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Kentaro Tokuda Last modified date:2020.05.27

Assistant Professor / Intensive Care Unit, kyushu University Hospital
Intensive Care Unit
Kyushu University Hospital




E-Mail
Homepage
https://kyushu-u.pure.elsevier.com/en/persons/kentaro-tokuda
 Reseacher Profiling Tool Kyushu University Pure
http://www.med.kyushu-u.ac.jp/kuaccm/
Department of Anesthesiology and Critical Care Medicine, Kyushu University Hospital .
Phone
092-642-5871
Fax
092-642-5874
Academic Degree
Doctor of Medical Science
Country of degree conferring institution (Overseas)
No
Field of Specialization
Anesthesiology, Critical Care Medicine, Intensive Care Medicine
Total Priod of education and research career in the foreign country
02years07months
Outline Activities
Clinical medicine (Intensive Care Medicine, Critical Care, and Anesthesia), Education for students of faculty of medicine
Research
Research Interests
  • Cardioprotective effects of thiosulfate against doxorubicin-induced cardiotoxicity
    keyword : Thiosulfate, Cardioprotection, Doxorubicin-induced cardiotoxicity
    2016.04~2019.03.
  • Hepatoprotective effects of hydrogen sulfide against acute liver failure
    keyword : Hydrogen sulfide, Acute Liver Failure, Hepatoprotective Effects
    2013.04~2016.03.
  • Pathophysiological roles of hydrgen sulfide in sepsis and systemic inflammation
    keyword : sepsis, systemic inflammation, hydrogen sulfide
    2009.09~2015.03.
Current and Past Project
  • Hepatoprotective effects of hydrogen sulfide against acute liver failure
  • Cardioprotective effects of hydrogen sulfide against systemic inflammation-induced myocardial dysfunction
Academic Activities
Reports
1. Hydrogen sulfide, known as a toxic gas with a characteristic rotten-egg odor, is produced in mammalian cells by sulfurtransferases in several ways. Hydrogen sulfide has been proved to act as one of gaseous signaling molecules together with nitric oxide and carbon monoxide regulating pathophysiological as well as physiological functions. Recently, hydrogen sulfide and its donors have been reported to exert various organ-protective effects in experimental settings. Proposed mechanisms by which hydrogen sulfide exhibits beneficial effects include anti-inflammation, anti-apoptosis, anti-oxidation, neuromodulation, and so on. Firstly, this review describes the history of hydrogen sulfide research. Second, physiological concentration of sulfide and its measurement are argued. To deliver hydrogen sulfide to the cells, not only hydrogen sulfide gas, which is a potentially toxic, but also hydrogen sulfide donors without toxic gas poisoning can be administered. Therefore, the development of novel hydrogen sulfide-releasing compounds is discussed in the end. This review is intended to introduce hydrogen sulfide not as a stinky gas but as a promising molecule with various therapeutic properties to clinicians. .
2. Anesthetic management of the patient with congestive heart faiure.
Papers
1. Manabu Kakinohana, Eizo Marutani, Kentaro Tokuda, Kotaro Kida, Shizuko Kosugi, Shingo Kasamatsu, Aurora Magliocca, Kohei Ikeda, Shinichi Kai, Masahiro Sakaguchi, Shuichi Hirai, Ming Xian, Masao Kaneki, Fumito Ichinose, Breathing hydrogen sulfide prevents delayed paraplegia in mice, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2018.12.003, 131, 243-250, 2019.02, Delayed paraplegia complicates the recovery from spinal cord ischemia or traumatic spinal cord injury. While delayed motor neuron apoptosis is implicated in the pathogenesis, no effective treatment or preventive measures is available for delayed paraplegia. Hydrogen sulfide exerts anti-apoptotic effects. Here, we examined effects of hydrogen sulfide breathing on the recovery from transient spinal cord ischemia. Breathing hydrogen sulfide starting 23 h after reperfusion for 5 h prevented delayed paraplegia after 5 min of spinal cord ischemia. Beneficial effects of hydrogen sulfide were mediated by upregulation of anti-apoptotic Bcl-XL and abolished by nitric oxide synthase 2 deficiency. S-nitrosylation of NFkB p65 subunit, which is induced by nitric oxide derived from nitric oxide synthase 2, facilitated subsequent sulfide-induced persulfidation of p65 and transcription of anti-apoptotic genes. These results uncover the molecular mechanism of the anti-apoptotic effects of sulfide based on the interaction between nitric oxide and sulfide. Exploitation of the anti-apoptotic effects of delayed hydrogen sulfide breathing may provide a new therapeutic approach for delayed paraplegia..
2. Eizo Marutani, Marina Yamada, Tomoaki Ida, Kentaro Tokuda, Kohei Ikeda, Shinichi Kai, Kazuhiro Shirozu, Kei Hayashida, Shizuko Kosugi, Kenjiro Hanaoka, Masao Kaneki, Takaaki Akaike, Fumito Ichinose, Thiosulfate mediates cytoprotective effects of hydrogen sulfide against neuronal ischemia, Journal of the American Heart Association, 10.1161/JAHA.115.002125, 4, 11, 2015.11, Background-Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. Methods and Results-We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating "carrier" molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. Conclusions-The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury..
3. Kazuhiro Shirozu, Kentaro Tokuda, Eizo Marutani, David Lefer, Rui Wang, Fumito Ichinose, Cystathionine γ-Lyase deficiency protects mice from Galactosamine/lipopolysaccharide-induced acute liver failure, Antioxidants and Redox Signaling, 10.1089/ars.2013.5354, 20, 2, 204-216, 2014.01, Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-Apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-Apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-Apoptotic mechanisms. Antioxid. Redox Signal. 20, 204-216..
4. Eizo Marutani, Shizuko Kosugi, Kentaro Tokuda, Ashok Khatri, Rebecca Nguyen, Dmitriy N. Atochin, Kotaro Kida, Klaus Van Leyen, Ken Arai, Fumito Ichinose, A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death, Journal of Biological Chemistry, 10.1074/jbc.M112.374124, 287, 38, 32124-32135, 2012.09, Physiological levels of H2S exert neuroprotective effects, whereas high concentrations of H2S may cause neurotoxicity in part via activation ofNMDAR.To characterize the neuroprotective effects of combination of exogenous H2S and NMDAR antagonism, we synthesized a novel H2S-releasing NMDAR antagonist N-((1r,3R,5S,7r)-3,5- dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzamide (S-memantine) and examined its effects in vitro and in vivo. S-memantine was synthesized by chemically combining a slow releasing H2S donor 4-(3-thioxo-3H-1,2- dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na2S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na2S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H2S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury..
5. Kentaro Tokuda, Kotaro Kida, Eizo Marutani, Ettore Crimi, Masahiko Bougaki, Ashok Khatri, Hideo Kimura, Fumito Ichinose, Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice, Antioxidants and Redox Signaling, 10.1089/ars.2011.4363, 17, 1, 11-21, 2012.07, Aims: The role of hydrogen sulfide (H2S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H2S breathing on LPS-induced changes in sulfide metabolism, systemic inflammation, and survival in mice. Results: Mice that breathed air alone exhibited decreased plasma sulfide levels and poor survival rate at 72 h after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) activity and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80 ppm of H2S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p<0.05). H2S breathing attenuated LPS-induced increase of plasma ALT activity and NOx levels and lung MPO activity. Inhaled H 2S suppressed LPS-induced upregulation of inflammatory cytokines, while it markedly induced anti-inflammatory interleukin (IL)-10 in the liver. Beneficial effects of H2S inhalation after LPS challenge were associated with restored sulfide levels and markedly increased thiosulfate levels in plasma. Increased thiosulfate levels after LPS challenge were associated with upregulation of rhodanese, but not cystathionine-γ-lyase (CSE), in the liver. Administration of sodium thiosulfate dose-dependently improved survival after LPS challenge in mice. Innovation: By measuring changes in plasma levels of sulfide and sulfide metabolites using an advanced analytical method, this study revealed a critical role of thiosulfate in the protective effects of H2S breathing during endotoxemia. Conclusion: These observations suggest that H2S breathing prevents inflammation and improves survival after LPS challenge by altering sulfide metabolism in mice..
6. Shizuka Minamishima, Kotaro Kida, Kentaro Tokuda, Huifang Wang, Patrick Y. Sips, Shizuko Kosugi, Joseph B. Mandeville, Emmanuel S. Buys, Peter Brouckaert, Philip K. Liu, Christina H. Liu, Kenneth D. Bloch, Fumito Ichinose, Inhaled nitric oxide improves outcomes after successful cardiopulmonary resuscitation in mice, Circulation, 10.1161/CIRCULATIONAHA.111.025395, 124, 15, 1645-1653, 2011.10, Background-: Sudden cardiac arrest (CA) is a leading cause of death worldwide. Breathing nitric oxide (NO) reduces ischemia/reperfusion injury in animal models and in patients. The objective of this study was to learn whether inhaled NO improves outcomes after CA and cardiopulmonary resuscitation (CPR). Methods and Results-: Adult male mice were subjected to potassium-induced CA for 7.5 minutes whereupon CPR was performed with chest compression and mechanical ventilation. One hour after CPR, mice were extubated and breathed air alone or air supplemented with 40 ppm NO for 23 hours. Mice that were subjected to CA/CPR and breathed air exhibited a poor 10-day survival rate (4 of 13), depressed neurological and left ventricular function, and increased caspase-3 activation and inflammatory cytokine induction in the brain. Magnetic resonance imaging revealed brain regions with marked water diffusion abnormality 24 hours after CA/CPR in mice that breathed air. Breathing air supplemented with NO for 23 hours starting 1 hour after CPR attenuated neurological and left ventricular dysfunction 4 days after CA/CPR and markedly improved 10-day survival rate (11 of 13; P=0.003 versus mice breathing air). The protective effects of inhaled NO on the outcome after CA/CPR were associated with reduced water diffusion abnormality, caspase-3 activation, and cytokine induction in the brain and increased serum nitrate/nitrite levels. Deficiency of the α1 subunit of soluble guanylate cyclase, a primary target of NO, abrogated the ability of inhaled NO to improve outcomes after CA/CPR. Conclusions-: These results suggest that NO inhalation after CA and successful CPR improves outcome via soluble guanylate cyclase-dependent mechanisms..
7. Kotaro Kida, Marina Yamada, Kentaro Tokuda, Eizo Marutani, Manabu Kakinohana, Masao Kaneki, Fumito Ichinose, Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson's disease, Antioxidants and Redox Signaling, 10.1089/ars.2010.3671, 15, 2, 343-352, 2011.07, Parkinson's disease is one of the major neurodegenerative disorders. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause Parkinson's disease-like symptoms and biochemical changes in humans and animals. Hydrogen sulfide (H2S) has been shown to protect neurons. The goal of this study was to examine the effects of inhaled H2S in a mouse model of Parkinson's disease induced by MPTP. Male C57BL/6J mice received MPTP at 80mg/kg and breathed air with or without 40 ppm H2S for 8h/day for 7 days. Administration of MPTP induced movement disorder and decreased tyrosine hydroxylase (TH)-containing neurons in the substantia nigra and striatum in mice that breathed air. Inhalation of H2S prevented the MPTP-induced movement disorder and the degeneration of TH-containing neurons. Inhaled H 2S also prevented apoptosis of the TH-containing neurons and gliosis in nigrostriatal region after administration of MPTP. The neuroprotective effect of inhaled H2S after MPTP administration was associated with upregulation of genes encoding antioxidant proteins, including heme oxygenase-1 and glutamate-cysteine ligase. These observations suggest that inhaled H 2S prevents neurodegeneration in a mouse model of Parkinson's disease induced by MPTP, potentially via upregulation of antioxidant defense mechanisms and inhibition of inflammation and apoptosis in the brain..
8. Kentaro Tokuda, Yoshimasa Motoyama, Yoichiro Kai, Yoshiro Sakaguchi, Sumio Hoka, Anesthetic management for a patient with significant orthostatic hypotension probably due to pure autonomic failure, Japanese Journal of Anesthesiology, 58, 8, 1010-1013, 2009.08, A 73-year-old man with severe orthostatic hypotension was scheduled for open cholecystectomy. His blood pressure was 126/80 mmHg in the supine position and 50/30 mmHg in the upright posture. Preoperative autonomic function tests suggested that postsynaptic fibers of the sympathetic nervous system were impaired, and the disorder was probably due to pure autonomic failure. Anesthesia was induced with thiamylal and vecuronium, and maintained with sevoflurane (3%) and fentanyl (100 μg). Epidural anesthesia was used in the latter half of the operation. Meticulous use of vasoactive drugs such as dopamine and phenylephrine as well as adequate maintenance of systemic blood volume by infusion of a crystalloid solution enabled his hemodynamic condition to become stable during anesthesia..
9. Kentaro Tokuda, T. Inamura, T. Uesaka, H. Kenai, A. Karashima, T. Matsushima, M. Fukui, Surgery for acoustic neurinoma treated by gamma-knife radiosurgery
A case report, Neurological Surgery, 29, 8, 761-765, 2001.08, A 52-year-old woman had a history of left hearing loss for 5 years. An acoustic neurinoma with 3.2 cm in diameter was diagnosed and treated with gamma-knife radiosurgery (19 Gy of marginal dose) 1 year and 4 months ago. She developed headache, nausea, and visual disturbance 1 month prior to admission. Slight left facial palsy appeared after radiosurgery. Magnetic resonance imaging demonstrated the tumor with central necrosis in the left cerebellopontine angle cistern, increasing in size to 3.5 cm in diameter, and hydrocephalus. Tumor removal was performed incompletely, because of the fibrous appearance of the tumor and severe adherence with the surrounding cerebellar tissue. Facial palsy did not worsen after surgery. Since the hydrocephalus was not resolved, a right ventriculo-peritoneal shunt was inserted. The clinical course in this case suggests that tumor removal followed by radiosurgery was an approximately effective treatment for large acoustic neurinoma..
Presentations
1. Organ-protective effects of endogeneous gasotransmitters.
2. Kentaro Tokuda, Emergency intubation with/without neuromuscular blocking agents outside of the operating room., Korean Association for Respiratory Care, 2018.07, [URL], Tracheal intubation outside of the operating room (OR), i.e. intensive care unit, emergency department, general wards, etc., is more problematic than that performed in the OR. A number of researchers have reported that the incidence of difficult intubation and the rate of complications associated with tracheal intubation is higher in cases of non-OR intubation than in elective surgical patients. There are several reasons as to why airway management in critically ill patients can be challenging. First, the patients are in a life-threatening condition that requires emergency intubation. Because their physiological reserve is highly impaired, they can rapidly progress to severe hypoxemia during intubation procedure or to profound hypotension or even cardiac arrest due to the administration of sedatives prior to intubation. Second, the preparation time to intubation is limited, preventing critical care physicians from evaluating the airway of the patients adequately, and the patients might be at risk of aspiration due to insufficient fasting time. Third, the availability of airway devices as well as staff skilled in airway management is limited outside of the OR.
One of the most contested issues associated with airway management in critical care is whether or not neuromuscular blocking agents (NMBA) should be used for emergent tracheal intubation in critically ill patients. It has been claimed that maintaining spontaneous respiration during emergency intubation is the best way to prevent the airway management from deteriorating in such patients. However, recent evidence has shown that the use of NMBA during emergency intubation facilitates the intubation procedure, improves the success rate of the first intubation attempt, and decreases the rate of procedure-related complications. Regardless of the effects of NMBA, the presence of skilled personnel is crucial for a successful procedure, and an airway evaluation predicting the difficulty of intubation prior to the procedure is useful when it can be performed. As with the procedure in the OR, emergency tracheal intubation outside the OR should not be performed until the airway is precisely evaluated so that we can decide whether or not to administer NMBA.
In this lecture, I will focus on the potential risks as well as the advantages associated with the use of NMBA during emergency intubation of critically ill patients.
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3. Neuromuscular blocking agents should not (or could not) be used for tracheal intubation outside of the operating rooms..
4. 徳田 賢太郎, 牧 盾, 賀耒 典之, 水口 壮一, 深田 光敬, 赤星 朋比古, 外 須美夫, 前原 喜彦, The Presepsin Level on ICU Admission Is a Marker of the Severity of ICU Patients. , 46th Critical Care Congress (Society of Critical Care Medicine), 2017.01.
5. Kentaro Tokuda, Improvement of postoperative analgesia by transversus abdominis plane block in patients with living donor hepatectomy, The 33rd Congress of the Scandinavian Society of Anaesthesiology and Intensive Care, 2015.06.
6. Kentaro Tokuda, Ken Yamaura, Midoriko Higashi, Sumio Hoka, The effect of cardiopulmonary bypass on the accuracy of non-invasive hemoglobin measurement by pulse co-oximetry, American society of Anesthesiologists 2014 Annual Meeting, 2014.10.
7. Kentaro Tokuda, Fumito Ichinose, Hepatoprotective effects of hydrogen sulphide against acute liver failure, European Society of Intensive Care Medicine 2014 Annual Meeting, 2014.09.
8. Kentaro Tokuda, Fumito Ichinose, Inhaled Hydrogen Sulfide Protects Mice against Acute Liver Failure, 14th Asian Australasian Congress of Anaesthesiologists, 2014.02, [URL], AIM: Acute liver failure is caused by massive hepatocyte apoptosis that is resistant to conventional medical therapies. Consequently, liver transplantation is required in many cases. An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis. In this model, LPS stimulates macrophages to release TNFα, which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure. Hydrogen sulfide (H2S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties. Previously, we reported that H2S attenuates liver dysfunction arising from LPS-induced systemic inflammation. It has been also reported that H2S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver. However, whether H2S exerts hepatoprotective effects against fulminant hepatitis, in which both inflammatory responses and apoptosis play pivotal roles, remains unknown.
METHODS: Mice were challenged with saline or combination of Gal and LPS and thereafter randomized to breathe either air alone or air supplemented with H2S for 6h.
RESULTS: Mice that breathed air after Gal/LPS challenge showed poor survival rate (13%) and marked increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma. In contrast, H2S inhalation for 6h after challenge markedly improved survival (60%, p < 0.05) and suppressed Gal/LPS-induced elevation of ALT and AST levels in plasma. Inhaled H2S suppressed TNFα in plasma at 1h after Gal/LPS challenge. Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H2S breathing inhibited activation of caspase 3, 8, and 9. Gal/LPS challenge did not increase gene expression of anti-inflammatory IL-10, whereas H2S inhalation after Gal/LPS challenge significantly increased IL-10 gene expression.
CONCLUSION: These results suggest that H2S protects mice from acute liver failure at least in part by inhibition of caspase activation and by augmentation of anti-inflammatory IL-10 expression in the liver. .
9. Kentaro Tokuda, Fumito Ichinose, Hydrogen Sulfide Protects Hepatocytes against Acute Liver Failure , Annual Meeting of American Society of Anesthesiologists 2012, 2012.10, Introduction: Acute liver failure is a fatal syndrome attributed to massive hepatocyte apoptosis that is resistant to conventional medical therapies. Consequently, liver transplantation is required in many cases. An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis. In this model, LPS stimulates macrophages to release TNFα, which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure. Hydrogen sulfide (H2S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties. Previously, we reported that H2S attenuates liver dysfunction arising from LPS-induced systemic inflammation. It has also been reported that H2S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver. However, whether H2S exerts hepatoprotective effects against acute liver failure, in which both inflammatory responses and apoptosis have pivotal roles, remains unknown. Here, we examined the impact of H2S on acute liver failure in mice induced by Gal and LPS or TNFα.
Methods: Mice were challenged with saline or combination of Gal (700 mg/kg) and LPS (10 µg/kg) intraperitoneally and thereafter randomized to breathe either air alone or air supplemented with H2S (80 ppm) for 6h.
Results: Mice that breathed air after Gal/LPS challenge showed poor survival rate and marked increase of alanine/aspartate aminotransferase (ALT/AST) in plasma. In contrast, H2S inhalation for 6h after challenge markedly improved survival (Fig. 1) and suppressed Gal/LPS-induced elevation of ALT and AST levels in plasma. Inhaled H2S suppressed TNFα in plasma at 1h after Gal/LPS challenge. Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H2S breathing inhibited activation of caspase 3, 8, and 9, suggesting inhaled H2S after Gal/LPS challenge suppressed both extrinsic and intrinsic pathways of caspase-dependent apoptosis in the liver (Fig. 2). Gal/LPS challenge increased phosphorylated STAT3 transcription factor. H2S inhalation after Gal/LPS challenge further augmented phosphorylation of STAT3 compared to air alone. The protective effects of H2S inhalation after Gal/LPS challenge were associated with upregulation of gene expression of anti-inflammatory IL-10, which stimulates STAT3 phosphorylation, in the liver. These results suggest that inhaled H2S contributes to survival of mice in acute liver failure at least in part through activation of IL-10/STAT3 pathway. To determine whether or not H2S protects hepatocytes directly, in vitro experiments using primary murine hepatocytes were conducted. GYY4137, an H2S donor, improved cell survival after stimulation with Gal/TNFα, suggesting H2S protects hepatocytes directly against lethal hepatic failure.
Conclusions: These results suggest that H2S protects mice from acute liver failure via direct hepatoprotective effects. These protective effects appear to be mediated at least in part by inhibition of caspase activation and by augmentation of IL-10/STAT3 signaling pathway in the liver. .
10. Kentaro Tokuda, Fumito Ichinose, Inhaled Hydrogen Sulfide Protects Mice against Gal/LPS-induced Acute Liver Failure
, Second International Conference on H2S Biology and Medicine, 2012.09, Introduction
Acute liver failure is a fatal syndrome attributed to massive hepatocyte apoptosis that is resistant to conventional medical therapies. Consequently, liver transplantation is required in many cases. An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis. In this model, LPS stimulates macrophages to release TNFα, which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure. Hydrogen sulfide (H2S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties. Previously, we reported that H2S attenuates liver dysfunction arising from LPS-induced systemic inflammation. It has also been reported that H2S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver. However, whether H2S exerts hepatoprotective effects against acute liver failure, in which both inflammatory responses and apoptosis play pivotal roles, remains unknown. Here, we examined the impact of inhaled H2S on acute liver failure in mice induced by Gal and LPS.
Methods
Mice were challenged with saline or combination of Gal (700 mg/kg) and LPS (10 μg/kg) intraperitoneally and thereafter randomized to breathe either air alone or air supplemented with H2S (80 ppm) for 6h.Results
Mice that breathed air after Gal/LPS challenge showed poor survival rate (13%) and marked increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma. In contrast, H2S inhalation for 6h after challenge markedly improved survival (60%, p < 0.05) and suppressed Gal/LPS-induced elevation of ALT and AST levels in plasma. Inhaled H2S suppressed TNFα in plasma at 1h after Gal/LPS challenge. Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H2S breathing inhibited activation of caspase 3, 8, and 9, suggesting inhaled H2S after Gal/LPS challenge suppressed both extrinsic and intrinsic pathways of caspase-dependent apoptosis in the liver. Gal/LPS challenge increased phosphorylated STAT3 transcription factor. H2S inhalation after Gal/LPS challenge further augmented phosphorylation of STAT3 compared to air alone. The protective effects of H2S inhalation after Gal/LPS challenge were associated with upregulation of gene expression of anti-inflammatory IL-10, which stimulates STAT3 phosphorylation, in the liver. These results suggest that inhaled H2S contributes to survival of mice in acute liver failure at least in part through activation of IL-10/STAT3 pathway.Conclusions
These results suggest that H2S protects mice from acute liver failure at least in part by inhibition of caspase activation and by augmentation of IL-10/STAT3 signaling pathway in the liver. .
11. Non-linear regression curve model for desaturation in pulse oximetry during breath-holding in healthy volunteers..
12. A Comparison of Finger, Ear and Forehead SpO2 on Detecting Oxygen Desaturation in Healthy Volunteers., [URL].
Membership in Academic Society
  • The Japanese Society of Intensive Care Medicine
  • Japanese Society of Anesthesiologists
  • European Society of Intensive Care Medicine
  • Society of Critical Care Medicine
  • American Society of Anesthesiologists
  • Japanese Society of Respiratory Care Medicine
  • Japanese Society of Cardiovascular Anesthesiologists
Educational
Educational Activities
Lectures for medical students (2 hours per week)
Other Educational Activities
  • 2020.02.
  • 2019.12.
  • 2018.07.
  • 2018.12.
  • 2019.03.
  • 2019.05.
  • 2019.05.
  • 2019.03.
  • 2013.06, Lecturer: the 25th Respiratory Care Seminar: "How to perform airway management".
  • 2012.06, Lecturer: the 22nd Respiratory Care Seminar: "How to perform airway management".