Hideo Iwasaka - Oita University Faculty of Medicine

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Name
Hideo Iwasaka
Affiliation
Oita University Faculty of Medicine
Location

Publications Authored By Hideo Iwasaka

2014Mar
Shock
Shock 2014 Mar;41(3):214-21
*Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine; and †Department of Anesthesiology, Almeida Memorial Hospital, Oita, Japan.

Reversed feeding uncouples peripheral and master clock gene rhythms and leads to an increased risk of disease development. The aim of this study was to determine the effects of clock gene uncoupling on sepsis-induced inflammation using a mouse cecal ligation and puncture (CLP) model. C57BL/6N mice were entrained to a 12-h light-dark cycle (lights on at 7 AM).Read More

Mice were permitted ad libitum feeding either during the night (7 PM-7 AM) or the nonphysiological light phase (7 AM-7 PM) for a week before CLP. In daytime-fed mice, phase inversion of clock gene expression was observed in the liver, but not in the suprachiasmatic nucleus. Daytime-fed mice also had decreased body weight and food intake. Survival rate was significantly lower in daytime-fed mice (29%) compared with nighttime-fed mice (54%) 72 h after CLP (P = 0.03). Serum levels of interleukin 6 (IL-6), tumor necrosis factor α, high mobility group box 1, IL-1α, IL-9, eotaxin, and granulocyte colony-stimulating factor increased in daytime-fed mice compared with nighttime-fed mice after CLP. Baseline expression levels of sirtuin peroxisome 1 and proliferator-activated receptor γ coactivator 1α in the liver decreased in daytime-fed mice compared with nighttime-fed mice. Thus, daytime feeding induces clock gene uncoupling, which leads to decreased expression of longevity-related and energy metabolism proteins. Daytime feeding may also increase the levels of inflammatory cytokines, thereby increasing mortality in a mouse sepsis model. Our findings suggest that uncoupling of peripheral and master clock gene rhythms by reversed feeding exacerbates inflammatory responses.

An important component of postoperative management includes alleviation of hepatic ischemia-reperfusion (I/R) injury, which commonly results from liver surgery. EPC-K1 is a hydroxyl radical scavenger reported to have mitigating effects on I/R injury in many organs. This study evaluates the effects of EPC-K1 on hepatic I/R injury.Read More


Rats were injected subcutaneously with either EPC-K1 (100 mg/kg) or saline. The hepatic artery and left branch of the portal vein were clamped for 45 min under general anesthesia. Indicators of liver function, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), and of liver tissue damage were evaluated after 6h and 24h of reperfusion. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and high-mobility group box 1 (HMGB1) protein were measured, and apoptosis was quantified via caspase 3/7 activity and TUNEL assay.
AST, ALT, and LDH levels increased significantly as a result of hepatic I/R injury, but were attenuated by EPC-K1 administration. Histologic findings revealed that normal structure of the hepatic parenchyma was maintained in rats pretreated with EPC-K1. TNF-α, IL-6, and HMGB1 levels rose significantly after reperfusion, together with activation of the inflammatory response. However, EPC-K1 administration suppressed levels of inflammatory markers and attenuated the inflammatory response. Moreover, EPC-K1 administration prevented apoptosis as determined by inhibition of caspase 3/7 activity and a decrease in apoptotic cells.
Results demonstrate that EPC-K1 inhibits the inflammatory response and suppresses apoptosis during hepatic I/R injury. This suggests that EPC-K1 has hepatoprotective effects, and may be a valuable and novel therapeutic agent in the clinical setting.

2012Jun
Masui
Masui 2012 Jun;61(6):643-8
Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601.

The American Society of Anesthesiologists (ASA) published a clinical practice guideline of preoperative fasting in 1999. A nationwide survey conducted in Japan in 2003 reveals that many hospitals have a much longer fasting period. We conducted a similar survey in three limited areas in Japan to assess the changes in fasting practice.Read More


A written questionnaire for preoperative fasting was sent to 50 hospital in 3 prefectures.
The duration of fasting for liquids tends to be shorter than those in the 2003 survey. The rates of application of the ASA guideline, however, are still low specifically in adults (4.2%), which is significantly lower than those in children (17.7%), or in infants (39.0%). The reasons for noncompliance are mainly due to organizational problems associated with scheduling of operation. Most hospitals aspire to have Japanese guideline about preoperative fasting periods.
Longer preoperative fasting periods are still common practice in Japanese hospitals.

2012May
J. Surg. Res.
J Surg Res 2012 May 9;174(1):136-41. Epub 2010 Dec 9.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Calorie restriction (CR) exerts cytoprotective effects by up-regulating survival factors, such as mammalian target of rapamycin (mTOR), sirtuin, and peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α). These survival factors have well-established roles in attenuating the inflammatory response. However, it is unclear whether CR affects sepsis-related inflammation.Read More

The purpose of this study was to determine whether CR affects sepsis-induced inflammation in a cecal ligation and puncture (CLP)-induced mouse model of sepsis.
Male C57BL/6N mice underwent alternate day calorie restriction or normal feeding for 8 d before CLP-induced sepsis. After induction of sepsis, liver and lung histopathology and serum levels of cytokines and survival factors were assessed.
Serum cytokine and high mobility group box protein 1 (HMGB1) levels were lower in animals that underwent alternate day calorie restriction compared with normally-fed mice after CLP. Alternate day calorie restriction also increased levels of sirtuin, PGC-1α, and mTOR. While 80% of mice in the CLP group died within 48 h after undergoing CLP, 50% of mice died in the ACR + CLP group (P < 0.05).
Alternate day calorie restriction decreased mortality in a mouse model of sepsis. In addition to attenuated organ injury, a significant reduction in cytokine and HMGB1 levels was observed. These findings suggest that alternative day calorie restriction may reduce excessive inflammation.

2012Feb
Inflammation
Inflammation 2012 Feb;35(1):249-58
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu City, Oita, 879-5593, Japan.

Autophagy is a natural process by which a cell maintains homeostasis, usually taking place unnoticed by adjacent cells. Glucose is involved in a negative feedback loop in autophagy. Autophagy is characterized by the induction and secretion of HMGB1, yet the nature of the inflammatory response during and the effect of glucose administration on autophagy are not well understood.Read More

Systemic inflammation was induced in experimental animals by LPS injection (7.5 mg/kg) followed by a continuous infusion of either 1%, 5%, or 25% glucose. Autophagy was visualized by immunohistochemistry 12 h after LPS injection. Likewise, protein levels of microtubule-associated protein light chain 3 (LC3)-II, autophagy-related protein 7 (Atg7), and high-mobility group box 1 (HMGB1) were assayed by western blot analysis. We found that autophagy increased in liver tissue in response to LPS-induced systemic inflammation. However, protein levels decreased in rats receiving LPS and a 5% glucose solution. Our results suggest that LPS-induced systemic inflammation increases autophagy in liver cells, potentially involving the upregulation of LC3-II, Atg7, and HMGB1. We also show that a 5% glucose infusion reduces autophagy. We propose that maintaining serum glucose levels with an adequate glucose dose improves systemic inflammation by reducing autophagy.

2011Dec
J. Surg. Res.
J Surg Res 2011 Dec 19;171(2):734-41. Epub 2010 Jun 19.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Sepsis is a major health threat that remains refractory to treatment. Impairment of normal cellular function due to oxidative stress is implicated in organ injury during systemic inflammatory responses. We investigated whether the new anti-oxidative drug, ETS-GS, could inhibit secretion of cytokines and mono-nitrogen oxides, thus reducing organ damage in a rat model of lipopolysaccharide-induced sepsis.Read More


Lipopolysaccharide was administered intravenously to male Wistar rats in order to establish a rat model of systemic inflammation. These rats were challenged with or without intravenous ETS-GS. Mouse macrophage RAW264.7 cells were stimulated with lipopolysaccharide, with or without simultaneous ETS-GS treatment, in order to elucidate the mechanism of action.
Histologic examination revealed that ETS-GS markedly reduced lipopolysaccharide-induced interstitial edema and leukocytic infiltration in lung tissue, and lipopolysaccharide-induced bleeding and leukocytic infiltration in liver tissue harvested 12 h after treatment. Cytokine (interleukin-6 and tumor necrosis factor-α) secretion was strongly induced by lipopolysaccharide; this induction was similarly inhibited by ETS-GS treatment. Likewise, lipopolysaccharide-induced secretion of mono-nitrogen oxides was inhibited by ETS-GS. In the in vitro studies, ETS-GS administration inhibited IκB phosphorylation.
ETS-GS blocked the lipopolysaccharide-induced inflammatory response and protected against acute lung and liver injury normally associated with endotoxemia in this rat model of systemic inflammation. Further, this protection may be mediated through the inhibition of nuclear factor κ-light-chain-enhancer of activated B cells activation. Our results suggest that ETS-GS is a potential therapeutic agent for sepsis.

2011Dec
J. Surg. Res.
J Surg Res 2011 Dec 1;171(2):762-8. Epub 2010 Jun 1.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Heat stroke is a condition characterized by high body temperature that can lead to hemorrhage and necrosis in multiple organs. Anticoagulants, such as danaparoid sodium (DA), inhibit various types of inflammation; however, the anti-inflammatory mechanism of action is not well understood. Given that heat stroke is a severe inflammatory response disease, we hypothesized that DA could inhibit inflammation from heat stress and prevent acute heat stroke.Read More


Male Wistar rats were given a bolus injection of saline or DA (50 U/kg body weight) into the tail vein just prior to heat stress (42 °C for 30 min). Markers of inflammation were then determined in serum and tissue samples.
In rats pretreated with DA, induction of cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α), nitric oxide (NO), and high mobility group box 1 (HMGB1) protein were reduced compared with saline-treated rats. Histologic changes observed in lung, liver, and small intestine tissue samples of saline-treated rats were attenuated in DA-treated rats. Moreover, DA pretreatment improved survival in our rat model of heat stress-induced acute inflammation.
Collectively, our findings demonstrate that DA pretreatment may have value as a new therapeutic tool for heat stroke.

2011Dec
J. Surg. Res.
J Surg Res 2011 Dec 18;171(2):719-25. Epub 2010 Apr 18.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Phosphate ester of vitamin C and vitamin E (EPCK1), a strong antioxidant, is a water- and lipid-soluble phosphate ester of vitamin C and vitamin E. In the current study, we tested whether EPCK1 inhibits oxidative stress and prevents systemic inflammation.
Mice were randomly divided into a negative control group, a lipopolysaccharide (LPS)-induced sepsis group, and a group treated with an intraperitoneal infusion of EPCK1 (10 mg/kg) prior to or following LPS administration.Read More

In addition, RAW 264.7 cells were treated with LPS in the presence or absence of EPCK1. We examined levels of high mobility group box 1 (HMGB1) protein and inducible nitric oxide synthase (iNOS) in both in vivo and in vitro experiments, and liver histopathology in the in vivo experiment.
Liver histopathology significantly improved in the EPCK1 group compared with the LPS group. Although LPS administration increased HMGB1 and nitric oxide (NO) secretion, EPCK1 decreased the secretion of these mediators in vitro and in vivo.
Our findings suggest that EPCK1 may inhibit inflammation and potentially function as a novel anti-inflammatory therapeutic agent.

2011Dec
J. Surg. Res.
J Surg Res 2011 Dec 8;171(2):777-82. Epub 2010 Jul 8.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Systemic inflammation, which is associated with various conditions such as sepsis, pneumonia, and trauma, can lead to multiple organ dysfunction syndrome. Systemic inflammation can be life-threatening and is often associated with conditions seen in the intensive care unit. Leukocytes exert a proinflammatory effect and damage various tissues during systemic inflammation.Read More

The purpose of this study was to determine whether leukocytapheresis therapy can prevent lipopolysaccharide (LPS)-induced systemic inflammation in a rat model.
Male Wistar rats weighing 250 to 300 g were used for all experiments. Rats received an LPS injection, followed 6 h later by filtration leukocytapheresis or mock treatment for 30 min under sevoflurane anesthesia. Systemic inflammation was induced in rats by intravenous LPS injection (7.5 mg/kg) followed by filtration leukocytapheresis. Following blood filtration, we evaluated lung and liver histology, serum cytokine levels, and survival rate of rats for each treatment group.
Histologic examination revealed markedly reduced inflammatory injury in lung and liver tissue harvested from rats 24 h after leukocytapheresis therapy compared with mock treatment. LPS-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion was also inhibited by leukocytapheresis therapy. Moreover, survival was significantly increased in rats treated with high-efficiency leukocytapheresis compared to mock-treated rats (P<0.05).
Taken as a whole, our findings indicate that filtration leukocytapheresis therapy protects against LPS-induced systemic inflammation. Therefore, leukocytapheresis shows potential as a new therapy for various systemic inflammatory diseases.

2011Dec
J. Surg. Res.
J Surg Res 2011 Dec 29;171(2):791-6. Epub 2010 Jul 29.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Systemic inflammation can result in multiple organ dysfunction syndrome, a potentially life-threatening condition. Some reports suggest that continuous hemodiafiltration can effectively remove proinflammatory cytokines from circulation during systemic inflammation. In the present study, we investigated whether continuous hemodiafiltration therapy could prevent LPS-induced systemic inflammation and improve survival in a rat model.Read More


Male Wistar rats were injected with lipopolysaccharide (LPS; 7.5 mg/kg body weight), and 6 h later were treated with either single-pass hemofiltration (C group), continuous hemofiltration (CHF group), continuous hemodiafiltration (CHDF group), or mock filtration (Control group). We performed histologic examinations of lung and liver tissues, determined serum cytokine levels, and survival rates for each treatment group, and compared cytokine removal between CHF and CHDF therapies.
Histologic examination revealed significant reduction in inflammation in lung and liver tissues harvested 24 h after CHDF compared with the Control group. Likewise, LPS-induced serum TNF-α and IL-6 levels decreased with continuous hemodiafiltration along with a significant improvement in survival. After 30 min of treatment, both CHF and CHDF removed significant amounts of TNF-α and IL-6 from the blood. However, serum cytokine levels measured before and after filtration were not significantly different.
Continuous hemodiafiltration therapy lowered inflammatory cytokines and increased survival rates in a rat model of systemic inflammation. Therefore, continuous hemodiafiltration may be a potential therapy for use against various systemic inflammatory diseases.

2011Dec
Surg. Today
Surg Today 2011 Dec 4;41(12):1617-21. Epub 2011 Oct 4.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita, 879-5593, Japan.

Postoperative stress produces an inflammatory response. Recent studies have shown that narcotic analgesics suppress the immune system. Nutritional management during perioperative care has also been reported to affect inflammation.Read More

We therefore examined whether remifentanil or glucose administration could ameliorate postsurgical inflammatory responses using a rat model of surgical stress.
We divided male Wistar rats randomly into five groups: (1) control, (2) sevoflurane+lactated Ringer's solution, (3) sevoflurane+lactated Ringer's solution with 1% glucose, (4) sevoflurane+remifentanil+lactated Ringer's solution, and (5) sevoflurane+remifentanil+ lactated Ringer's solution with 1% glucose. In all groups, serum samples were obtained at various time points after surgery, and secreted cytokine concentrations were determined. In addition, we assessed the activation of protein kinase B (Akt) and forkhead/winged helix box class O (FOXO3), which play a role in gluconeogenesis/stress responses.
Surgical stress increased the serum concentrations of tumor necrosis factor-α and interleukin-6. Groups receiving remifentanil with anesthesia showed an attenuated inflammatory response. The inflammatory response was also reduced by administering 1% glucose. Furthermore, 1% glucose induced Akt and FOXO3 phosphorylation in the quadriceps femoris muscle 12 h after surgery.
Anesthesia based on remifentanil and perioperative administration of lactated Ringer's solution containing 1% glucose may be able to control inflammatory responses caused by surgical stress.

2011Nov
J. Surg. Res.
J Surg Res 2011 Nov 23;171(1):226-33. Epub 2010 Feb 23.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Oita, Japan.

Ischemia-reperfusion (I/R) contributes to acute kidney injury (AKI). On the other hand, anti-oxidative drugs help to prevent renal injury caused by I/R. The current study examined whether a new antioxidant, ETS-GS, inhibits reactive oxygen species (ROS) generation and thereby prevents renal I/R injury in rodent models.Read More


Rats with experimentally-induced renal I/R injury were treated concurrently with an intravenous injection of either ETS-GS or saline. Anesthesia was induced with sevoflurane.
Histologic examination revealed marked reduction of interstitial congestion, edema, inflammation, and hemorrhage in kidney tissue harvested 24 h after ETS-GS treatment. Renal I/R-induced secretion of nitric oxide (NO) in serum was inhibited by ETS-GS treatment. Furthermore, malondialdehyde (MDA) levels in the kidney were significantly lower in ETS-GS-treated rats with renal I/R. Moreover, when murine macrophage-like RAW264.7 cells were stimulated with antimycin A in the presence or absence of simultaneous ETS-GS treatment, ETS-GS decreased ROS levels.
Thus, ETS-GS lowered ROS levels in cultured cells, reduced serum NO levels, decreased renal MDA levels, and protected rats against I/R-induced kidney injury. Given these in vitro and in vivo findings, ETS-GS is a strong candidate for future exploration of therapeutic potential in various human I/R diseases.

2011Nov
J. Surg. Res.
J Surg Res 2011 Nov 7;171(1):251-8. Epub 2010 Apr 7.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Diabetes is a common comorbidity in patients with various medical conditions. Tight glucose control is known to improve systemic inflammation; however, whether it is effective in diabetic patients is unknown. The purpose of this study was to examine how strict glucose control affects systemic inflammation in diabetic patients.Read More


Male Wistar rats. We determined the effect of insulin therapy on cardiac function in a rat model of systemic inflammation. We administered lipopolysaccharide intravenously, with or without insulin, to streptozotocin-induced diabetic rats. After induction of systemic inflammation, we determined serum cytokine (IL-6 and TNFα) and nitrate/nitrite levels and measured cardiac function.
Cytokine levels and cardiac function were significantly reduced in diabetic rats compared to non-diabetic rats. Moreover, insulin treatment was associated with higher cytokine levels and decreased cardiac function.
In systemic inflammatory conditions, diabetes increases various proinflammatory mediators and inhibits cardiac function; insulin treatment exacerbates these effects. Thus, strict glucose control may not be desirable in diabetic patients with systemic inflammatory conditions.

2011Oct
Surg. Today
Surg Today 2011 Oct 16;41(10):1385-90. Epub 2011 Sep 16.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita, 879-5593, Japan.

Recent studies have reported that controlling blood glucose with insulin can suppress systemic inflammation. In the present study, we evaluated how perioperative intensive insulin therapy (IIT) influences the inflammatory response in an artificial pancreas during cardiac surgery with cardiopulmonary bypass.
We randomly divided the patients undergoing cardiac surgery with cardiopulmonary bypass into two groups: an IIT group (n = 13) and a conventional treatment (CT) group (n = 12).Read More

For the IIT group, blood glucose control was initiated with an artificial pancreas at initiation of surgery. Blood glucose was maintained at 100 mg/dl until 24 h postoperatively. Blood samples were collected to determine changes in serum cytokine levels over time.
Patients' characteristics did not differ significantly between groups. Blood glucose levels were significantly higher in the CT group after surgery. Serum levels of tumor necrosis factor-α, interleukin-6, and high-mobility group box 1 were higher in the CT group than in the IIT group.
Use of IIT in the artificial pancreas during the perioperative period significantly decreased the inflammatory response. Moreover, we did not find evidence of hypoglycemia in those treated with IIT. This suggests that use of IIT in an artificial pancreas can be safe and effective for critically ill patients.

2011Oct
Middle East J Anaesthesiol
Middle East J Anaesthesiol 2011 Oct;21(3):375-83
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Oita, Japan.

In order to enhance postoperative recovery, preoperative consumption of carbohydrate (CHO) drinks has been used to suppress metabolic fluctuations. Trace elements such as zinc and copper are known to play an important role in postoperative recovery. Here, we examined the effects of preoperatively consuming a CHO drink containing zinc and copper.Read More


Subjects were 122 elective surgery patients divided into two groups (overnight fasting and CHO groups); each group was further divided into morning or afternoon surgery groups. Subjects in the CHO group consumed 300 mL of a CHO drink the night before surgery, followed by 200 ml before morning surgery or 700 ml before afternoon surgery (> or =2 hours before anesthesia induction). Blood levels of glucose, nonesterified fatty acids (NEFA), retinol-binding protein, zinc, and copper were determined.
One subject in the CHO group was excluded after refusing the drink. There were no adverse effects from the CHO drink. NEFA levels increased in the fasting groups. Although zinc levels increased in the CHO group immediately after anesthesia induction, no group differences were observed the day after surgery.
Preoperative consumption of a CHO drink containing trace elements suppressed preoperative metabolic fluctuations without complications and prevented trace element deficiency. Further beneficial effects during the perioperative period can be expected by adding trace elements to CHO supplements.

2011Jul
J. Surg. Res.
J Surg Res 2011 Jul 3;169(1):85-91. Epub 2009 Nov 3.
Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, Yufu City, Oita, Japan.

Heat shock protein 72 (HSP72(a)) exhibits cell- and organ-protective effects in response to inflammation. Moreover, high mobility group box 1 (HMGB1) protein is a lethal mediator of acute inflammation. We examined associations between HMGB1 expression and protective effects observed when whole-body hyperthermia (WH) induces HSP72 in a lipopolysaccharide (LPS(b))-induced inflammation model.Read More


Serum cytokine and HMGB1 levels, as well as HSP72 and HMGB1 expression in lung tissue were analyzed after WH treatment. Furthermore, effects of prior induction of HSP72 and silencing of HSP72 on HMGB1 secretion were examined in cultured RAW264.7 cells.
Survival improved significantly from 33% in the LPS group to 78% in the WH+LPS group. Interleukin-6, tumor necrosis factor-α, and HMGB1 concentrations were significantly lower in WH-treated rats. Furthermore, inflammation was reduced in lungs of WH-treated rats. Prior induction of HSP72 resulted in significantly decreased HMGB1 secretion by RAW264.7 cells in vitro, while silencing of HSP72 prevented this decrease.
Our results suggest that HSP72 induction by thermal pretreatment reduced inflammation and improved survival in the LPS-induced systemic inflammation model. These effects, which were associated with inhibition of HMGB1 expression, potentially involve HSP-mediated inhibition of HMGB1 secretion.

2011Jun
J. Surg. Res.
J Surg Res 2011 Jun 26;168(1):111-8. Epub 2009 Aug 26.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

The incidence and prevalence of diabetes have recently increased. Hyperglycemia, which is commonly seen in intensive care medicine, is associated with increased morbidity and mortality. For instance, diabetes is associated with altered immune and hemostatic responses.Read More

High mobility group box 1 (HMGB1) protein plays a key role in various inflammatory diseases. This study investigated the increase in lung damage due to diabetes and the rise in HMGB1 levels in a lipopolysaccharide (LPS)-induced systemic inflammation rat model. Diabetes was induced by streptozotocin infusion 4 wk prior to LPS administration, followed by measurements of blood glucose and serum cytokine levels. Separate cohorts were sacrificed 12h post-LPS administration and analyzed for lung damage. Diabetic animals had significantly higher blood glucose and enhanced lung damage. In addition, levels of serum HMGB1, tumor necrosis factor-α, and interleukin-6 were increased in diabetic rats. Diabetes may exacerbate systemic inflammation as evidenced by higher serum HMGB1 and cytokine levels and enhanced lung damage in the rat systemic inflammation model.

2011Jun
J Anesth
J Anesth 2011 Jun 29;25(3):392-7. Epub 2011 Apr 29.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita, 879-5593, Japan.

Estradiol is a female hormone required for maintaining pregnancy and developing follicles in the ovary. Estradiol has been shown to perform a variety of physiological activities, including pain reduction. In this study, we tested the hypothesis that estradiol exerts antinociceptive effects in a rat model of inflammatory hyperalgesia.Read More


We established a subacute hyperalgesia model using plantar injection of Freund's complete adjuvant (FCA) in Sprague-Dawley rats. We administered estradiol every 24 h, beginning 12 h after FCA administration, and used the plantar test to determine its effect on hyperalgesia. To determine the mechanism of action of estradiol, we evaluated the role of the opioid antinociceptive system using naloxone and the role of the descending pain inhibitory system using the α-2-receptor antagonist yohimbine and the serotonin receptor antagonist methysergide.
Administration of FCA induced hyperalgesia, which was significantly reduced by estradiol treatment compared to controls. Moreover, this effect was not antagonized by naloxone, but was attenuated by α-2-receptor and serotonin-receptor antagonists.
Estradiol is known to perform a variety of physiological functions. Our findings suggest that one such function is antinociception via an interaction with α-2 receptors and serotonin receptors.

2011Mar
Shock
Shock 2011 Mar;35(3):289-92
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Septic shock is characterized by systemic inflammation and can lead to hemorrhage and necrosis in multiple organs. Septic shock is one of the leading causes of death. Studies have reported that septic shock is strongly associated with coagulation abnormality.Read More

The adenosine diphosphate (ADP) receptor antagonist, clopidogrel sulfate (CS), inhibits platelet function. Thus, we hypothesized that CS could inhibit LPS-induced systemic inflammation in a rat model. Male Wistar rats weighing 250 to 300 g received an LPS injection, followed 6 h later by filtration leukocytapheresis or mock treatment for 30 min under sevoflurane anesthesia. Five days before LPS injection, rats were given an oral dose of water or CS (10 mg/kg body weight). Levels of proinflammatory markers were determined in serum and tissue samples, and high-mobility group box 1 (HMGB1) expression was evaluated in lung and liver tissues. Compared with LPS-treated rats, induction of cytokines (IL-6 and TNF-α) was reduced in rats pretreated with CS. In addition, histological changes observed in lung and liver tissue samples of LPS-treated rats were attenuated in CS-pretreated rats. Clopidogrel sulfate pretreatment also reduced LPS-induced HMGB1 expression in lung and liver tissues. Collectively, our findings demonstrate that CS pretreatment may have value as a new therapeutic tool against systemic inflammation.

2011Feb
J Anesth
J Anesth 2011 Feb 6;25(1):57-64. Epub 2010 Nov 6.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita 879-5593, Japan.

Total parenteral nutrition (TPN) is commonly carried out in the clinical setting. However, effects of TPN on the immune system, including dendritic cells (DC), are not well understood. The purpose of this study was to determine whether TPN affects DC activation and infiltration into the intestinal barrier.Read More


Male Wistar rats were given conventional nutrition (CN) or TPN for 7 days. DCs were visualized by immunohistochemistry. Levels of nucleotide-binding oligomerization domain protein 2 (NOD2) and high-mobility group box 1 (HMGB1) protein were assessed by Western blot.
The number of DCs at the small intestinal barrier was significantly increased in the TPN group (9.2 ± 3.1 cells/microscopic field) compared with the CN group (0.5 ± 0.6 cells/microscopic field; p < 0.05), as were protein expression levels of NOD2 and HMGB1.
These results suggest that TPN increases activation and infiltration of DCs into the small intestine, potentially involving an increase in NOD2 and HMGB1 levels in the small intestine.

2011Jan
J. Surg. Res.
J Surg Res 2011 Jan 25;165(1):142-50. Epub 2009 Jun 25.
Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, Yufu City, Oita, Japan.

High mobility group box 1 (HMGB1) is an important late mediator of acute lung injury. Gabexate mesilate (GM) is a synthetic protease inhibitor with some anti-inflammatory action. We aimed to evaluate the effect of GM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats.Read More

Prior to the injection of LPS to induce lung injury, rats were administered saline or GM. Injury to the lung and expression of HMGB1, plasminogen activator inhibitor-1 (PAI-1), and protease-activated receptor-2 (PAR-2) were examined. In an accompanying in vitro study, we performed LPS stimulation under GM administration in a mouse macrophage cell line and measured the quantity of HMGB1 and cytokines in the supernatant, and cell signal in the cells. Histologic examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the GM+LPS group compared wih the LPS group. Furthermore, LPS-induced increases in PAI-1 and PAR-2 activity and in plasma HMGB1 concentrations were lower in the rats given both GM and LPS than in the rats given LPS alone. Release of HMGB1 and cytokines from the cell after the administration of LPS were decreased by GM. Phosphorylation of IκB was inhibited by GM. GM may have inhibited PAI-1 and PAR-2, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. This indicates that GM can inhibit lung injury induced by LPS in rats. GM is a candidate for use in novel strategies to prevent or minimize lung injury in sepsis.

2010Dec
Korean J Pain
Korean J Pain 2010 Dec 1;23(4):247-53. Epub 2010 Dec 1.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu, Japan.

Epidural anesthesia is widely used to provide pain relief, whether for surgical anesthesia, postoperative analgesia, treatment of chronic pain, or to facilitate painless childbirth. In many cases, however, the epidural catheter is inserted blindly and the indwelling catheter position is almost always uncertain.
In this study, the loss-of-resistance technique was used and an imaging agent was injected through the indwelling epidural anesthesia catheter to confirm the position of its tip and examine the migration rate.Read More

Study subjects were patients scheduled to undergo surgery using general anesthesia combined with epidural anesthesia. Placement of the epidural catheter was confirmed postoperatively by injection of an imaging agent and X-ray imaging.
The indwelling epidural catheter was placed between upper thoracic vertebrae (n = 83; incorrect placement, n = 5), lower thoracic vertebrae (n = 123; incorrect placement, n = 5), and lower thoracic vertebra-lumbar vertebra (n = 46; incorrect placement, n = 7). In this study, a relatively high frequency of incorrectly placed epidural catheters using the loss-of-resistance technique was observed, and it was found that incorrect catheter placement resulted in inadequate analgesia during surgery.
Although the loss-of-resistance technique is easy and convenient as a method for epidural catheter placement, it frequently results in inadequate placement of epidural catheters. Care should be taken when performing this procedure.

2010Nov
Gen Thorac Cardiovasc Surg
Gen Thorac Cardiovasc Surg 2010 Nov 11;58(11):580-3. Epub 2010 Nov 11.
Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, 1-1 Hasamamachi, Yufu, Oita, 879-5593, Japan.

We describe a rare case of a 79-year-old woman who developed herpes simplex virus pneumonia after mitral valve replacement. The patient showed persistent hypoxemia with bilateral glass-like shadows on chest radiography. Cytopathology examination of intratracheal secretions revealed herpes simplex virus infection.Read More

The patient, who improved gradually after acyclovir administration, was taken off the ventilator completely. Physicians should consider viral pulmonary infection to be a potential cause of unexplained hypoxemia that does not respond to conventional antibiotic treatment in critically ill, immunocompromised patients.

2010Oct
Shock
Shock 2010 Oct;34(4):402-6
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Heatstroke, a severe inflammatory response disease, is a medical emergency characterized by high body temperature. The protein C anticoagulant system inhibits inflammation resulting from various causes. Thrombomodulin (TM), a widely expressed glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system.Read More

We tested the hypothesis that TM could prevent acute inflammation induced by heat stress in a rodent model. Male Wistar rats received a bolus of 1 mg x kg of body weight of TM or saline injected into the tail vein, followed by heat-stress treatment (exposure to 42°C for 30 min). Serum concentrations of cytokines (IL-1β, IL-6, and TNF-α), NO, and high-mobility group box 1 (HMGB1) protein were measured at various time points after treatment. We observed a decrease in the levels of cytokines and HMGB1 protein in sera of TM-treated animals over time. Inhibition of NO overproduction by recombinant TM was observed during heat stress-induced inflammation. Because of the decline in inflammatory marker levels, TM ameliorated injury to various organs in the rat model of heat stress-induced acute inflammation. As TM exhibited a strong anti-inflammatory effect in a rat model of acute inflammation induced by heat stress, TM represents a potential therapeutic for heatstroke prevention or management in patients.

2010Oct
Biomed. Res.
Biomed Res 2010 Oct;31(5):263-71
Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, Yufu, Oita, Japan.

The dysregulated metabolism associated with diabetes mellitus (DM) impairs membrane trafficking events in the liver, including the process of autophagy, which is an essential ongoing cellular process that is highly regulated by nutrients, endocrine factors, and signaling pathways. High-mobility group box 1 (HMGB1) is a nuclear protein with a known role in systemic inflammation and the related various organ injuries. However, its relationship to autophagy is not well understood.Read More

The aim of this study was to investigate the effects of inflammation injury on autophagy in the liver in a rat model of DM. DM was induced in animals with streptozotocin, followed four weeks later by induction of inflammation by LPS injection. At 12 h after LPS administration, autophagy was assessed by immunohistochemistry and Western blot analysis of microtubule-associated protein light chain 3 (LC3)-II, as well as transmission electron microscopy. Expression of HMGB1 was also examined by immunohistochemistry and Western blot analysis. Western blot analysis of liver tissue revealed that levels of LC3-II and HMGB1 protein increased in DM rats subjected to LPS-induced inflammation compared with non-DM rats. Autophagy was particularly enhanced in DM rats. Thus, autophagy might be related to progression to organ injury in patients with DM, and inflammation in these patients might be associated with over-induction of autophagy and increased HMGB1 expression.

2010Jul
Inflamm. Res.
Inflamm Res 2010 Jul 3;59(7):511-8. Epub 2010 Jan 3.
Department of Anesthesiology and Intensive Care Medicine, Oita University, Yufu City, Japan.

Systemic inflammatory mediators, including the high mobility group box 1 (HMGB1) protein, play important roles in the development of various inflammatory conditions. Although anticoagulants, such as antithrombin III (AT III), inhibit inflammation resulting from various causes, their anti-inflammatory mechanism of action is not well understood. Nevertheless, as heat stroke is a severe inflammatory response disease, we hypothesized that AT III would inhibit inflammation and prevent heat stress-induced acute heat stroke.Read More


Male Wistar rats received a bolus injection of saline or 250 U of AT III per kg of body weight into the tail vein, followed by heat stress (exposure to 42 degrees C for 30 min). Levels of cytokines (interleukin-1 beta, interleukin-6, and TNF-alpha), NOx, and HMGB1 were measured in serum and tissue at regular intervals for 6 h after the heat stress induction.
Levels of cytokines, NOx, and HMGB1 in serum decreased over time in AT III-treated rats. AT III pretreatment also reduced NOx levels during heat stress-induced inflammation. As a result, AT III pretreatment improved survival in a rat model of heat stress-induced acute inflammation.
Our data suggest that AT III pretreatment inhibited the secretion of cytokines, NOx, and HMGB1, and prevented heat stress-induced acute inflammation.

2010Jul
Neurochem. Res.
Neurochem Res 2010 Jul 25;35(7):1010-6. Epub 2010 Mar 25.
Department of Anaesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi-Yufu, City-Oita, 879-5593, Japan.

Electron spin resonance (ESR)-silent ascorbate solutions generate a detectable, likely concentration-dependent signal of ascorbyl free radicals (AFR) immediately upon addition of a molar excess of dimethyl sulfoxide (DMSO). We aimed to perform quantitative ESR analysis of AFR in real time after addition of DMSO (AFR/DMSO) to evaluate ascorbate concentrations in fresh hippocampus or plasma following systemic administration of kainate in mice. Use of a special tissue-type quartz cell allowed immediate detection of AFR/DMSO ESR spectra in fresh tissues from mice.Read More

AFR/DMSO content was increased significantly in fresh hippocampus or plasma obtained during kainate-induced seizures of mice, reaching maximum levels at 90 min after intraperitoneal administration of 50 mg/kg kainic acid. This suggests that oxidative injury of the hippocampus resulted from the accumulation of large amounts of ascorbic acid in the brain after kainic acid administration. AFR/DMSO content measured on an ESR spectrometer can be used for real-time evaluation of ascorbate content in fresh tissue. Due to the simplicity, good performance, low cost and real-time monitoring of ascorbate, this method may be applied to clinical research and treatment in the future.

Sivelestat, a neutrophil elastase inhibitor, has been used to treat acute lung injury (ALI) with varying levels of clinical success. Variable baseline levels of oxidative stress in patients with ALI have been proposed as one explanation for inconsistent results.
Using a bedside electron spin resonance spectrometer, we evaluated electron spin resonance signal intensities of serum ascorbyl free radicals supplemented with dimethyl sulfoxide (AFR/DMSO) in patients with ALI.Read More


We found a positive correlation between AFR/DMSO and ascorbate levels, suggesting that serum AFR/DMSO measurements may serve as a surrogate for real-time assessments of oxidative stress. Levels of AFR/DMSO in patients with ALI were significantly lower than those found in healthy controls. Stratified analyses revealed that baseline AFR/DMSO levels were significantly lower in patients with ALI who failed to respond to sivelestat compared with those who did respond.
Our results suggest that the clinical efficacy of sivelestat is dependent on baseline oxidative stress levels.

2010Mar
Shock
Shock 2010 Mar;33(3):282-8
Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, 1-1 Idaigaoka Hasamamachi Yufu, Oita City, 879-5593, Japan.

Sepsis remains a major health threat in intensive care medicine. The physiological functions of the coagulation cascade extend beyond blood coagulation and play a pivotal role in inflammation. We investigated whether the use of recombinant thrombomodulin (rTM), which has activity comparable with antithrombin, tissue factor pathway inhibitor, and activated protein C, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of LPS-induced systemic inflammation.Read More

Rats treated with an intravenous injection of either rTM or saline were injected concurrently with intravenous LPS. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with or without simultaneous rTM treatment. Histological examination revealed marked reductions of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 h after treatment with both agents compared with LPS administration alone. LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by treatment with rTM. The presence of HMGB1 protein in the lung was examined by immunohistochemistry; the number of HMGB1-positive cells was significantly lower in LPS-treated animals that also received rTM. In the in vitro studies, rTM administration inhibited the activation of nuclear factor-kappa B by inhibiting I kappa B phosphorylation. The anticoagulant rTM blocked the LPS-induced inflammatory response and protected against acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, rTM is a strong candidate as a therapeutic agent for various systemic inflammatory diseases.

2010Jan
Yakugaku Zasshi
Yakugaku Zasshi 2010 Jan;130(1):87-94
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Oita University, Yufu, Oita, Japan.

Objectives of the prospective, open-label study were to investigate pharmacokinetics of doripenem and determine appropriate doripenem regimens during continuous hemodiafiltration (CHDF) in critically ill patients with renal failure (creatinine clearance <30 ml/min) in the intensive care unit at a university hospital in Japan. Six patients received intravenous (IV) administration of 250 mg of doripenem every 12 or 24 hours during CHDF (dialysis rate, 500 ml/h; hemofiltration rate, 300 ml/h) via a polysulfone hemofilter. Doripenem concentrations in pre- and post-membrane blood (plasma) samples collected at specified times during one dosing interval were measured in order to calculate pharmacokinetic parameters and clearance via hemodiafiltration.Read More

Mean half-life (+/-standard deviation) of doripenem was 7.9+/-3.7 hours. Total body clearance of doripenem was 58.0+/-12.7 ml/min, including clearance of 13.5+/-1.6 ml/min via CHDF. An IV dose of 250 mg of doripenem every 12 hours during CHDF provided adequate plasma concentrations for critically ill patients with renal failure, without resulting in accumulation upon steady-state. Thus, under the conditions tested, CHDF appeared to have little effect on doripenem clearance. Therefore, the blood level of doripenem can be satisfactorily controlled by adjustment of doripenem dose and dosing interval, in accordance with residual renal function in patients receiving CHDF.

2010Jan
Surg. Today
Surg Today 2010 28;40(2):137-45. Epub 2010 Jan 28.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita, Japan.

Recent studies have increased our understanding of the important role that the immune system plays in ischemia-reperfusion (I/R) injury. Although dendritic cells (DCs) are important regulators of intestinal immunity, their role in the response to intestinal I/R injury is not well understood. The aim of this study was to determine whether I/R injury affects DC infiltration into the intestinal barrier.Read More


Wistar rats were subjected to I/R injury or a sham operation. Dendritic cells were visualized by immunohistochemistry, and after 12 h of reperfusion protein levels for nucleotide-binding oligomerization domain protein 2 (NOD2), high-mobility group box 1 (HMGB1), and Toll-like receptor 4 (TLR4) were assayed by Western blotting.
The number of DCs increased at the small intestine barrier in response to intestinal I/R. A Western blot analysis of small intestinal tissue revealed that levels of NOD2, HMGB1, and TLR4 protein increased in rats subjected to I/R injury in comparison to control rats.
These results suggest that intestinal I/R increases the infiltration of DCs into the small intestine, thus potentially involving the upregulation of NOD2, HMGB1, and TLR4. Therefore, intestinal I/R might activate DCs through NOD2 and HMGB1.

2009Dec
Int J Hyperthermia
Int J Hyperthermia 2009 Dec;25(8):626-33
Department of Anaesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Oita, Japan.

Hyperthermia-induced activation of stress response proteins allows cells to withstand metabolic insults. In this study we set out to determine whether insulin secretion by pancreatic beta cells was affected by the acute inflammatory response, systemic inflammation-induced hyperglycaemia, and whole-body hyperthermia. Given that systemic-inflammation induces ER stress, we further examined whether hyperthermia can attenuate the extent of LPS-induced ER stress.Read More


Rats were randomised and divided into three treatment groups. Control rats received a 0.9% NaCl solution. Rats in the lipopolysaccharide (LPS) group received 7.5 mg of LPS/kg. Rats in the whole-body hyperthermia (WBH) + LPS group were exposed to 42 degrees C for 15 min, followed by injection with 7.5 mg of LPS/kg after 48 h. Glucose-potentiated insulin release and extent of ER stress were measured in beta cells.
LPS inhibited glucose-induced insulin release from islet cells and induced the expression of Bip/GRP78, XBP-1, and CHOP transcripts. The inhibition of glucose-induced insulin release and induction of ER stress proteins by LPS was attenuated by WBH.
Our findings suggest that LPS-induced systemic inflammation decreased insulin release due to the effects of ER stress proteins on insulin secretion. Furthermore, the induction of ER stress proteins was prevented by pretreating rats with WBH. This may suggest that inhibiting the induction of ER stress proteins through WBH can restore insulin release in various disease states.

2009Nov
J Anesth
J Anesth 2009 18;23(4):594-6. Epub 2009 Nov 18.
Department of Anesthesiology and Intensive Care Medicine, Yufu, Oita, Japan.

Secondary hyperthyroidism can often complicate gestational trophoblastic disease, a malignant uterine cancer. We report here the perioperative management of hyperthyroidism due to hydatidiform mole. A 53-year-old woman underwent emergency surgery due to suspicion of hydatidiform mole.Read More

Tachycardiac atrial fibrillation was detected by electrocardiography at the preoperative examination. No abnormalities were found in blood count, coagulation, biochemical tests, chest radiographs, or respiratory function. General anesthesia with nitrous oxide, oxygen, and sevoflurane, combined with fentanyl and 1% mepivacaine, was administered intermittently from an epidural catheter. Intraoperative events included hypotension and tachycardia, although in general, tachycardia was prevented with antiarrhythmic agents and transfusion with a plasma expander and crystalloid fluid. Hyperthyroidism was highly suspected from the patient's clinical course and was confirmed by high levels of preoperative serum free triiodothyronine (T3) and thyroxine (T4). The patient became euthyroid within a few days after mole evacuation and did not require an antiarrhythmic agent after her return to the inpatient ward.

2009Oct
Pancreas
Pancreas 2009 Oct;38(7):746-51
Departments of Anesthesiology and Intensive Care Medicine, Oita University, Yufu City, Japan.

Systemic inflammatory mediators, including the protein high-mobility group box 1 (HMGB1), play an important role in the development of acute pancreatitis. Anticoagulants, such as antithrombin III (AT III), inhibit inflammation resulting from various causes, but their mechanism of action is not well understood. Because acute pancreatitis is a severe inflammatory disease, we hypothesized that AT III would inhibit inflammation and prevent cerulein-induced acute pancreatitis.Read More


Experimental animals received or were saline injected with a bolus of 250 IU/kg of AT III followed by intraperitoneal injections of 50 mg/kg of cerulein. Levels of cytokines (interleukin 6 and tumor necrosis factor alpha), nitric oxide (NO), and HMGB1 were measured in serum and pancreatic tissue at regular intervals for 12 hours after the cerulein injection.
Pancreas histopathology and wet-dry ratio significantly improved in the AT III-injected (250 IU/kg) animals compared with the saline-injected rats. Serum and pancreas HMGB1 levels decreased over time in AT III-treated animals. Antithrombin III also decreased cytokine, NO, and HMGB1 levels during cerulein-induced inflammation. As a result, AT III ameliorated the pathologic pancreas in the rat model of cerulein-induced acute pancreatitis.
Antithrombin III treatment inhibited the secretion of cytokines, NO, and HMGB1 and prevented cerulein-induced acute pancreatitis in the rat model.

2009Aug
Intensive Care Med
Intensive Care Med 2009 Aug 16;35(8):1471-8. Epub 2009 Jun 16.
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita 879-5593, Japan.

Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model.
We used male Wistar rats.Read More

Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)).
We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7 murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of IkappaB phosphorylation.
Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.

2009Jul
Shock
Shock 2009 Jul;32(1):94-9
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Systemic inflammatory mediators, including the protein high-mobility group box 1 (HMGB1), play an important role in the development of acute pancreatitis. Anticoagulants such as danaparoid sodium (DA) may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesized that DA would act as an inhibitor of inflammation and prevent cerulein-induced acute pancreatitis.Read More

Male Wistar rats were used as subjects in this study. Each received a bolus of 50 U/kg of DA or saline-injected into the tail vein, followed by 4 injections of 50 mg/kg cerulean (i.p.) at 1-h intervals. Cytokine (IL-6), NO, and HMGB1 levels in serum and pancreatic tissue were measured after the cerulein injection. Pancreas histopathology and wet-dry ratio significantly improved in the DA-injected (50 U/kg) animals compared with saline-injected rats. Serum and pancreatic HMGB1 levels decreased over time in DA-treated animals. Danaparoid sodium also decreased cytokine, NO, and HMGB1 levels during cerulein-induced inflammation. As a result, DA ameliorated pancreas pathology in the rat model of cerulein-induced acute pancreatitis. This study demonstrates that DA treatment prevents cerulein-induced acute pancreatitis in a rat model. This effect may be mediated through inhibition of cytokines, NO, and HMGB1.

2009Jul
Crit. Care Med.
Crit Care Med 2009 Jul;37(7):2223-7
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu City, Oita, Japan.

Hyperglycemia is frequently observed in nondiabetic patients during acute illness. Furthermore, intensive insulin therapy significantly reduces mortality and morbidity due to several critical illnesses, including cardiac or infectious diseases. The purpose of this study was to determine whether cardiac function is affected by hyperglycemia and its treatment with insulin.Read More


Lipopolysaccharide (LPS) was administered intravenously to rats, with or without the administration of insulin with glucose.
University Medical Center research laboratory.
Male Wistar rats.
In this study, we determined the effect of hyperglycemia and insulin therapy on cardiac function in an LPS-induced systemic inflammation model.
Levels of serum cytokines, nitrate/nitrite, and high-mobility group box 1 protein after LPS treatment were measured in hyperglycemic rats and those treated with insulin. The following parameters were examined to assess cardiac function in Langendorff-perfused hearts: left ventricular developed pressure, left ventricular end-diastolic pressure, and left ventricular pressure development during isovolumetric contraction (+dP/dtmax) and relaxation (-dP/dtmin). We observed that levels of cytokines, nitrate/nitrite, and high-mobility group box 1 significantly increased. However, treatment of hyperglycemic rats with insulin was associated with significantly less severe disease as assessed by cytokine levels. Furthermore, hyperglycemia was associated with decreased +dP/dtmax and -dP/dtmin in Langendorff-perfused hearts of hyperglycemic rats, whereas insulin treatment improved these parameters.
Hyperglycemia was associated with the induction of various inflammatory mediators and an inhibition of cardiac function. Treatment of hyperglycemia with insulin protected against inflammation and cardiac dysfunction in a rat model of LPS-induced systemic inflammation. This improvement is likely because of the neutralization of deleterious effects associated with hyperglycemia and the specific actions of insulin on the inflammatory response.

2009May
Shock
Shock 2009 May;31(5):515-20
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Previous studies suggest that the blockade of beta-adrenoceptors augments the release of inflammatory regulators in response to proinflammatory stimuli. High-mobility group box 1 (HMGB-1) is a key mediator in the development of sepsis. We investigated whether landiolol, a short-acting selective beta1-adrenoceptor-blocking agent, can attenuate acute lung injury and cardiac dysfunction in a rat model of endotoxin-induced sepsis.Read More

We administered LPS i.v. to rats, with or without simultaneous treatment with landiolol (0.1 mg/kg per min). After the induction of sepsis by LPS treatment, we measured cytokine and HMGB-1 levels in the serum and lung tissue. In addition, we performed histopathology, determined wet-to-dry weight ratios, and measured cardiac function and cell signaling in the lung. Cotreatment with landiolol was associated with significantly less severe disease, as assessed by lung histopathology and cardiac function metrics. Serum and lung HMGB-1 levels were lower over time among landiolol-treated animals. Furthermore, nuclear factor-kappaB activity was inhibited by the administration of landiolol. Cotreatment with the selective beta1-adrenoceptor-blocking agent landiolol protects against acute lung injury and cardiac dysfunction in a rat model of LPS-induced systemic inflammation. Treatment was associated with a significant reduction in serum levels of the inflammation mediator HMGB-1 and histological lung damage.

2009May
J Anesth
J Anesth 2009 15;23(2):288-91. Epub 2009 May 15.
Department of Brain and Nerve Science and Department of Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.

Resuscitation and acute cerebral damage after cardiopulmonary arrest often induce a systemic inflammatory response and subsequently cause multiple organ failure, including acute lung injury (ALI). Sivelestat has been reported to be effective for ALI associated with systemic inflammatory response syndrome (SIRS), but the effectiveness and safety of the drug for infants has not been confirmed. We report a 33-day-old infant who developed acute respiratory distress syndrome (ARDS) following hypoxic encephalopathy immediately after successful resuscitation from cardiopulmonary arrest.Read More

Sivelestat was administered continuously for 7 days with no adverse reactions, and consolidations on a chest radiograph were diminished and impaired oxygenation was markedly alleviated. Our experience suggests that intravenous sivelestat offers a new therapeutic strategy for infantile ARDS/ALI, but further investigation of the indication, administration period, and dosage is required.

2009Mar
Eur J Pain
Eur J Pain 2009 Mar 6;13(3):249-52. Epub 2008 Jun 6.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

Pulsed radiofrequency (PRF) has been reported to be effective in the treatment of several types of pain. The mechanism of action, however, is not well known. In a recent study, the antinociceptive effects of acute thermal pain were shown to be mediated via descending pain inhibitory pathways.Read More

In this study we observed an analgesic effect of PRF treatment in an adjuvant induced inflammatory pain model in rats. In this model, sciatic nerves were treated with PRF at 37 degrees and 42 degrees , which inhibited hyperalgesia in the inflammatory groups when compared to RF and sham treatment. This effect was attenuated after intrathecal administration of the alpha2-adrenoceptor antagonist yohimbine, the selective 5-HT3 serotonin receptor antagonist MDL72222, and the non-selective serotonin receptor antagonist methysergide. All three drugs were found to significantly inhibit the analgesic effect of PRF. The results suggest that the analgesic action of PRF involves the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways.

2009Mar
Masui
Masui 2009 Mar;58(3):298-307
Department of Anesthesiology and Intensive Care Medicine, Fuculty of Medicine, Oita University, Yufu 879-5593.

Since the strict blood glucose control by intensive insulin therapy was introduced as a life-saving maneuver, a lot of beneficial effects have been reported. The intensive insulin therapy has also been recommended in cardiac surgeries, particularly with cardiopulmonary bypass (CPB) which often induces hyperglycemia resulting from the excessive stress response. Recently, however, some groups have reported that intensive insulin therapy often leads to a serious complication like hypoglycemia, and they have expressed opposition to the therapeutic benefit.Read More

These studies indicated that the same target level of blood glucose did not provide the beneficial outcome to all patients, and that the optimal level of blood glucose differed depending on the individual patient and care setting. In order to determine the target level for blood glucose resulting in the lowest risk-to-benefit ratio, we must take into account various factors, such as variability of blood glucose concentration, presence or absence of diabetes, care setting, and perioperative nutritional management.

2009Feb
Crit. Care Med.
Crit Care Med 2009 Feb;37(2):626-33
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan.

Sepsis remains a major health threat in intensive care medicine. The renin-angiotensin system (ACE) affects inflammatory responses. In addition, angiotensin-converting enzyme inhibitors act to ameliorate lung injury.Read More

To investigate whether the widely used ACE inhibitor enalapril, used to treat hypertension, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of lipopolysaccharide (LPS)-induced sepsis.
Randomized, prospective animal study.
University medical center research laboratory.
Male Wistar rats.
LPS was administered intravenously to rats, with or without intraperitoneal pretreatment with enalapril. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with and without simultaneous enalapril treatment.
Histologic examination showed marked reduction of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 hours after treatment with both agents compared with LPS administration alone. Plasma concentration of angiotensin II was strongly induced by LPS; this induction was inhibited by the enalapril pretreatment. Likewise, LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by enalapril. The presence of HMGB1 protein in the lung was examined directly by immunohistochemistry; the number of stained cells was significantly lower in LPS-treated animals that also received enalapril. In the in vitro studies, enalapril administration inhibited the phosphorylation of IkappaB.
The ACE inhibitor enalapril blocked the LPS-induced inflammatory response and protected against the acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, enalapril is a strong candidate as a therapeutic agent for sepsis.

2008Oct
Intensive Care Med
Intensive Care Med 2008 Oct 24;34(10):1812-9. Epub 2008 May 24.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan.

Intravenous immunoglobulin therapy has been proposed as an advanced treatment for sepsis. Yet, its benefit remains unclear and the mechanism of action is poorly understood. One key mediator in the development of sepsis is high mobility group box 1 (HMGB1).Read More

Therefore, we examined the serum and lung tissue levels of HMGB1 in a rat model of sepsis.
Prospective controlled animal study in a university laboratory.
Rats received either cecal ligation and puncture-induced sepsis or had additional intravenous immunoglobulin treatment in boluses of 100, 300, or 1,000 mg/kg.
After induction of sepsis and respective treatment conditions, histopathology, wet/dry weight ratios, and signaling molecules were examined in pulmonary tissue. Serum and pulmonary levels of cytokine and HMGB1 were measured. High dose intravenous immunoglobulin (1,000 mg/kg)-treated animals demonstrated significantly improved survival and pulmonary histopathology compared to the control rats. Serum and pulmonary HMGB1 levels were lower over time among intravenous immunoglobulin-treated animals. Furthermore, administration of intravenous immunoglobulin resulted in inhibition of NF-kappaB activity.
High-dose intravenous immunoglobulin decreased the mortality and pulmonary pathology in a rat model of sepsis. A significant reduction in HMGB1 levels was also observed, which may be mediated by inhibition of inflammation and NF-kappaB.
23. Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI): experimental models.

2008Sep
Shock
Shock 2008 Sep;30(3):280-4
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

The present study examined whether total enteral nutrition (TEN) and total parenteral nutrition (TPN) differentially modulates ghrelin, inflammatory mediator production, and cardiac dysfunction induced by LPS. Rats received isocaloric parenteral or enteral nutrition through implanted vascular catheters or gastrostomy tubes for 7 days. Enteral nutrition was provided in conventional (TEN-C) and immunonutrition (TEN-I) formulations.Read More

Subsequently, rats were injected i.v. with LPS. Serum ghrelin, TNF-alpha, and high mobility group box 1 levels were determined by enzyme-linked immunosorbent assay. Myocardiac function was also assessed via the Langendorff isolated heart technique. The TEN-C increased plasma ghrelin and inhibited inflammatory mediators both before and after LPS administration when compared with TPN or TEN-I. Furthermore, animals receiving TPN and TEN-I had significantly lower left ventricular developed pressure but increased pressure development during isovolumetric contraction (dP/dt(max)) and relaxation (dP/dt(min)) when compared with animals receiving TEN-C after LPS-induced shock (P < 0.05). We conclude that TEN-C more effectively increased plasma ghrelin levels than TPN and TEN-I. The maintenance of higher ghrelin levels in TEN-C rats was associated with inhibiting various inflammatory mediators and maintaining cardiac function during LPS-induced septic shock.

2008Sep
Anesth. Analg.
Anesth Analg 2008 Sep;107(3):1058-63
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi-Yufu City-Oita 879-5593, Japan.

Low-level laser therapy (LLLT) has been reported to relieve pain, free of side effects. However, the mechanisms underlying LLLT are not well understood. Recent studies have also demonstrated that opioid-containing immune cells migrate to inflamed sites and release beta-endorphins to inhibit pain as a mode of peripheral endogenous opioid analgesia.Read More

We investigated whether pre-irradiation of blood by LLLT enhances peripheral endogenous opioid analgesia.
The effect of LLLT pretreatment of blood on peripheral endogenous opioid analgesia was evaluated in a rat model of inflammation. Additionally, the effect of LLLT on opioid production was also investigated in vitro in rat blood cells. The expression of the beta-endorphin precursors, proopiomelanocortin and corticotrophin releasing factor, were investigated by reverse transcription polymerase chain reaction.
LLLT pretreatment produced an analgesic effect in inflamed peripheral tissue, which was transiently antagonized by naloxone. Correspondingly, beta-endorphin precursor mRNA expression increased with LLLT, both in vivo and in vitro.
These findings suggest that that LLLT pretreatment of blood induces analgesia in rats by enhancing peripheral endogenous opioid production, in addition to previously reported mechanisms.

2008Aug
Inflammation
Inflammation 2008 Aug;31(4):227-34
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi-Yufu, City-Oita 879-5593, Japan.

Neutrophil elastase (NE) plays an important role in the progression of acute lung injury (ALI). Sivelestat sodium hydrate (Sivelestat) is a highly specific synthetic inhibitor of NE. High mobility group box 1 (HMGB1) is one of the key mediators in the development of sepsis.Read More

The aim of this study was to evaluate the effect of sivelestat and to determine whether it can reduce lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomly divided into a negative control group, an LPS-induced sepsis group, and a group treated with sivelestat prior to LPS administration. Animals in the sivelestat group received a bolus of 10 mg/kg of sivelestat injected into the intraperitoneal cavity before the LPS treatment. Furthermore, rats were administered sivelestat at 0, 1, 3, and 6 h following LPS treatment. We measured cytokine and HMGB1 levels in the serum after the induction of sepsis. In addition, we observed histopathology, wet/dry weight ratio, inducible nitric oxide synthase and HMGB1 expression in the lung tissue. Lung histopathology was significantly improved in the sivelestat group compared to the LPS group. Serum and pulmonary HMGB1 levels were lower over time among sivelestat-treated animals. Furthermore, inhibition of NF-kappaB activity was observed with the administration of sivelestat. These results suggest that sivelestat reduces LPS-induced lung injury at least partially by inhibiting inflammation and NF-kappaB activity.

2008Aug
Crit. Care Med.
Crit Care Med 2008 Aug;36(8):2407-13
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan.

Hyperglycemia and insulin resistance are commonly seen in septic patients and are associated with increased morbidity and mortality. High mobility group box 1 (HMGB1) protein has been shown to play a key role as a significant factor in sepsis pathogenesis. This study investigated the increase in lung damage because of hyperglycemia and HMGB1 increase in a lipopolysaccharide-induced septic rat model and the potential for insulin therapy to reduce this lung damage by decreasing the serum level of HMGB1.Read More


Randomized, prospective animal study.
University medical center research laboratory.
Male Wistar rats.
Septic hyperglycemia was induced by infusion of glucose immediately after administration of lipopolysaccharide in rats.
Animals were monitored for blood glucose. Separate cohorts were killed at 12 and 24 hrs postlipopolysaccharide administration and analyzed for HMGB1 and lung damage. The effects of insulin treatment were also examined. Hyperglycemic septic animals had significantly higher blood glucose and enhanced lung damage. In addition, HMGB1 was increased in the serum of hyperglycemic rats. On the other hand, insulin treatment for hyperglycemia resulted in significantly lower blood glucose and decreased both the lung damage and the serum level of HMGB1. In an in vitro study, insulin treatment inhibited the activation of NF-kappaB.
Hyperglycemia is associated with higher HMGB1 levels and lung damage in sepsis. Insulin therapy significantly reduced lung damage, suggesting that management of hyperglycemia with insulin might decrease HMGB1 levels in the serum and lung tissue. One of the mechanisms that could contribute to the inhibition of HMGB1 secretion might be related to the inhibition of NF-kappaB.

2008Jun
Crit Care
Crit Care 2008 2;12(2):R43. Epub 2008 Apr 2.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan.

Systemic inflammatory mediators, including high mobility group box 1 (HMGB1), play an important role in the development of sepsis. Anticoagulants, such as danaparoid sodium (DA), may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesised that DA would act as an inhibitor of systemic inflammation and prevent endotoxin-induced acute lung injury in a rat model.Read More


We used male Wistar rats. Animals in the intervention arm received a bolus of 50 U/kg of DA or saline injected into the tail vein after lipopolysaccharide (LPS) administration. We measured cytokine (tumour necrosis factor (TNF)alpha, interleukin (IL)-6 and IL-10) and HMGB1 levels in serum and lung tissue at regular intervals for 12 h following LPS injection. The mouse macrophage cell line RAW 264.7 was assessed following stimulation with LPS alone or concurrently with DA with identification of HMGB1 and other cytokines in the supernatant.
Survival was significantly higher and lung histopathology significantly improved among the DA (50 U/kg) animals compared to the control rats. The serum and lung HMGB1 levels were lower over time among DA-treated animals. In the in vitro study, administration of DA was associated with decreased production of HMGB1. In the cell signalling studies, DA administration inhibited the phosphorylation of IkappaB.
DA decreases cytokine and HMGB1 levels during LPS-induced inflammation. As a result, DA ameliorated lung pathology and reduces mortality in endotoxin-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of cytokines and HMGB1.

2008Jun
Circ. J.
Circ J 2008 Jun;72(6):1012-7
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu 879-5593, Japan.

Sepsis can be exacerbated by an inappropriate immune response and the severe impact of this disease on the cardiovascular system is well documented. High mobility group box 1 (HMGB1) protein is an important mediator in the pathogenesis of sepsis and its role in cardiovascular system dysfunction was investigated in an lipopolysaccharide (LPS)-induced rat model of sepsis.
Twelve hours after intravenous bolus injections of LPS (5 mg/kg), rats were killed and heart samples were harvested.Read More

Immunoblot analysis was performed to assess expression levels of HMGB1 in cardiac myocytes. Left ventricular developed pressure (LVDP) served as a measure of systolic function. LPS administration was associated with an increase in the expression of HMGB1 in cardiac myocytes and a decrease in cardiac function. Hearts from the LPS-treated rats were also perfused with recombinant HMGB1 and cardiac function measured. The dose-dependent effects observed with elevated HMGB1 included decreased LVDP, decreased left ventricular (LV) + dP/dt(max), decreased absolute value of LV- dP/dt(min), and increased LV end-diastolic pressure.
HMGB1 stimulation produces a negative inotropic effect during septic shock, suggesting an important role for this molecule in cardiovascular system dysfunction during sepsis.

2008May
Cardiovasc. Pathol.
Cardiovasc Pathol 2008 May-Jun;17(3):129-38. Epub 2007 Oct 24.
Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima 890-8520, Japan.

C-reactive protein (CRP) is widely used as a sensitive biomarker for inflammation. Increasing evidence suggests that CRP plays a role in inflammation. High-mobility group box-1 (HMGB1), a primarily nuclear protein, is passively released into the extracellular milieu by necrotic or damaged cells and is actively secreted by monocytes/macrophages.Read More

Extracellular HMGB1 as a potent inflammatory mediator has stimulated immense curiosity in the field of inflammation research. However, the molecular dialogue implicated between CRP and HMGB1 in delayed inflammatory processes remains to be explored.
The levels of HMGB1 in culture supernatants were determined by Western blot analysis and enzyme-linked immunosorbent assay in macrophage RAW264.7 cells. Purified CRP induced the release of HMGB1 in a dose- and time-dependent fashion. Immunofluorescence analysis revealed nuclear translocation of HMGB1 in response to CRP. The binding of CRP to the Fc gamma receptor in RAW264.7 cells was confirmed by fluorescence-activated cell sorter analysis. Pretreatment of cells with IgG-Fc fragment, but not IgG-Fab fragment, efficiently blocked this binding. CRP triggered the activation of p38MAPK and ERK1/2, but not Jun N-terminal kinase. Moreover, both p38MAPK inhibitor SB203580 and small interfering RNA significantly suppressed the release of HMGB1, but not the MEK1/2 inhibitor U-0126.
We demonstrated for the first time that CRP, a prominent risk marker for inflammation including atherosclerosis, could induce the active release of HMGB1 by RAW264.7 cells through Fc gamma receptor/p38MAPK signaling pathways, thus implying that CRP plays a crucial role in the induction, amplification, and prolongation of inflammatory processes, including atherosclerotic lesions.

2008Apr
J. Surg. Res.
J Surg Res 2008 Apr 25;145(2):251-6. Epub 2007 Jul 25.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan.

The purpose of the present study was to determine whether total enteral nutrition (TEN) or total parenteral nutrition (TPN) differ in their modulation of ghrelin production and cardiac dysfunction induced by lipopolysaccharide (LPS).
Vascular catheters or gastrostomy tubes were surgically placed into rats who received isocaloric parenteral or enteral nutrition postoperatively. After 7 d, the rats were injected intravenously with LPS (2.Read More

5 mg/kg). Serum ghrelin levels were determined by enzyme-linked immunosorbent assay and myocardiac function was assessed via the Langendorff isolated heart technique.
Before and after the administration of LPS, TEN was found to be more effective at increasing the plasma ghrelin levels than TPN. After LPS administration, left-ventricular developed pressure decreased in animals receiving TPN when compared with animals receiving TEN. Animals receiving TPN also had significant reductions in their maximal rates of increase (+dp/dt max) and decrease (-dp/dt max) in left ventricular pressure when compared with animals receiving TEN (unpaired t-test, P < 0.05). Upon reperfusion after 30 min of ischemia, the left ventricular resting tension decreased in animals receiving TPN compared with animals receiving TEN. Thereafter, left-ventricular developed pressure, +dp/dt max, and -dp/dt max decreased in the TEN recipients in comparison to the TPN-receiving animals.
We conclude that TEN more effectively increases plasma ghrelin levels than TPN. The maintenance of higher ghrelin levels in TEN-fed rats is associated with maintaining cardiac function during LPS-induced septic shock.

2008Feb
Intensive Care Med
Intensive Care Med 2008 Feb 17;34(2):361-7. Epub 2007 Oct 17.
Oita University Faculty of Medicine, Department of Brain and Nerve Science, Anesthesiology, 1-1 Idaigaoka, Hasamamachi, Yufu City, Oita 879-5593, Japan.

High mobility group box 1 (HMGB1) is an important factor in the development of sepsis. Previous work suggests that antithrombin III (ATIII) inhibits inflammation, but the mechanism of action is still poorly understood.
Prospective controlled animal study in a university laboratory.Read More


Rats were randomly divided into a lipopolysaccharide (LPS)-induced sepsis control group and an ATIII-treated experimental group. Animals in the experimental group received a bolus of 250 units/kg of ATIII injected into the tail vein.
Animals receiving high-dose ATIII (250 units/kg) had significantly improved lung histopathology and survival compared to the control rats. We measured serum and lung levels of various cytokines and HMGB1 at regular intervals from 0 to 12 h after the induction of sepsis and demonstrated lower HMGB1 levels over time in ATIII-treated animals. In an in vitro experiment, we stimulated the mouse macrophage cell line RAW 264.7 with LPS in the presence or absence of ATIII. Subsequent measurement of HMGB1 concentrations in the supernatant and cell signaling molecules in cell lysates revealed an ATIII dose-dependent decrease in HMGB1 release. Furthermore, inhibition of IkB and p42 phosphorylation was observed with the administration of ATIII, suggestive of downstream signaling pathways.
High-dose ATIII decreases lung pathology and reduces mortality in a rat sepsis model. This finding may be mediated by the inhibition of HMGB1.

2007Dec
Lasers Surg Med
Lasers Surg Med 2007 Dec;39(10):797-802
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi-Yufu City-Oita 879-5593, Japan.

Low-level laser therapy (LLLT) has been reported to relieve pain with minimal side effects. Recent studies have demonstrated that opioid-containing immune cells migrate to inflamed sites and release beta-endorphins to inhibit pain as a mode of peripheral endogenous opioid analgesia. The present study investigates whether LLLT may enhance peripheral endogenous opioid analgesia.Read More


The effect of LLLT on opioid analgesia and production was evaluated in vivo in a rat model of inflammation as well as in vitro in Jurkat cells, a human T-cell leukemia cell line. mRNA expression of the beta-endorphin precursors proopiomelanocortin and corticotrophin releasing factor was assessed by reverse transcription polymerase chain reaction.
LLLT produced an analgesic effect in inflamed peripheral tissue which was transiently antagonized by naloxone. Beta-endorphin precursor mRNA expression increased with LLLT, both in vivo and in vitro.
This study demonstrates that LLLT produces analgesic effects in a rat model of peripheral inflammation. We further revealed an additional mechanism of LLLT-mediated analgesia via enhancement of peripheral endogenous opioids. These findings suggest that LLLT induces analgesia in rats by enhancing peripheral endogenous opioid production in addition to previously reported mechanisms.

2007Sep
Lung
Lung 2007 Sep-Oct;185(5):287-93. Epub 2007 Jul 16.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasamamachi, Yufu City, Oita, 879-5593, Japan.

The hyperthermia-induced activation of the stress protein response allows cells to withstand metabolic insults that would otherwise be lethal. This phenomenon is referred to as thermotolerance. Heat shock protein 70 (HSP70) has been shown to play an important role in this hyperthermia-related cell protection.Read More

HSP70 confers protection against cellular and tissue injury. Our objective was to determine the effect of heat stress on the histopathology of pulmonary fibrosis caused by the administration of lipopolysaccharide (LPS) in Wistar rats. The rats were randomly divided into three groups. In the control group, rats were heated to 42 degrees C for 15 min. In the LPS group, rats were given LPS in 0.9% NaCl solution (10 mg/kg body weight). In the WH (whole-body hyperthermia) +LPS group, rats were heated to 42 degrees C for 15 min, and 48 h later they were injected with LPS dissolved in a 0.9% NaCl solution (10 mg/kg body weight). We investigated lung histopathology and performed a Northern blot analysis daily. Hyperthermia was shown to reduce tissue injury caused by the administration of LPS. Pulmonary tissue HSP70 mRNA was found to be elevated at 3 h after heating. HSP70 protein levels in the serum increased after whole-body hyperthermia. However, neither the expression of HSP47 mRNA nor the expression of type I or type III collagen mRNA was induced by the administration of LPS after whole-body hyperthermia. These data indicate that thermal pretreatment is associated with the induction of HSP70 protein synthesis, which subsequently attenuates tissue damage in experimental lung fibrosis.

2007Jul
Toxicology
Toxicology 2007 Jul 1;236(3):199-207. Epub 2007 May 1.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita 879-5593, Japan.

The most common cause of death from poisoning by the widely used, but highly toxic herbicide paraquat is respiratory failure from pulmonary fibrosis, which develops through pathological overproduction of extracellular matrix proteins such as the collagens. Heat shock protein (HSP47) is a collagen-specific molecular chaperone that assists in the posttranslational modifications of procollagens during collagen biosynthesis. We investigated whether treatment with an HSP47-antisense oligonucleotide would inhibit paraquat-induced pulmonary fibrosis in Wistar rats.Read More

Rats randomized into three groups (control, paraquat, and paraquat+antisense). Paraquat (20 mg/kg/day) (n=16) or a saline control (n=10) was administered to groups of Wistar rats. Intratracheal administration of the antisense oligonucleotide (100 nmol/kg in saline) was performed after the initial paraquat treatment (n=16). Treatment with paraquat alone induced pulmonary fibrosis in the entire group, while treatment with the antisense oligonucleotide alone did not produce any substantial change in lung histology. Administration of antisense oligonucleotides produced a substantial reduction in paraquat-induced pulmonary fibrosis. An immunoblot analysis confirmed that the HSP47-antisense oligonucleotide inhibited HSP47 production. These findings indicate that the HSP47-antisense oligonucleotide inhibited paraquat-induced pulmonary fibrosis and pneumopathy in rats.

2007Jun
Eur. J. Pharmacol.
Eur J Pharmacol 2007 Jun 12;564(1-3):174-80. Epub 2007 Mar 12.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu City, Oita 879-5593, Japan.

Acute respiratory distress syndrome (ARDS) confers high morbidity, and in part due to pulmonary fibrosis. The 47-kDa heat shock protein 47 (HSP 47) is a collagen-specific molecular chaperone that has been shown to play a major role in the processing and secretion of procollagen. We examined the effect of antisense oligonucleotides against HSP 47 in Wistar rats with lipopolysaccharide (LPS)-induced pulmonary fibrosis.Read More

These rats expressed heat shock protein (HSP) 47 and collagen in response to LPS. The distribution of HSP 47 was similar to that of collagen, and all control rats displayed pulmonary fibrosis after intratracheal administration of 20 mg/kg LPS alone. Antisense oligonucleotides (100 nmol/kg dissolved in saline) were administered with the LPS among experimental subjects. Subsequent immunoblot analysis confirmed the inhibition of HSP 47 by the administration of antisense oligonucleotides. The oligonucleotides significantly improved pulmonary fibrosis among those rats administered LPS, but the oligonucletides themselves did not produce any significant changes in the behavior or histology of the lungs among control rats. These findings suggest that HSP 47 antisense oligonucleotides improve lung fibrosis among rats with LPS-induced pneumopathy.

2007May
Respir. Res.
Respir Res 2007 May 15;8:37. Epub 2007 May 15.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Idaigaoka-Hasamamachi-Yufu City-Oita, Japan.

The most common pathologic form of pulmonary fibrosis arises from excessive deposition of extracellular matrix proteins such as collagen. The 47 kDa heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that has been shown to play a major role during the processing and/or secretion of procollagen.
To determine whether inhibition of HSP47 could have beneficial effects in mitigating bleomycin-induced pulmonary fibrosis in rats.Read More


All experiments were performed with 250-300 g male Wistar rats. Animals were randomly divided into five experimental groups that were administered: 1) saline alone, 2) bleomycin alone, 3) antisense HSP47 oligonucleotides alone, 4) bleomycin + antisense HSP47 oligonucleotides, and 5) bleomycin + sense control oligonucleotides. We investigated lung histopathology and performed immunoblot and immunohistochemistry analyses.
In rats treated with HSP47 antisense oligonucleotides, pulmonary fibrosis was significantly reduced. In addition, treatment with HSP47 antisense oligonucleotides significantly improved bleomycin-induced morphological changes. Treatment with HSP47 antisense oligonucleotides alone did not produce any significant changes to lung morphology. Immunoblot analyses of lung homogenates confirmed the inhibition of HSP47 protein by antisense oligonucleotides. The bleo + sense group, however, did not exhibit any improvement in lung pathology compared to bleomycin alone groups, and also had no effect on HSP47 expression.
These findings suggest that HSP47 antisense oligonucleotide inhibition of HSP47 improves bleomycin-induced pulmonary fibrosis pathology in rats.

2007Apr
Shock
Shock 2007 Apr;27(4):429-35
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Yufu City, Oita, Japan.

In recent investigations, high-mobility group box 1 (HMGB1) has been recognized to be an important factor in the development of sepsis. On the other hand, a serine protease inhibitor, nafamostat mesilate (NM) inhibits the enzyme activities of various protease and coagulation factors. We examined whether NM could inhibit HMGB1 in a rat sepsis model and thus could potentially be useful for treating sepsis.Read More

We administered NM to rats before administering lipopolysaccharide and thereafter measured the HMGB1 levels of the serum and lung tissue. We used a mouse macrophage cell line and we performed lipopolysaccharide stimulation under NM administration and thereafter measured the quantity of HMGB1 and cytokines in the supernatant, and cell signal in the cells. We were thereby able to reduce the degree of injury to pulmonary tissue by administering NM. The HMGB1 levels of the serum and lung tissue were thus found to be inhibited. This action was confirmed at the cell level, and the release of HMGB1 and cytokines from the cell decreased. Regarding the cell signal in each cell, we observed the inhibition of the phosphorylation of IkappaB. We thus concluded that it is possible to prevent the occurrence of pulmonary disorders in an endotoxic shock model by administering NM, however, this also inhibits the cell signal in a cell, mainly by the phosphorylation of IkappaB, thereby inhibiting the HMGB1 levels. Our findings thus suggest that the administration of NM may therefore potentially improve the condition of patients who have septic shock.

2007Apr
J Anesth
J Anesth 2007 30;21(2):164-70. Epub 2007 May 30.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan.

High mobility group box 1 (HMGB1) protein has recently been shown to be an important late mediator of acute lung injury and a promising therapeutic target. Nafamostat mesilate (NM) is a broad-range synthetic protease inhibitor with some anti-inflammatory action. The purpose of this study was to evaluate the effect of NM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats.Read More


Male Wistar rats were given either saline (LPS group) or NM (NM+LPS group) 30 min before the intravenous injection of a bolus of LPS (5 mg.kg(-1)). After the administration of LPS, injury to the lung and the expression of HMGB1, tumor necrosis factor-alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1) were examined.
Histological examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the NM+LPS group compared to the LPS group. Furthermore, the LPS-induced increases in PAI-1 activity and in plasma TNF-alpha concentrations were also lower in the rats given both NM and LPS than in the rats given LPS alone.
The anticoagulatory activity of NM may have inhibited PAI-1, while its anti-inflammatory activity blockaded TNF-alpha, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. These findings indicate that NM can inhibit the lung injury induced by LPS in rats. NM is an excellent candidate for use in new therapeutic strategies to prevent or minimize lung injury.

2007Feb
Lung
Lung 2007 Jan-Feb;185(1):31-7. Epub 2007 Feb 15.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu City, Oita, 879-5593, Japan.

Diffuse alveolar damage is the histopathologic hallmark of acute respiratory distress syndrome (ARDS). A significant proportion of ARDS survivors have residual pulmonary fibrosis and compromised pulmonary function. On the other hand, heat shock protein 47 (HSP47) is a collagen-binding stress protein that is assumed to act as a collagen-specific molecular chaperone during the biosynthesis and secretion of procollagen in living cells.Read More

The synthesis of HSP47 has been reported to correlate with that of collagen in several cell lines. We examined the expression of HSP47 mRNA and protein during the progression of lipopolysaccharide (LPS)-induced ARDS in rat lung. Male Wistar rats were randomly divided into two groups: a control group with instillation of 0.9% NaCl solution alone, and a LPS group with instillation of LPS dissolved in 0.9% NaCl solution (10 mg/kg). Histologic changes thereafter appeared in the LPS-treated rats. Northern blot analysis revealed the expression of HSP47 mRNA to be markedly induced during the progression of lung damage in parallel with type I and type III collagen mRNA. These results suggest that the upregulation of HSP47 and collagen may play an important role in the fibrotic process of LPS-induced ARDS lung.

We evaluated the effect of landiolol, a novel ultra-short-acting receptor-selective blocker, on bispectral index scale (BIS).
Ten patients scheduled for off-pump coronary artery bypass (OPCAB) surgery under fast-track cardiac anesthesia were analyzed. Anesthesia was maintained with appropriate additional administration of fentanyl (total dose: 10-15 microg x kg(-1)) and vecuronium under inhalation of a mixture of oxygen, air and sevoflurane (less than 2%).Read More

Landiolol was administered continuously for 5 min, when the heart rate (HR) was 80 or more per minute and the BIS values were kept between 40-60. HR, mean arterial pressure (MAP), cardiac index (CI) and BIS values were recorded at 4 time points (after induction of anesthesia, before administration of landiolol, immediately before comple- tion of administration, and 15 minutes after completion of administration).
HR decreased significantly by landiolol administration, but there were no significant changes in MAP, CI and BIS.
This study suggests that landiolol does not affect BIS in OPCAB surgery patients under fast-track cardiac anesthesia.

2005Mar
Injury
Injury 2005 Mar;36(3):387-94
Department of Anesthesiology, Faculty of Medicine, Oita University, Idaigaoka, Hasama-machi, Oita 879-5593, Japan.

The acute respiratory distress syndrome (ARDS) is often caused by fat tissue embolism. One of the most common animal models of ARDS is produced by direct administration of oleic acid (OA). Activated leukocytes are critically involved in the pathological mechanism in this model.Read More

Human urinary trypsin inhibitor (UTI) is known to inhibit production of tumor necrosis factor (TNF)-alpha, which potently stimulates leukocyte activation. The purpose of this study was to clarify whether UTI improves OA-induced lung injury in rats by inhibiting activated leukocytes via TNF-alpha production.
Rats were subjected to a single intravenous administration of OA into the pedicle vein. Acute lung injury was evaluated by arterial blood gases and histological changes in lungs. Pulmonary vascular permeability, accumulation of neutrophils, and the levels of TNF-alpha in lung tissues were also examined. Rats were divided into four experimental groups: a sham operated, OA, OA + UTI, and OA + nitrogen mustard (NM)-induced leukocytopenia group. UTI was intravenously administered 30 min before OA administration. Leukocytopenia was induced by the administration of NM.
UTI significantly improved the OA-induced histological changes for 4 h after OA administration. The OA-induced reduction of PaO2, the increase of pulmonary vascular permeability, and the levels of MPO activity and TNF-alpha in lung tissues were significantly improved in rats administrated UTI. The effects in the leukocytopenia group were similar to those in the UTI-administered group.
Leukocytes play a critical role in the development of OA-induced lung injury. It was suggested that UTI contributed to the reduction in the OA-induced lung injury by inhibiting TNF-alpha and thereby suppressing leukocyte.

2004Dec
Nippon Rinsho
Nihon Rinsho 2004 Dec;62(12):2237-43
Anesthesiology, Department of Brain and Nerve Science, Oita University Faculty of Medicine.

The activation of a pro-inflammatory cascade after infection, major surgery, burn or trauma appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. It is well known that T-cell plays a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th).Read More

Th1 lymphocytes produce IFN-gamma and IL-2, favoring cell mediated immunity; Th2 cells secrete IL-4, IL-5, IL-10, IL-13, favoring humoral immunity. Cytokines produced in systemic inflammatory response syndrome (SIRS) may effect Th subset predominance and subsequent immune responses. We measured Thl/Th2 balance in patients with severe sepsis, SIRS patients with non sepsis, and healthy subjects by flow cytometry. In patients with severe sepsis, Th2 antibody mediated (humoral) immune responses predominate. We believe that severe sepsis clearly induce polarization of T-helper lymphocyte activity with a clear shift in Th2 direction. This type of response may lead immunosuppression. Modulation of Th cell subset predominance may present a novel therapeutic option in the treatment of severe sepsis.

2004Dec
Masui
Masui 2004 Dec;53(12):1411-3
Department of Brain and Nerve Science (Anesthesiology), Faculty of Medicine, Oita University, Oita 879-5593.

A 54-year-old female patient was scheduled for retroperitoneoscopic nephrectomy. Anesthesia was induced with propofol and maintained with nitrous oxide/sevoflurane and epidural anesthesia. One hour after the start of the surgery, arterial oxygen saturation suddenly decreased from 99% to 94%.Read More

Because her oxygenation gradually improved and hemodynamics was stable, the operation was continued. After the end of the surgery, left pneumothorax was found on a chest X ray. The patient was extubated following thoracocentesis that had improved her pneumothorax and oxygenation. There is no report of pneumothorax in retroperitoneoscopic nephrectomy, as far as we know, although several cases have been reported in laparoscopic nephrectomy. We must be careful of pneumothorax in both laparoscopic and retroperitoneoscopic nephrectomy.

Cerebral blood flow partly plays a pivotal role in cerebral complications among cardiac surgery patients. We evaluated the effect of colforsin daropate (colforsin) on cerebral blood flow in cardiac surgery patients under cardiopulmonary bypass (CPB) by transcranial Doppler sonography (TCD).
Eighteen patients scheduled for coronary artery bypass surgery under CPB were assigned randomly to two groups:colforsin group (n=9) and control group (n=9).Read More

We assessed cardiac function by measuring cardiac index (CI) and systemic vascular resistance index (SVRI). Cerebral blood flow was evaluated by measuring the peak systolic blood flow velocity (Vs), end-diastolic blood flow velocity (Vd) together with mean blood flow velocity (Vm), and calculated the pulsatility index (PI) in the left carotid siphon by TCD. After baseline measurement, the colforsin loading dosage was increased from 0.25 to 0.5 microg x kg(-1) x min(-1) in colforsin group every 60 minutes.
Colforsin significantly increased CI and decreased SVRI compared with pre-levels. In both groups there were no significant changes in Vs, Vd, Vm and PI.
We have demonstrated that colforsin is effective for hemodynamics without cerebral blood flow change in cardiac surgery patients under cardiopulmonary bypass.

2003Sep
Antimicrob. Agents Chemother.
Antimicrob Agents Chemother 2003 Sep;47(9):2914-21
Department of Anesthesiology, Oita Medical University, Oita, Japan.

A cyclic polyisoprenoid compound, geranylgeranylacetone (GGA), has been used as antiulcer drug. GGA is also a potent inducer of heat shock proteins (HSPs). HSPs are considered to induce an antiviral effect; however, the detailed mechanism is unknown.Read More

To determine whether GGA might show antiviral activity and what the mechanism is, the effect of GGA against influenza virus (strain PR8) infection in vivo and in vitro was investigated. The results demonstrated that GGA treatment strongly suppressed the deleterious consequences of PR8 replication and was accompanied by an increase in HSP70 gene expression in mice. Results from in vitro analyses demonstrated that GGA significantly inhibited the synthesis of PR8-associated proteins and prominently enhanced expression of human myxovirus resistance 1 (MxA) followed by increased HSP70 transcription. Moreover, GGA augmented the expression of an interferon-inducible double-strand RNA-activated protein kinase (PKR) gene and promoted PKR autophosphorylation and concomitantly alpha subunit of eukaryotic initiation factor 2 phosphorylation during PR8 infection. It is proposed that GGA-induced HSP70 has potent antiviral activity by enhancement of antiviral factors and can clinically achieve protection from influenza virus infection.

2003Feb
Mol. Cell. Biochem.
Mol Cell Biochem 2003 Feb;244(1-2):77-81
Department of Anesthesiology, Faculty of Medicine, Oita Medical University, Oita-gun, Oita, Japan.

We have investigated effects of various energy substrates including glucose, lactate and pyruvate on the recovery of the high energy phosphate levels after high-K+ stimulation in rat brain slices by using 31P NMR. It was found that lactate, pyruvate and glucose almost equally supported the recovery of phosphocreatine (PCr) levels after high-K+ stimulation (60 mM, 8 min) in artificial cerebrospinal fluid (ACSF). In iodoacetic acid (IAA) and fluorocitrate (FC)-pretreated slices, whereas glucose was unable to be utilized, the recovery of the PCr level after high-K+ stimulation in ACSF containing lactate was completely abolished, the recovery of the PCr in ACSF containing pyruvate was unaffected.Read More

These results indicate that neurons themselves can utilize pyruvate as an exogenous energy substrate, but not lactate, without glial support. In intact brain, glucose may be metabolized to pyruvate in glial cells and then transported to neurons as an energy substrate. These suggest an astrocyte-neuron pyruvate shuttle mechanism of the brain energy metabolism in vivo. We also investigated the effect of ischemic-preconditioning in FC-pretreated slices, which showed that the PCr levels recovered substantially in ACSF containing lactate after high-K+ stimulation. This indicates that after the preconditioning, such as ischemia, neurons themselves acquired the ability to utilize lactate as an energy substrate.

2002Dec
Life Sci.
Life Sci 2002 Dec;72(4-5):557-64
Department of Anesthesiology, Oita Medical University, Hasama, 879-5593, Oita, Japan.

We examined the utilization of lactate as an energy substrate in ischemic preconditioned slices obtained from the rat brain left hemisphere, of which the contralateral middle cerebral artery was occluded 48 h before the slice preparation. The levels of high-energy phosphates in the brain slices were measured using 31P NMR with a time resolution of 4 min at 25 degrees C. When iodoacetic acid-pretreated brain slices were further treated with fluorocitrate, a glial toxin, for 2 h (neuron-rich slices), the recovery of the phosphocreatine (PCr) level in artificial cerebrospinal fluid (ACSF) containing lactate after high-K+ stimulation was completely abolished in intact slices, whereas the PCr level in ischemic preconditioned slices well recovered in otherwise similar conditions.Read More

These results indicated that neurons, when preconditioned with ischemia, acquire the ability to utilize lactate as an energy substrate. In parallel experiments, we recorded population excitatory postsynaptic potentials and spikes from granule cells in hippocampal slices. Population spikes of intact slices in ACSF containing lactate were completely abolished in 30 min, but those of the ischemic preconditioned slices were maintained well over 50%. These results show that ischemic preconditioning may induce certain systematic changes in neurons, such as the expression of lactate transporters and/or the activation of lactate dehydrogenase.