Additional Wide Resection of Infantile Dermatofibrosarcoma Protuberans after Unplanned Excision: A Case Report.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive intermediate soft tissue neoplasm that occurs in the dermis. DFSP generally occurs in young to middle-aged adults and rarely in infancy. Because of its extreme rarity, DFSP is difficult to diagnose and treat, especially when it occurs in infancy. In this paper, we reported a case of infantile DFSP in which we performed additional wide resection with a 3-cm horizontal margin for a mass that had previously undergone unplanned excision. No tumor recurrence has been seen for 3 years postoperatively. We suggest that the possibility of DFSP should always be considered when an enlarging superficial mass is identified on the trunk, even in an infant. Additionally, radical local treatment is as important for DFSP in infancy as it is for DFSP in adults, even after unplanned excision.

Sepsis-associated neuroinflammation in the spinal cord.

Septic patients commonly present with central nervous system (CNS) disorders including impaired consciousness and delirium. Today, the main mechanism regulating sepsis-induced cerebral disorders is believed to be neuroinflammation. However, it is unknown how another component of the CNS, the spinal cord, is influenced during sepsis. In the present study, we intraperitoneally injected mice with lipopolysaccharide (LPS) to investigate molecular and immunohistochemical changes in the spinal cord of a sepsis model. After LPS administration in the spinal cord, pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha mRNA were rapidly and drastically induced. Twenty-four-hour after the LPS injection, severe neuronal ischemic damage spread into gray matter, especially around the anterior horns, and the anterior column had global edematous changes. Immunostaining analyses showed that spinal microglia were significantly activated and increased, but astrocytes did not show significant change. The current results indicate that sepsis induces acute neuroinflammation, including microglial activation and pro-inflammatory cytokine upregulation in the spinal cord, causing drastic neuronal ischemia and white matter edema in the spinal cord.

Preliminary Clinical Outcome of One-level Mobi-C Total Disc Replacement in Japanese Population.

INTRODUCTION: In 2018, the first Mobi-CⓇ total disk replacement (TDR) case was performed in Japan. In this study, we examined the preliminary clinical outcome of Mobi-CⓇ for degenerative cervical spine disease. METHODS: We examined 24 consecutive patients who underwent 1-level TDR after 2018 and followed up for more than 6 months after surgery. The evaluation criteria included age, gender, diagnosis, follow-up period, surgical level, implant size, surgery time, intraoperative bleeding volume, complications, revision surgery, imaging findings, JOA score, and various questionnaires. RESULTS: The mean age was 52.7 years, 13 males and 11 females. There were 15 cases of cervical disk herniation and 9 cases of cervical spondylosis. The mean follow-up period was 17.4 months. Surgical levels were C3/4 in 4 cases, C4/5 in 2 cases, C5/6 in 16 cases, and C6/7 in 2 cases. The mean operation time was 138.5 minutes, the amount of intraoperative bleeding was 32.1 ml, and there were no serious intraoperative complications. The range of motion of the affected level increased significantly, from 6.6 degrees preoperatively to 12.2 degrees at final follow-up. No patients required revision surgery at final follow-up, and there were no cases of heterotopic ossification or adjacent segment disease. One patient exhibited radiculopathy due to mild subsidence 1 year after surgery, and 1 had asymptomatic contact of device plates. Preoperative and final JOA scores improved from 11.7 to 15.8 points, and NRS improved from 4.3 to 1.3 points for neck pain and 4.3 to 1.7 points for arm pain. Preoperative and final NDI improved from 39.7% to 14.0%, and EQ-5D improved from 0.602 to 0.801. CONCLUSIONS: The short-term treatment outcomes of Mobi-CⓇ TDR were generally favorable. Spine surgeons should comply with guidelines when introducing this procedure and strive to adopt this new technology in Japan.

[One-stage Radical Surgery for Aortoesophageal Fistula after Graft Replacement of Descending Aorta].

A 31-year-old woman was referred to our institution because of aortoesophageal fistula (AEF) six months after the descending aortic replacement for acute aortic dissection. We operated one-stage repair of the AEF. Thoracoscopic esophagectomy was firstly performed in prone position from right thoracic cavity, and then the esophagus was reconstructed with gastric conduit via posterior mediastinal route with omental flap. Secondly, graft replacement of the descending aorta using lateral oblique straight incision was performed and the graft was covered with omental flap simultaneously. The postoperative course was uneventful, and she started oral intake on the 13th day after surgery. Although the one-stage surgery for the AEF is highly invasive, it could be a good option for selected cases.

A case of left ventricular free wall rupture after insertion of an IMPELLA® left ventricular assist device diagnosed by transesophageal echocardiography.

BACKGROUND: The IMPELLA® is a minimally invasive left ventricular assist device. We report a case in which transesophageal echocardiography (TEE) was useful in diagnosis of left ventricular rupture after IMPELLA® insertion. CASE PRESENTATION: A 75-year-old man presented to the emergency room with chest pain and underwent percutaneous coronary intervention for 100% stenosis of the left anterior descending branch #7. An IMPELLA® was inserted to stabilize the circulation, but hypotension persisted. Transthoracic echocardiography revealed increased pericardial effusion and suspicion of free wall left ventricular rupture, leading to emergency surgery. TEE revealed the IMPELLA® straying into the left ventricle apical wall and cardiac tamponade. Hemorrhage was observed from the thinning free wall and the tip of the IMPELLA® was palpable. The IMPELLA® was removed and the left ventricular wall was repaired. CONCLUSIONS: The IMPELLA® requires implantation of the tip in the left ventricle, but it should be noted that a fragile ventricular wall can be easily perforated.

Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development.

Most clinically used general anesthetics have demonstrated neurotoxicity in animal studies, but the related mechanisms remain unknown. Previous studies suggest that anesthetics affect neuronal development through neuroinflammation, and significant effects of neuroinflammation on neurogenesis and neuronal disease have been shown. In the present study, we treated pregnant mice with 2% sevoflurane for 3 h at gestational day 15.5 and analyzed the expression of proinflammatory cytokines, including IL-6 and IL-17, in fetal mice brains. Sevoflurane induced IL-6 mRNA significantly, but did not upregulate IL-17. Other volatile anesthetics, including isoflurane, enflurane, and halothane, induced IL-6 mRNA in fetal brains as well as sevoflurane, but propofol did not. Sevoflurane and isoflurane showed the same effects in cultured microglia and astrocytes, but not in neurons. Because IL-6 induction in fetal brains may affect neuronal precursor cells (NPCs), numbers of NPCs in the subventricular zone were studied, revealing that maternal sevoflurane treatment significantly increases NPCs in offspring at 8 weeks after birth (p8wk). But this effect was absent in IL-6 knockout mice. Finally, behavioral experiments also revealed that maternal sevoflurane exposure causes learning impairments in p8wk offspring. These findings collectively demonstrate that maternal exposure to volatile anesthetics upregulates IL-6 in fetal mice brains, and the effects could result in long-lasting influences on neuronal development.

Effect of propofol on androgen receptor activity in prostate cancer cells.

Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells.

Relationship Between Intraoperative Hypotension and Acute Kidney Injury After Living Donor Liver Transplantation: A Retrospective Analysis.

OBJECTIVE: Acute kidney injury (AKI) is common after liver transplantation (LT) and has a significant impact on outcomes. Although several risk factors for post-LT AKI have been identified, the effect of intraoperative hemodynamic status on post-LT AKI remains unknown. Therefore, the authors aimed to investigate the relationship between hemodynamic parameters during LT and postoperative AKI. DESIGN: A retrospective observational study. SETTING: University hospital. PARTICIPANTS: Patients who underwent living donor LT (n = 231). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Severe AKI (stages 2-3 according to recent guidelines) was the primary outcome. Multivariable logistic regression analysis was used to control for confounding variables to obtain the independent relationship between intraoperative hemodynamic parameters (mean arterial pressure [MAP] and cardiac index) and severe AKI. The prevalence of severe AKI was 30.7%. Nadir MAP during the surgery was independently predictive of severe AKI (adjusted odds ratio, 2.11 [95% confidence interval, 1.32-3.47] per 10-mmHg decrease; p = 0.002). Subgroup analyses based on various patient or operative variables and extensive sensitivity analyses showed substantially similar results. Severe hypotension (MAP<40 mmHg), even for fewer than 10 minutes, was related significantly to severe AKI (adjusted odds ratio, 3.80 [95% confidence interval, 1.17-12.30]; p = 0.026). In contrast, nadir cardiac index was not related significantly to severe AKI. CONCLUSIONS: The authors found an independent relationship between degree of intraoperative hypotension and risk of severe AKI in living donor LT recipients. Severe hypotension, even for a short duration, was related significantly to severe AKI.

Off-Pump Bilateral Cadaveric Lung Transplantation Is Associated With Profound Intraoperative Hypothermia.

OBJECTIVES: Changes in body temperature (BT) during lung transplantation never have been reported. The authors investigated the time-dependent changes in BT during lung transplantation and compared them between off-pump lung transplantation and lung transplantation using extracorporeal membrane oxygenation (ECMO). DESIGN: A retrospective observational study. SETTING: University hospital. PARTICIPANTS: Patients who underwent cadaveric lung transplantation (15 bilateral lung transplantation [BLT] and 31 single-lung transplantation [SLT]). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients received multimodal therapy to prevent intraoperative hypothermia, including increased environmental temperature, intravenous fluid warming, and the use of forced-air and circulating water warmers. Data of BT during the surgery were collected, and the time course and the extent of BT decrease during the surgery were analyzed. ECMO support during the surgery was necessary for 66.7% of BLT patients and 35.5% of SLT patients; patient characteristics were comparable between off-pump and ECMO-supported lung transplantation. In patients undergoing off-pump BLT, BT decreased continuously to 32.9°C when reperfusion was completed and gradually recovered thereafter. The decrease in BT was significantly larger during off-pump BLT compared with ECMO-supported BLT (3.5°C±0.5°C compared with 0.6°C±0.5°C, p = 0.002) and was≥3°C in all patients. Patients undergoing off-pump SLT had a similar time trend for their BTs (continuous decrease until reperfusion and subsequent recovery), but the extent of BT decrease was much smaller than that in off-pump BLT patients (1.0°C±0.5°C). CONCLUSIONS: Patients undergoing off-pump BLT were at high risk of profound intraoperative hypothermia despite multimodal preventive therapy.

[Difficult Ventilation Requiring Emergency Endotracheal Intubation during Awake Craniotomy Managed by Laryngeal Mask Airway].

We report a case of difficult ventilation requiring emergency endotracheal intubation during awake craniotomy managed by laryngeal mask airway (LMA). A 45-year-old woman was scheduled to receive awake craniotomy for brain tumor in the frontal lobe. After anesthetic induction, airway was secured using ProSeal LMA and patient was mechanically ventilated in pressure-control mode. Patient's head was fixed with head-pins at anteflex position, and the operation started. About one hour after the start of the operation, tidal volume suddenly decreased. We immediately started manual ventilation, but the airway resistance was extremely high and we could not adequately ventilate the patient. We administered muscle relaxant for suspected laryngospasm, but ventilatory status did not improve; so we decided to conduct emergency endotracheal intubation. We tried to intubate using Airwayscope or LMA-Fastrach, but they were not effective in our case. Finally trachea was intubated using transnasal fiberoptic bronchoscopy. We discuss airway management during awake craniotomy, focusing on emergency endotracheal intubation during surgery.

The clinical course of anesthetic induction in lung transplant recipients with pulmonary complications after hematopoietic stem cell transplantation.

PURPOSE: We examined the clinical course of anesthetic induction in lung transplant recipients with pulmonary complications after hematopoietic stem cell transplantation (post-HSCT), focusing on ventilatory management. We aimed to determine the incidence of oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction in post-HSCT lung transplant recipients, and to explore factors associated with their development. METHODS: Nineteen consecutive patients who underwent lung transplantation post-HSCT at Kyoto University Hospital (Japan) were retrospectively studied. Data regarding patient characteristics, preoperative examination, and clinical course during anesthetic induction were analyzed. RESULTS: The incidence of oxygen desaturation (SpO2 < 90 %) during anesthetic induction and severe respiratory acidosis (pH < 7.2) after anesthetic induction were 21.1 and 26.3 %, respectively. Reduced dynamic compliance (Cdyn) during mechanical ventilation was significantly associated with oxygen desaturation during anesthetic induction (p = 0.01), as well as severe respiratory acidosis after anesthetic induction (p = 0.01). The preoperative partial pressure of carbon dioxide in arterial blood (PaCO2; r = -0.743, p = 0.002) and body mass index (BMI; r = 0.61, p = 0.021) significantly correlated with Cdyn, and multivariate analysis revealed that both PaCO2 and BMI were independently associated with Cdyn. CONCLUSIONS: Oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction frequently occur in post-HSCT lung transplant recipients. Low Cdyn may, at least partially, explain oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction. Moreover, preoperative hypercapnia and low BMI were predictive of low Cdyn.

[Evaluation of postoperative pain intensity after ear, nose, and throat surgery--the effect of intraoperative fentanyl use].

BACKGROUND: This study was designed to determine postoperative pain levels after ear, nose, and throat (ENT) surgery, and also to examine whether intraoperative fentanyl use during ENT surgery enhances the quality of postoperative pain control. METHODS: The distribution of pain scores and rescue analgesic requirements among 198 patients undergoing ENT surgery were examined. Multivariate logistic regression analysis was performed to identify independent factors associated with moderate to severe postoperative pain (maximal pain score ≥ 5 on the numerical rating scale) and postoperative nausea and vomiting (PONV). RESULTS: 27.8% of patients experienced moderate to severe postoperative pain after ENT surgery. The distribution of postoperative pain levels was similar among procedures performed on different anatomical regions. Intraoperative fentanyl use was not associated with moderate to severe postoperative pain (adjusted odds ratio (95% confidence interval) :1.03 (0.51-2.13))]. On the other hand, intraoperative fentanyl use was independently associated with PONV [3.10 (1.25-8.92); P = 0.0138]. CONCLUSIONS: Prevalence of moderate to severe postoperative pain after ENT surgery was approximately 28%. Intraoperative fentanyl use was not associated with a decreased incidence of moderate to severe postoperative pain, but was significantly associated with PONV.

General anesthetics inhibit LPS-induced IL-1ß expression in glial cells.

BACKGROUND: Glial cells, including microglia and astrocytes, are considered the primary source of proinflammatory cytokines in the brain. Immune insults stimulate glial cells to secrete proinflammatory cytokines that modulate the acute systemic response, which includes fever, behavioral changes, and hypothalamic-pituitary-adrenal (HPA) axis activation. We investigated the effect of general anesthetics on proinflammatory cytokine expression in the primary cultured glial cells, the microglial cell line BV-2, the astrocytic cell line A-1 and mouse brain. METHODOLOGY/PRINCIPAL FINDINGS: Primary cultured glial cells were exposed to lipopolysaccharide (LPS) in combination with general anesthetics including isoflurane, pentobarbital, midazolam, ketamine, and propofol. Following this treatment, we examined glial cell expression of the proinflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α). LPS-induced expression of IL-1ß mRNA and protein were significantly reduced by all the anesthetics tested, whereas IL-6 and TNF-α mRNA expression was unaffected. The anesthetics suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation, but did not affect nuclear factor-kappaB and activator protein-1 activation. The same effect was observed with BV-2, but not with A-1 cells. In the mouse experiments, LPS was injected intraperitoneally, and isoflurane suppressed IL-1ß in the brain and adrenocorticotropic hormone in plasma, but not IL-1ß in plasma. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that general anesthetics inhibit LPS-induced IL-1ß upregulation in glial cells, particularly microglia, and affects HPA axis participation in the stress response.

Orthostatic intolerance during early mobilization following video-assisted thoracic surgery.

PURPOSE: Early postoperative mobilization is crucial for early ambulation to reduce postoperative pulmonary complications after lung resection. However, orthostatic intolerance (OI) may delay patient recovery, leading to complications. It is therefore important to understand the prevalence of and predisposing factors for OI following video-assisted thoracic surgery (VATS), which have not been established. This study evaluated the incidence of OI, impact of OI on delayed ambulation, and predisposing factors associated with OI in patients after VATS. METHODS: This retrospective cohort study consecutively analyzed data from 236 patients who underwent VATS. The primary outcome was defined as OI with symptoms associated with ambulatory challenge on postoperative day 1 (POD1), including dizziness, nausea and vomiting, feeling hot, blurred vision, or transient syncope. Multivariate logistic regression was performed to identify independent factors associated with OI. RESULTS: Of the 236 patients, 35.2 % (83) experienced OI; 45.8 % of these could not ambulate at POD1, compared with 15.7 % of patients without OI (P < 0.001). Factors independently associated with OI included advanced age [odds ratio 2.83 (1.46-5.58); P = 0.002], female gender [odds ratio 2.40 (1.31-4.46); P = 0.004], and postoperative opioid use [odds ratio 2.61 (1.23-5.77); P = 0.012]. Use of thoracic epidural anesthesia was not independently associated with OI [odds ratio 0.72 (0.38-1.37); P = 0.318]. CONCLUSION: Postoperative OI was common in patients after VATS and significantly associated with delayed ambulation. Advanced age, female gender, and postoperative opioid use were identified as independent predisposing factors for OI.

Hydrogen sulfide inhibits hypoxia- but not anoxia-induced hypoxia-inducible factor 1 activation in a von hippel-lindau- and mitochondria-dependent manner.

AIMS: In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H(2)S) is an endogenously synthesized gaseous molecule that acts as an important signaling molecule in the living body. Transcription factor hypoxia-inducible factor 1 (HIF-1) is known to respond to intracellular reduced oxygen (O(2)) availability, which is regulated by an elaborate balance between O(2) supply and demand. However, the effect of H(2)S on HIF-1 activity under hypoxic conditions is largely unknown in mammalian cells. In this study, we tried to elucidate the effect of H(2)S on hypoxia-induced HIF-1 activation adopting cultured cells and mice. RESULTS: The H(2)S donors sodium hydrosulfide and sodium sulfide in pharmacological concentrations reversibly reduced cellular O(2) consumption and inhibited hypoxia- but not anoxia-induced HIF-1α protein accumulation and expression of genes downstream of HIF-1 in established cell lines. H(2)S did not affect HIF-1 activation induced by the HIF-α hydroxylases inhibitors desferrioxamine or CoCl(2). Experimental evidence adopting von Hippel-Lindau (VHL)- or mitochondria-deficient cells indicated that H(2)S did not affect neosynthesis of HIF-1α protein but destabilized HIF-1α in a VHL- and mitochondria-dependent manner. We also demonstrate that exogenously administered H(2)S inhibited HIF-1-dependent gene expression in mice. INNOVATION: For the first time, we show that H(2)S modulates intracellular O(2) homeostasis and regulates activation of HIF-1 and the subsequent gene expression induced by hypoxia by using an in vitro system with established cell lines and an in vivo system in mice. CONCLUSIONS: We demonstrate that H(2)S inhibits hypoxia-induced HIF-1 activation in a VHL- and mitochondria-dependent manner.

Detection of the onset of ischemia and carcinogenesis by hypoxia-inducible transcription factor-based in vivo bioluminescence imaging.

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential.

Fentanyl activates hypoxia-inducible factor 1 in neuronal SH-SY5Y cells and mice under non-hypoxic conditions in a µ-opioid receptor-dependent manner.

Hypoxia-inducible factor 1 (HIF-1) is the main transcription factor responsible for hypoxia-induced gene expression. Perioperative drugs including anesthetics have been reported to affect HIF-1 activity. However, the effect of fentanyl on HIF-1 activity is not well documented. In this study, we investigated the effect of fentanyl and other opioids on HIF-1 activity in human SH-SY5Y neuroblastoma cells, hepatoma Hep3B cells, lung adenocarcinoma A549 cells and mice. Cells were exposed to fentanyl, and HIF-1 protein expression was examined by Western blot analysis using anti-HIF-1α and ß antibodies. HIF-1-dependent gene expression was investigated by semi-quantitative real-time reverse transcriptase (RT)-PCR (qRT-PCR) and luciferase assay. Furthermore, fentanyl was administered intraperitoneally and HIF-1-dependent gene expression was investigated by qRT-PCR in the brains and kidneys of mice. A 10-µM concentration of fentanyl and other opioids, including 1 µM morphine and 4 µM remifentanil, induced HIF-1α protein expression and HIF-1 target gene expression in an opioid receptor-dependent manner in SH-SY5Y cells with activity peaking at 24h. Fentanyl did not augment HIF-1α expression during hypoxia-induced induction. HIF-1α stabilization assays and experiments with cycloheximide revealed that fentanyl increased translation from HIF-1α mRNA but did not stabilize the HIF-1α protein. Furthermore, fentanyl induced HIF-1 target gene expression in the brains of mice but not in their kidneys in a naloxone-sensitive manner. In this report, we describe for the first time that fentanyl, both in vitro and in vivo, induces HIF-1 activation under non-hypoxic conditions, leading to increases in expression of genes associated with adaptation to hypoxia.

General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain.

BACKGROUND: Erythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS). EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF)-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10-1.0%). Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.

Persisting mild hypothermia suppresses hypoxia-inducible factor-1alpha protein synthesis and hypoxia-inducible factor-1-mediated gene expression.

The transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in regulating gene expression in response to hypoxia-ischemia. Ischemia causes the tissue not only to be hypoxic but also to be hypothermic because of the hypoperfusion under certain circumstances. On the other hand, the induced hypothermia is one of the most common therapeutic modalities to extend tolerance to hypoxia. Although hypoxia elicits a variety of cellular and systemic responses at different organizational levels in the body, little is known about how hypoxia-induced responses are affected by low temperature. We examined the influence of mild hypothermic conditions (28-32 degrees C) on HIF-1 in both in vitro and in vivo settings. In vitro experiments adopting cultured cells elucidated that hypoxia-induced HIF-1 activation was resistant to 4-h exposure to the low temperature. In contrast, exposure to the low temperature as long as 24 h suppressed HIF-1 activation and the subsequent upregulation of HIF-1 target genes such as VEGF or GLUT-1. HIF-1alpha protein stability in the cell was not affected by hypothermic treatment. Furthermore, intracellular ATP content was reduced under 1% O(2) conditions but was not largely affected by hypothermic treatment. The evidence indicates that reduction of oxygen consumption is not largely involved in suppression of HIF-1. In addition, we demonstrated that HIF-1 DNA-binding activity and HIF-1-dependent gene expressions induced under 10% O(2) atmosphere in mouse brain were not influenced by treatment under 3-h hypothermic temperature but were inhibited under 5-h treatment. On the other hand, we indicated that warming ischemic legs of mice for 24 h preserved HIF-1 activity. In this report we describe for the first time that persisting low temperature significantly reduced HIF-1alpha neosynthesis under hypoxic conditions, leading to a decrease in gene expression for adaptation to hypoxia in both in vitro and in vivo settings.

The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages.

PURPOSE: Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor of hypoxia-induced gene expression. Anesthetics and perioperative drugs have been reported to affect HIF-1 activity. However, the effect of propofol on HIF-1 activity is not well documented. In this study, we investigated the effect of propofol on HIF-1 activation using macrophage-differentiated THP-1 cells. METHODS: Cells were exposed to lipopolysaccharide (LPS) under 20 or 1% O(2) conditions with or without propofol treatment. The cell lysate was subjected to Western blot analysis using anti-HIF-1alpha and HIF-1beta antibodies. HIF-1-dependent gene expression was investigated by quantitative real-time reverse-transcriptase PCR analysis and luciferase assay. The amount of cellular lactate and ATP was assayed. RESULTS: Propofol suppressed HIF-1alpha protein accumulation induced by LPS, but not by hypoxia in the THP-1 cells in a dose-dependent manner by inhibiting the neo-synthesis of HIF-1alpha protein. Induction of the HIF-1 downstream gene expression including glucose transporter 1, enolase 1, lactate dehydrogenase A, pyruvate dehydrogenase kinase-1 and vascular endothelial growth factor was inhibited by propofol. Propofol suppressed LPS-induced lactate accumulation and ATP content in THP-1 cells. CONCLUSION: Our experimental results indicate that propofol inhibits HIF-1 activation and downstream gene expression induced by LPS and suppressed HIF-1-dependent glucose metabolic reprogramming. HIF-1 suppression by propofol in macrophages may explain molecular mechanisms behind the inhibitory effect of propofol on cellular inflammatory responses.