Intraoperative massive bleeding is associated with high rates of mortality and anesthetic management of massive bleeding is challenging because it is necessary to achieve volume resuscitation and electrolyte correction simultaneously during massive transfusion. We report a case of life-threatening bleeding of more than 80,000 mL during liver transplantation in which real-time QTc monitoring was useful for an extremely large amount of calcium administration for treatment of hypocalcemia. A 47-year-old female with a giant liver due to polycystic liver disease was scheduled to undergo liver transplantation. During surgery, life-threatening massive bleeding occurred. The maximum rate of blood loss was approximately 15,000 mL/hr and the total amount of estimated blood loss was 81,600 mL. It was extremely difficult to maintain blood pressure and a risk of cardiac arrest continued due to hypotension. In addition, even though administration of insulin and calcium was performed, electrolyte disturbances of hyperkalemia and hypocalcemia with prolongation of QTc interval occurred. At that time, we visually noticed that the QT interval was shortened in response to bolus calcium administration, and we used the change of real-time QTc interval as a supportive indicator for calcium correction. This monitoring allowed for us to administer calcium at an unusually high rate, by which progression of hypocalcemia was prevented. Levels of hemoglobin and coagulation factors were preserved both by restriction of crystalloid infusion and by a massive transfusion protocol. The patient was extubated without pulmonary edema or cardiac overload and was finally discharged without any sequelae. Intensive and cooperative management for massive transfusion and electrolyte correction using QTc monitoring was considered to be a key for successful management.

DOI： 10.1155/2021/6635696

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Previous studies suggested that phospholipase Cβ3 (PLCβ3), which is a common downstream component in the signaling cascade, plays an important role in peripheral mechanisms of perception including nociception. However, detailed profiles of PLCβ3-expressing dorsal root ganglion (DRG) neurons and involvement of PLCβ3 in inflammatory and postoperative pain have not been fully investigated. PURPOSE: We evaluated neurochemical char0acteristics of PLCβ3-expressing DRG neurons in mice and then we examined the effects of selective knockdown of PLCβ3 expression in DRGs on inflammatory and postoperative pain. METHODS: Male C57BL/6-strain mice were used. For the inflammatory model, each mouse received subcutaneous injection of complete Freund's adjuvant (CFA) in the left hindpaw. For the postoperative pain model, a plantar incision was made in the left hindpaw. PLCβ3 antisense oligodeoxynucleotide or PLCβ3 mismatch oligodeoxynucleotide was intrathecally administered once a day for three consecutive days in each model. The time courses of thermal hyperalgesia and mechanical hyperalgesia were investigated. Changes in PLCβ3 protein levels in DRGs were evaluated by Western blotting. RESULTS: Immunohistochemical analysis showed that high proportion of the PLCβ3-positive profiles were biotinylated isolectin B4-positive or transient receptor potential vanilloid subfamily 1-positive. PLCβ3 protein level in DRGs during CFA-induced inflammation was comparable to that at baseline. Intrathecal administration of PLCβ3 antisense oligodeoxynucleotide, which significantly suppressed PLCβ3 expression in DRGs, did not affect pain thresholds in normal conditions but inhibited CFA-induced thermal and mechanical hyperalgesia both at the early and late phases compared to that in mismatch oligodeoxynucleotide-treated mice. Intrathecal administration of PLCβ3 antisense oligodeoxynucleotide also inhibited surgical incision-induced thermal and mechanical hyperalgesia. CONCLUSION: Our results uncover a unique role of PLCβ3 in the development and maintenance of inflammatory pain induced by CFA application and in those of surgical incision-induced pain, although PLCβ3 does not play a major role in thermal nociception or mechanical nociception in normal conditions.

DOI： 10.2147/jpr.s280565

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The aim of this study was to elucidate normative features of vagal motor-evoked potentials (MEPs) induced by transcranial electrical stimulation (TES) and to determine the influence of functional decline of the recurrent laryngeal nerve (RLN) on vagal MEPs during thyroid surgery. METHODS: A total of 54 patients undergoing elective thyroid surgery under general anesthesia were enrolled in this study. Vagal MEPs induced by TES were measured from the vocal cord using one of two types of electrodes (wire type or wide and flat type) mounted on an endotracheal tube. We investigated the effects of stimulation intensity and train pulse number on vagal MEP amplitude, the time course of vagal MEP amplitude during surgery, and the effects of functional decline of the RLN on vagal MEPs. RESULTS: The success rate of vagal MEP monitoring with wide- and flat-type electrodes was significantly higher than that with wire-type electrodes. Reliable vagal MEPs were obtained at a stimulation intensity of approximately 300 V with 3 or more pulses in 91% of the patients without preoperative RLN palsy (RLNP), and the amplitude was augmented with increasing stimulation intensity and train pulse number. Vagal MEP amplitude decreased during thyroid surgery and then partially recovered at the end of surgery. Vagal MEP amplitude recorded from the electrode ipsilateral to preoperative RLNP was significantly lower than that on the contralateral intact side. CONCLUSION: Vagal MEPs induced by TES can be obtained with a high success rate during thyroid surgery and would reflect functional status of the RLN.

DOI： 10.1007/s00540-018-2601-x

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aim of this study was to elucidate the characteristics of accuracy of subcutaneous continuous glucose monitoring (SCGM) in the perioperative period for neurosurgical and cardiac surgery patients. METHODS: Forty-five subjects, including healthy volunteers (n = 15), neurosurgical patients (n = 15), and cardiac surgery patients (n = 15), were enrolled. A subcutaneous sensor of the MiniMed™ 620G SCGM system was inserted into the upper arm. On the day after sensor insertion, SCGM data and blood glucose data were collected simultaneously and compared. In cardiac surgery patients, data were continuously collected on postoperative day (POD) 1 and POD 3. Clarke error grid analysis and Bland-Altman analysis were performed to assess the accuracy of SCGM. RESULTS: Clarke error grid analysis showed clinical acceptance of the SCGM system with 82.7% and 86.8% of the data being within zone A for healthy volunteers and neurosurgical patients, respectively. Mean biases were -2.1 mg/dL in healthy volunteers and -8.3 mg/dL in neurosurgical patients. In cardiac surgery, although Clarke error grid analysis showed clinical acceptance, 65.3% of the data were within zone A and mean bias was -23.5 mg/dL. Changes in accuracy of SCGM in individuals occurred during cardiopulmonary bypass (CPB), and SCGM tended to show a lower glucose level. On POD 1 and POD 3, the accuracy improved, and 85.0% and 86.3% of the data were within zone A. CONCLUSIONS: Although the accuracy of the SCGM system was clinically acceptable in the perioperative period, sensor accuracy was affected by CPB and showed lower glucose levels.

DOI： 10.1089/dia.2018.0140

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Insulinoma is a rare neuroendocrine tumor that causes hypoglycemia due to unregulated insulin secretion. Blood glucose management during insulinoma resection is therefore challenging. We present a case in which real-time subcutaneous continuous glucose monitoring (SCGM) in combination with intermittent blood glucose measurement was used for glycemic control during surgery for insulinoma resection. The SCGM system showed the trends and peak of interstitial glucose in response to glucose loading and the change of interstitial glucose before and after insulinoma resection. These data were helpful for adjusting the glucose infusion; therefore, we think that an SCGM system as a supportive device for glucose monitoring may be useful for glucose management during surgery.

DOI： 10.1155/2018/6248467

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

A patient with congenital insensitivity to pain with anhidrosis (CIPA) underwent revision of total hip arthroplasty under general anesthesia with only propofol. During surgery, neither elevation of stress hormones nor hemodynamic changes associated with pain occurred; however, when blood was rapidly lost, compensatory tachycardia was observed. Although patients with CIPA are complicated with autonomic disturbance due to dysfunction of postganglionic sympathetic fibers, this compensatory response indicated that the adrenal glands in patients with CIPA secrete catecholamine as part of a compensatory response during bleeding under general anesthesia.

DOI： 10.1155/2018/9593458

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Since acute respiratory failure (ARF) is a life-threatening complication, particularly in the gestational period, differential diagnosis and rapid treatment are required. Among the various causes of sudden onset of ARF, thyroid storm is a rare cause in a parturient complicated with well-controlled hyperthyroidism. In this case report, we describe a parturient with hyperthyroidism in whom a thyroid storm manifesting congestive heart failure and pulmonary edema developed just before an emergency ceasarean section, even though hyperthyroidism was well-controlled with antithyroid drugs. CASE PRESENTATION: A 36-year-old pregnant woman was diagnosed as having clinical chorioamnionitis, and an emergency cesarean section was performed at 25 weeks of pregnancy. She had a complication of hyperthyroidism accompanied by mild mitral regurgitation, and she had been treated with methimazole. She was treated with ritodrine and MgSO4 for the threat of premature delivery. At the preoperative consultation, her percutaneous oxygen saturation (SpO2) was 98% on room air. When she was admitted to the operating room, her heart rate and blood pressure were 130 beats/min and 196/78 mmHg, respectively. SpO2 was 88% on room air without any symptoms; however, just after starting oxygen administration via a facemask, she complained of severe respiratory distress and became agitated. Partial pressure of arterial oxygen was 108 mmHg with an inspiratory oxygen fraction of 1.0. Chest radiography revealed pulmonary congestion, and transesophageal echocardiography revealed normal right ventricular function without an embolus and severe mitral regurgitation with preserved left ventricular function. Contrast-enhanced computed tomography after the operation revealed no pulmonary embolus but revealed a pulmonary effusion, and free triiodothyronine level was increased at the onset of dyspnea. Therefore, we diagnosed the causes of sudden onset of dyspnea as pulmonary edema and congestive heart failure induced by a thyroid storm. CONCLUSION: Sudden onset of a thyroid storm just before a cesarean section occurred in a patient with several risk factors of thyroid storm and pulmonary edema, including pregnancy, treatment with tocolytic agents, and infection. The involvement of these multiple factors was considered to be the cause of the sudden onset of the thyroid storm and the cause of rapidly progressive pulmonary edema.

DOI： 10.1186/s40981-017-0088-3

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Robotic surgery with carbon dioxide (CO2) insufflation to the thorax is frequently performed to gain a better operative field of view, although its intraoperative complications have not yet been discussed in detail. We treated two patients with difficult ventilation caused by distal migration of a double-lumen endotracheal tube (DLT) during robotic thymectomy. In the first case, migration of the DLT during one-lung ventilation (OLV) occurred after CO2 insufflation to the bilateral thoraxes was started. Oxygenation rapidly deteriorated because dependent lung expansion was restricted by CO2 insufflation. In the second case, migration of the DLT during OLV occurred while CO2 insufflation to a unilateral thorax and mediastinum was performed. In both cases, once migration of the DLT during OLV occurred with CO2 insufflation, readjusting the DLT became very difficult because our manipulation of bronchofiberscopy was prevented by the robot arms located above the patient's head and because deformation of the trachea/bronchus induced by CO2 insufflation caused a poor image of the bronchofiberscopic view. Thus, during robotic-assisted thoracoscopic surgery with CO2 insufflation, since there is a potential risk of difficult ventilation with a DLT and since readjustment of the DLT is very difficult, discontinuing CO2 insufflation and switching to double-lung ventilation are needed in such a situation.

DOI： 10.1155/2017/3403045

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

We present 2 cases of severe re-expansion pulmonary edema (RPE) after one-lung ventilation (OLV) for thoracic surgery. A 32-y-old woman with multiple lung metastases developed severe RPE after OLV during lung resection surgery. A 37-y-old man with infective endocarditis also developed severe RPE after OLV for mitral valve plasty with minimally invasive cardiac surgery. In both cases, results of a preoperative pulmonary function test and oxygenation were almost normal, and pleural effusion or pulmonary congestion was not detected in preoperative computed tomography; however, there was a possibility that subclinical lung injury existed before surgery. The levels of interleukin-8 and monocyte chemotactic protein-1, which are thought to play important roles in the development of lung injury, in bronchial secretions were extremely high after the onset of RPE. These results suggest that the pathogenesis of RPE shares, at least in part, a common pathophysiology of acute lung injury.

DOI： 10.4187/respcare.03759

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

An 18-month-old female infant was scheduled for resection of a laryngeal saccular cyst inducing narrow airway. Since the cyst protruded from the left side of the epiglottis and the vocal cord was compressed to the right side, a difficult airway was anticipated. In addition, there was a risk of tracheal occlusion by rupture of the cyst Awake intubation was considered to be dangerous. Slow induction with sevoflurane and neuromusclar blockade was attempted, preparing reversal of the neuromusclar blockade. Fortunately, mask ventilation was achieved without difficulty. It was necessary to insert a tracheal tube avoiding the cyst We used McGrath MAC (Aircraft Medical Co., UK), which enabled us to manipulate the tracheal tube. A tracheal tube was successfully inserted under McGrath monitor guidance.

PubMed

researchmap

Language：English  

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 54-year-old woman with atlantoaxial subluxation in rheumatoid arthritis was scheduled for total elbow arthroplasty. Since her neck was stabilized with a cervical collar and her interincisor distance was 1.5 finger-breadth, a difficult airway was anticipated. Anesthesia was induced with propofol and fentanyl. Mask ventilation was barely achieved with difficulty Then insertion of an Intlock with Airwayscope (AWS) into the pharynx was attempted but could not be performed because of restriction of neck mobility and small mouth opening. Although only Intlock separated from AWS could be inserted into the pharynx, oropharyngeal bleeding occurred and we could not obtain an appropriate view on the monitor. Following aspiration of blood, the trachea was intubated using a flexible fiberoptic bronchoscope under AWS guidance. After the operation, a view of bronchoscopy by an otolaryngologist revealed three lacerations from the mucosa to muscle layer in the pharynx. The lacerations could have resulted from use of AWS in a patient with a small mouth opening and with vulnerable mucosa due to long-term steroid therapy.

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 41-year-old man weighing 196 kg (body mass index of 62.5 kg m2) with renal cancer was scheduled for laparoscopic right nephrectomy. On the day before surgery, we confirmed the intraoperative patient position with the patient and medical staff to prevent neurological deficit during the intraoperative period. For postoperative analgesia and prevention of respiratory complications, an epidural catheter was inserted under radiography and ultrasound guidance. Difficult airway was anticipated, and we attempted awake intubation in the left lateral position with Airwayscope (AWS). The vocal cord was visualized with AWS; however, because of his small oral cavity, we could not place the Intlock of AWS to insert the tracheal tube appropriately. Using a flexible fiberoptic bronchoscope under AWS guidance, the trachea was intubated. During neumoperitoneum at 12 mmHg, mechanical ventilation was achieved without hypercapnia, hypoxia or elevated airway pressure, with rate of 12 min-1, FIO2 of 0.6, PIP of 25 cmH2O and PEEP of 8 cmH2O. The surgery was completed and his trachea was extubated in the operating room. He did not develop any perioperative complications and was discharged on the 10th day after the surgery.

PubMed

researchmap

Language：English  

DOI： 10.1007/s12630-012-9790-9

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Although transforming growth factor (TGF)-β1 is a well-known immunosuppressive cytokine, little is known about the role of its downstream transcription factors, Smad2 and Smad3, in the suppression of macrophage activation. Previous studies have demonstrated that Smad3 is critical for the suppression of LPS-mediated inducible nitric oxide (NO) synthase (iNOS) induction, although the role of Smad2 remains to be investigated. In this study, we found that iNOS induction was enhanced in Smad2-deficient bone marrow-derived macrophages (BMDMs) and peritoneal macrophages in vitro and tumor-associated macrophages in vivo, compared with wild-type (WT) macrophages. However, TGF-β1 still suppressed iNOS induction in Smad2-deficient macrophages. In Smad2/3 double knockout (KO) (Smad2/3 DKO) BMDMs, LPS-mediated NO/iNOS induction was more strongly elevated than in Smad2 or Smad3 single KO BMDMs, and its suppression by exogenous TGF-β1 was severely impaired. These data suggest that Smad2 and Smad3 redundantly regulate iNOS induction. Similarly, the production of IL-6 and TNFα, but not IL-10 was augmented in Smad2/3 DKO BMDMs, suggesting that Smad2 and Smad3 also redundantly suppressed some cytokines production. In Smad2/3 DKO macrophages, TLR3- as well as TLR4-mediated IRF3 activation and IFN-β production were strongly augmented, which resulted in hyper STAT1 phosphorylation. Furthermore, IFN-β- and IFN-γ-induced iNOS induction in the absence of TLR signaling and STAT1 transcriptional activity were augmented in Smad2/3 DKO BMDMs. These results suggest that Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway.

DOI： 10.1093/intimm/dxr126

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Suppression of IL-2 βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4(+) T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2(-/-)Smad3(+/-) T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.

DOI： 10.1074/jbc.M111.236794

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Suppressor of cytokine signaling-1 (SOCS1) has been shown to be an essential negative regulator of cytokine responses, including those of IFNγ, IL-2, IL-4 and IL-7. SOCS1 deficiency resulted in hyperactivation not only of T cells in general but also of NKT cells specifically. Consistent with previous reports, T- and NKT-cell-specific deletion of Socs1 in mice resulted in enhanced sensitivity to ConA-induced hepatitis. Compared with wild-type (WT) NKT cells, SOCS1-deficient NKT cells produced larger quantities of IFNγ in response to ConA and proliferated faster in response to IL-2 and IL-15. To our surprise, however, SOCS1-deficient NKT cells did not respond to the synthetic glycolipid ligand alpha-galactosylceramide (α-GalCer), though they did respond to sulfatide. α-GalCer-CD1d-tetramer-positive type I NKT [invariant NKT (iNKT)] cells were marginally detected in the periphery of SOCS1-conditional knockout (cKO) mice, suggesting that most of the SOCS1-deficient NKT cells at the periphery were type II NKT cells. Consistently, invariant Vα14 expression was much lower in SOCS1-deficient NKT cells than in WT NKT cells, indicating that iNKT cell homeostasis was abnormal in SOCS1-cKO mice. This reduction in iNKT cells was not observed in mice of an IFNγ-deficient background. These results suggest that SOCS1 is an important regulator of the balance between type I and type II NKT cells at the periphery.

DOI： 10.1093/intimm/dxq469

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.

DOI： 10.1016/j.bbrc.2010.10.058

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Sprouty proteins have been shown to negatively regulate a variety of receptor tyrosine kinase (RTK) signaling pathways and are considered to be tumor suppressor proteins. The pathophysiological functions of Sproutys in vivo remain to be investigated. In this study, we examined the physiological function of Sprouty4 as an angiogenic regulator, using Sprouty4 knockout (KO) mice and cells. We found that transplanted tumor cells grow much faster in Sprouty4 KO mice than in wild type (WT) mice, which we associate with enhanced neovascularization in the tumors transplanted into Sprouty4 KO mice. Moreover, vascular endothelial growth factor (VEGF)-A-induced angiogenesis and vascular permeability in vivo were enhanced in Sprouty4 KO mice compared with WT mice. Ex vivo angiogenesis, which we induced by VEGF-A, basic fibroblast growth factor (bFGF), and sphingosine-1-phosphate (S1P), was also enhanced in the aortas of Sprouty4 KO mice. We demonstrated that Sprouty4 suppresses Ras-independent VEGF-A and S1P signaling, while it does not affect Ras-dependent VEGF-C signaling. These data indicate that Sprouty4 selectively suppresses Ras-independent angiogenic factor signals and is an important negative regulator of pathophysiological angiogenesis.

DOI： 10.1111/j.1349-7006.2009.01214.x

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

DOI： 10.1038/nm.1999

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

T(h) cells have long been divided into two subsets, T(h)1 and T(h)2; however, recently, T(h)17 and inducible regulatory T (iTreg) cells were identified as new T(h) cell subsets. Although T(h)1- and T(h)2-polarizing cytokines have been shown to suppress T(h)17 and iTreg development, transcriptional regulation of T(h)17 and iTreg differentiation by cytokines remains to be clarified. In this study, we found that expression of the growth factor independent 1 (Gfi1) gene, which has been implicated in T(h)2 development, was repressed in T(h)17 and iTreg cells compared with T(h)1 and T(h)2 lineages. Gfi1 expression was enhanced by the IFN-gamma/STAT1 and IL-4/STAT6 pathways, whereas it was repressed by the transforming growth factor-beta1 stimulation at the promoter level. Over-expression of Gfi1 strongly reduced IL-17A transcription in the EL4 T cell line, as well as in primary T cells. This was due to the blockade of recruitment of retinoid-related orphan receptor gammat to the IL-17A promoter. In contrast, IL-17A expression was significantly enhanced in Gfi1-deficient T cells under T(h)17-promoting differentiation conditions as compared with wild-type T cells. In contrast, the impacts of Gfi1 in iTregs were not as strong as in T(h)17 cells. Taken together, these data strongly suggest that Gfi1 is a negative regulator of T(h)17 differentiation, which represents a novel mechanism for the regulation of T(h)17 development by cytokines.

DOI： 10.1093/intimm/dxp054

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

It has been shown that transforming growth factor beta1 (TGF-beta1) is critical in the generation of CD4(+)CD25(+)Foxp3(+)-inducible regulatory T cells (iTregs) from naïve CD4(+)T cells. However, in contrast to natural Tregs, TGF-beta1-induced iTregs rapidly lose both Foxp3 expression and suppression activity. We found that TGF-beta1-induced Foxp3 levels were maintained by the addition of the anti-interleukin 4 (IL-4) antibody or by STAT6 gene deletion. Thus, IL-4 is an important suppressor of Foxp3 induction, and T helper 2 development is a major cause for the disappearance of iTreg during long culture. Using promoter analysis in EL4 cells and primary T cells, we identified a silencer region containing a STAT6 binding site. STAT6 binding to this site reduced TGF-beta1-mediated Foxp3 promoter activation and chromatin modification. Retinoic acid has also been shown to suppress loss of Foxp3 induced by TGF-beta1. Retinoic acid in the presence of TGF-beta1 reduced STAT6 binding to the Foxp3 promoter and enhanced histone acetylation, thereby reverting the effect of IL-4. We propose that antagonistic agents for neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and the promotion of tolerance in Th2-dominated diseases such as allergy.

DOI： 10.1074/jbc.M801123200

PubMed

researchmap