The Relevance of Leukotriene B4 to the Development of Acute Lung Injury Induced by Lipopolysaccharide

Acute lung injury (ALI) induced by lipopolysaccharide (LPS) develops by the activation of leukocytes via various mediators. Leukotriene B4 (LTB4) has a strong effect on activation and migration of leukocytes. We investigated the role of LTB4 in the chain leading to the development of ALI induced by LPS, by observing how an LTB4 receptor antagonist, ONO-4057, suppresses or mitigates leukocyte activation and migration. The 36 rabbits used in the experiment were divided into 3 groups: C group (control group of 12 rabbits treated with physiological saline solution only); L group (of 12 rabbits treated with 20 ?g/kg LPS) and L-O group (of 12 rabbits treated with, first, 10 mg/kg ONO-4057, then LPS). Blood samples were taken before, 3 h after and 6 h after the injection of drugs; then the rabbits were exsanguinated. The right and left lungs were removed for wet/dry weight ratio and bronchoalveolar lavage fluid (BALF) measurements, respectively. We measured: the leukocyte counts in the peripheral blood, the chemiluminescence (CL) intensity to measure the amount of oxygen free radical species (active oxygen species) production, the LTB4 concentration in the blood, the complement activity levels (CH50), the polymorphonuclear neutrophil elastase (PMN-E) and myeloperoxidase (MPO) levels in BALF, and the wet/dry weight ratio of the right lung. The leukocyte counts in L and L-O rabbits decreased significantly 3 h after LPS injection, then were regained by the 6th h. Regarding CL (with and without zymosan stimulation), there was no significant difference over time for C group. For L group, the zymosan-stimulated CL showed a significant increase at the 6th h, whereas the non-stimulated CL showed significant increases at the 3rd and 6th h. For L-O group, the zymosan-stimulated CL showed a significant increase at the 6th h, whereas the non-stimulated CL increased after 3 h, then slightly decreased after 6 h. The LTB4 levels showed significant increases at the 6th h for both L and L-O groups. The CH50 showed significant decreases at 6th h for both L and L-O groups. The MPO activity in the BALF was significantly high for both the L and L-O groups. There was a tendency for a high PMN-E level in the BALF for L group. The mean wet/dry weight ratio of the right lung was significantly high for L group, compared to both C and L-O groups. Although an inhibitory effect on LTB4 receptors by ONO-4057 failed to prevent leukocyte migration, it successfully suppressed the activity of non-stimulated CL, MPO and PMN-E, and, as a result, prevented the wet/dry weight ratio from increasing

Racemic Ketamine and S(+)-Ketamine Concentrations in Cerebrospinal Fluid after Epidural and Intravenous Administration in Rabbits

The pharmacokinetic characteristic of ketamine, particularly the shift from the epidural space to the cerebrospinal fluid (CSF), is still unclear. Furthermore pharmacokinetic differences between racemic ketamine and S(+)-ketamine are not clearly described when administered into the epidural space. We measured plasma and CSF concentrations of racemic ketamine and S(+)-ketamine after 2 mg/kg intravenous or 2 mg/kg epidural injection in 32 rabbits, and calculated pharmacokinetic parameters by the moment analysis method. The elimination half time of S(+)-ketamine was significantly shorter than that of racemic ketamine and the systemic distribution volume of S(+)-ketamine was significantly smaller than that of racemic ketamine in the CSF. Pharmacokinetic parameters in the CSF after epidural injection of racemic versus S(+)-ketamines were: maximum concentration, 0.4 ± 0.1 versus 0.6 ± 0.2 ?g/mL (not significant); time to maximum concentration, 9.7 ± 2.1 versus 9.0 ± 3.4 min (not significant); elimination half time, 127.1 ± 25.2 versus 89.3 ± 19.4 min (P = 0.005); area under the curve, 56.4 ± 6.4 versus 56.6 ± 11.0 ?g?mL/min (not significant); and distribution volume, 19,463.5 ± 3266.1 versus 13,613.3 ± 4895.2 mL (P = 0.014), respectively. When injected intravenously, there was no significant difference in these parameters of the CSF between racemic and S(+)-ketamines. Racemic ketamine passed easily through the blood brain barrier when administered intravenously. It also shifted to the CSF through the systemic circulation, even when they were administered epidurally. S(+)-Ketamine had similar movement as racemic ketamine

Evaluation of Exhaled Nitric Oxide in Thoracic Surgery Patients under One Lung Ventilation Using a Newly Designed Online Exhaled Nitric Oxide Measuring System

Measurement of exhaled nitric oxide (NO) has been gaining much interest lately. However, an ideal measuring system is not yet available in the clinical setting. The aims of the present study were to construct an exhaled NO measuring system and to investigate the effects of one lung ventilation (OLV) on exhaled NO output in patients who underwent thoracic surgery. At first, the NO measuring system was constructed with an NO analyzer, a respiratory flowmeter and a data processing computer system in which the algorithm was indwelled for correcting the distorted NO output wave form. Then, accuracy of this system was tested by using a simulator. This simulator was reworked in order to simulate NO production from the lung under both spontaneous respiration and mechanical ventilation. The data of peak NO concentration (pNO) and NO output (VNO) obtained with the NO monitoring system were significantly correlated with "alveolar" NO concentration (aNO) and exhaled NO volume from the simulator. Then, exhaled NO was measured in 12 thoracic surgery patients who underwent OLV using this system. pNO and VNO were significantly decreased by about half during OLV, and returned to baseline 25 min after releasing OLV. These data suggest that the newly designed online exhaled NO measuring system accurately detected aNO and exhaled NO volume in a breath-by-breath manner, and OLV for about 3 h did not influence the NO output from the lung after releasing OLV in thoracic surgery patients

Geranylgeranylacetone Ameliorates Inflammatory Response to Lipopolysaccharide (LPS) in Murine Macrophages: Inhibition of LPS Binding to The Cell Surface

We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-α (TNF-α) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 µg/ml). GGA (80 µM) treatment 2 h before LPS addition significantly suppressed TNF-α and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4

Quantitative spatial mapping of distorted state phases during the metal-insulator phase transition for nanoscale VO2 engineering

ABSTRACT Vanadium dioxide (VO2) material, known for changing physical properties due to metal-insulator transition (MIT) near room temperature, has been reported to undergo a phase change depending on the strain. This fact can be a significant problem for nanoscale devices in VO2, where the strain field covers a large area fraction, spatially non-uniform, and the amount of strain can vary during the MIT process. Direct measurement of the strain field distribution during MIT is expected to establish a methodology for material phase identification. We have demonstrated the effectiveness of geometric phase analysis (GPA), high-resolution transmission electron microscopy techniques, and transmission electron diffraction (TED). The GPA images show that the nanoregions of interest are under tensile strain conditions of less than 0.4% as well as a compressive strain of about 0.7% (Rutile phase VO2[100] direction), indicating that the origin of the newly emerged TED spots in MIT contains a triclinic phase. This study provides a substantial understanding of the strain-temperature phase diagram and strain engineering strategies for effective phase management of nanoscale VO2

Quantitative spatial mapping of distorted state phases during the metal-insulator phase transition for nanoscale VO₂ engineering

Vanadium dioxide (VO2) material, known for changing physical properties due to metal-insulator transition (MIT) near room temperature, has been reported to undergo a phase change depending on the strain. This fact can be a significant problem for nanoscale devices in VO2, where the strain field covers a large area fraction, spatially non-uniform, and the amount of strain can vary during the MIT process. Direct measurement of the strain field distribution during MIT is expected to establish a methodology for material phase identification. We have demonstrated the effectiveness of geometric phase analysis (GPA), high-resolution transmission electron microscopy techniques, and transmission electron diffraction (TED). The GPA images show that the nanoregions of interest are under tensile strain conditions of less than 0.4 % as well as a compressive strain of about 0.7 % (Rutile phase VO2[100] direction), indicating that the origin of the newly emerged TED spots in MIT contains a triclinic phase. This study provides a substantial understanding of the strain-temperature phase diagram and strain engineering strategies for effective phase management of nanoscale VO2.</p