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Biomedical subjects

H Tomoike

Publications and source records attributed to H Tomoike.

At least 37 records · Page 2Linked to original sources
PubMed2000

Nitric oxide enhances expression and shedding of tumor necrosis factor receptor I (p55) in endothelial cells.

The biological actions of tumor necrosis factor-alpha (TNF-alpha) are mediated by 2 distinct receptors, TNF-RI (p55) and TNF-RII (p75). The extracellular domains of both receptors are shed in soluble form (sTNF-RI and sTNF-RII). The soluble receptors are involved in regulating TNF-alpha activities and may have therapeutic potential as TNF-neutralizing agents. However, it remains unclear as to what kind of physiological molecule can regulate TNF receptors. Nitric oxide (NO) mediates a variety of biological and pathophysiological functions. We hypothesized that NO may modulate the expression and shedding of TNF-RI. An NO donor, diethylamine/NO complex (NOC 5), increased sTNF-RI in the supernatants of ECV304, a human umbilical vein cell line, in a dose-dependent manner. TNF-RI mRNA in these cells was upregulated by NOC 5. 8-Br-cGMP and peroxynitrate had no effect on sTNF-RI release. Genistein and herbimycin A, inhibitors of tyrosine kinase, inhibited sTNF-RI release. Herbimycin A inhibited the levels of TNF-RI mRNA enhanced by NOC 5, which downregulated the surface expression of TNF-RI, indicating that NO is also involved in the shedding process of TNF-RI. The shedding of TNF-RI was abolished by a synthetic inhibitor of matrix metalloproteinase, KB-R8301. In conclusion, NO enhanced the release of sTNF-RI from endothelial cells by a cGMP-independent mechanism. Dual pathways suggested for NO-induced sTNF-RI release include (1) enhanced expression of TNF-RI, at least partially, by a tyrosine kinase-dependent mechanism and (2) increased shedding of TNF-RI by a type of metalloproteinase.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease.

Although circulating tumor necrosis factor (TNF)-alpha levels have been found to be increased in weight-losing patients with chronic obstructive pulmonary disease (COPD), the main causes for this phenomenon remain to be elucidated. Since hypoxia itself can enhance the production of the TNF-alpha in vitro, we studied the relationship between hypoxemia and activities of the TNF-alpha system, including circulating TNF-alpha and soluble TNF-receptors (sTNF-R; sTNF-R55 and -R75) levels, in 27 COPD patients and 15 age-matched healthy controls. The COPD patients showed a significant weight loss (body mass index = 18.1 +/- 2.8 versus 22.8 +/- 2.2 [mean +/- SD] kg/m(2); p < 0.0001. % fat = 16.3 +/- 5.9 versus 24.3 +/- 4.9 %; p < 0.001), and hypoxemia (Pa(O2 )= 62.2 +/- 9.5 versus 88.6 +/- 5.9 mm Hg; p < 0.0001) as compared with the healthy controls. Serum TNF-alpha (6.15 +/- 1.08 versus 5.41 +/- 1.60 pg/ml; p < 0.05) and plasma sTNF-R55 (1.15 +/- 0.49 versus 0.67 +/- 0.13 ng/ml; p < 0.0001) and sTNF-R75 (3.54 +/- 1.16 versus 2.25 +/- 0.43; p < 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. There were inverse correlations between Pa(O(2)) and circulating TNF-alpha and sTNF-R levels in patients with COPD (TNF-alpha; r = -0.426, p = 0.0297; sTNF-R55: r = -0.587, p = 0.0027; sTNF-R75: r = -0.573, p = 0.0035). In addition, we found inverse correlations between sTNF-R levels and % fat in COPD patients (sTNF-R55: r = -0.442, p = 0.0272; sTNF-R75: r = -0. 484, p = 0.0155). TNF-alpha levels correlated well with sTNF-R levels (sTNF-R55: r = 0.488, p = 0.0127; sTNF-R75: r = 0.609, p = 0. 0019). These relationships were not observed in the healthy controls. These data suggest that systemic hypoxemia noted in patients with COPD is associated with activation of the TNF-alpha system in vivo, which may be a factor contributing to the weight loss in patients with the disease.

Aged↗
PubMed2000

Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells.

Macrolide antibiotics are known to be effective for the treatment of chronic inflammatory airway diseases including diffuse panbronchiolitis, chronic bronchitis, and bronchial asthma. Other than having antimicrobial activities, macrolides have antiinflammatory effects, such as the inhibition of cytokine production. In the present study we investigated the effects of clarithromycin (CAM) on interleukin (IL)-8 gene expression and protein levels, using the human bronchial epithelial cell line BET-1A. Northern blot analyses showed that CAM inhibited tumor necrosis factor (TNF)-alpha-induced IL-8 gene expression in a dose- and incubation time-dependent manner. The half-life of IL-8 messenger RNA transcripts in TNF-alpha-treated BET-1A cells did not change with CAM. Transfection studies with BET-1A cells, using fusion genes composed of the 5'-flanking sequences of the IL-8 gene and a luciferase reporter gene, demonstrated potent promoter activity in a 174-bp segment (-130 to +44 bp relative to the transcription start site). This segment includes activator protein (AP)-1 and nuclear factor (NF)-kappaB-like sites, and exhibited its strongest response to TNF-alpha. TNF-alpha-induced promoter activity in this segment showed a significant repression by CAM. However, a 156-bp segment (-112 to +44 bp) that does not include an AP-1 site but includes an NF-kappaB-like site did not show a significant repression of TNF-alpha-induced promoter activity by CAM. Mutation of the AP-1 binding site abrogated the suppression by CAM of TNF-alpha-induced enhancement of luciferase activity. In accord with promoter analyses, an electrophoretic mobility shift assay showed that CAM repressed AP-1 binding in TNF-alpha-treated BET-1A cells; however, TNF-alpha induced both AP-1 and NF-kappaB binding activities in BET-1A cells. These data suggest that macrolides such as CAM repress IL-8 gene transcription mainly via the AP-1 binding site in human bronchial epithelial cells. Our findings provide a novel mechanism for the antiinflammatory function of macrolides, implicating a target for the development of new drugs for treating chronic airway inflammation.

5' Untranslated Regions↗
PubMed2000

4-aminopyridine inhibits the occurrence of ventricular fibrillation but not ventricular tachycardia in the reperfused, P6olated rat heart.

The 4-aminopyridine (4-AP)-sensitive transient outward current (Ito) has been reported to play an important role in the ischemia- or high [Ca2+]o-induced reentrant ventricular arrhythmias. However, the role of 4-AP sensitive Ito in reperfusion arrhythmia remains unknown. Rat hearts were perfused with Tyrode solution (control), and treated with 0.5 micromol/L verapamil, 1 micromol/L glibenclamide, 10 micromol/L E-4031 or 2 mmol/L 4-AP. After a 10-min perfusion, hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. The effects of the ion-channel blockers on the incidence of ventricular tachycardia (VT), torsades de pointes (Tdp) and ventricular fibrillation (VF) during the reperfusion period were investigated. Verapamil and 4-AP abolished VF and Tdp. The incidence of VT was also attenuated by verapamil, but not by 4-AP. Glibenclamide and E-4031 (a blocker of a rapidly activating component of delayed rectifier K+ current) did not affect the incidence of those tachyarrhythmias. Accordingly, (1) the underlying mechanism of VF or Tdp is different from that of VT, and (2) 4-AP sensitive Ito is required for the occurrence of reperfusion Tdp or VF in the present model.

4-Aminopyridine↗
PubMed2000

Anisotropic effects of sodium channel blockers on the wavelength for ventricular excitation in dogs.

The purpose of this study was to determine the anisotropic effects of sodium channel blockers on wavelength (WL) and proarrhythmia. In 18 anesthetized, open chest dogs, a 64-electrode array was placed on the left ventricle and the ventricle was constantly paced. Disopyramide, lidocaine or flecainide was intracoronarily administered. Conduction velocity (theta) and activation-recovery interval (ARI) were measured in the longitudinal (L) and transverse (T) directions. Flecainide markedly decreased thetaL, but did not alter thetaT or ARIs in either direction. As a result, the wavelength was significantly shortened only in the L direction. Disopyramide or lidocaine did not show direction-dependent effects on theta or WL. In 3 of 6 dogs with flecainide exposure, ventricular fibrillation (VF) developed. However, no VF occurred with disopyramide or lidocaine. Accordingly, the WL is dependent on the fiber orientation of myocardium. The anisotropic shortening of the WL may explain the character of the proarrhythmia observed with flecainide.

Action Potentials↗
PubMed2000

Alterations in the inotropic responses to forskolin and Ca2+ and reduced gene expressions of Ca2+-signaling proteins induced by chronic volume overload in rabbits.

Volume overload results in eccentric cardiac hypertrophy, but it is still unknown how this mechanical overload modulates the inotropic response to exogenous Ca2+ or adenylyl cyclase stimulation. Inotropic responsiveness in vivo and the levels of gene expression of Ca2+ signaling proteins were studied in rabbit hearts hypertrophied as a result of volume overload at 4 and 12 weeks after arteriovenous shunt formation. In sham-operated control rabbits, left ventricular (LV)+dP/dt was augmented in response to graded doses of CaCl2. Dose-related changes of LV+dP/dt to CaCl2 were attenuated significantly in shunt rabbits with volume overload. Forskolin dose-dependently augmented LV+dP/dt in sham rabbits, which was also attenuated significantly in rabbits with volume overload. The mRNA levels of dihydropyridine receptor, Na+/Ca2+ exchanger, sarcoplasmic reticulum Ca2+-ATPase, and ryanodine receptor decreased significantly at 4 and 12 weeks in the volume-overload rabbits compared with the sham rabbits, but the mRNA levels of phospholamban and calsequestrin remained unchanged. Chronic volume overload alters contractile responsiveness to Ca2+ or adenylyl cyclase stimulation, and downregulation of steady state mRNA levels of Ca2+ signaling proteins might be, at least in part, related to this pathologic process.

Animals↗
PubMed2000

Dobutamine stress echocardiography for the diagnosis of myocardial viability: assessment of left ventricular systolic velocities in longitudinal axis by pulsed Doppler tissue imaging.

Dobutamine (DOB) stress two-dimensional echocardiography is an established method for the detection of viable myocardium, but conventional assessment of wall motion is subjective. We measured quantitatively the left ventricular systolic velocities along the longitudinal axis by pulsed Doppler tissue imaging (DTI). In 30 patients with previous myocardial infarction, pulsed DTI focused on the infarct area was performed from an apical two- or four-chamber view before and during DOB (10 microg/kg/min) stress one day before coronary angioplasty. We calculated peak systolic velocity (S), regional pre-ejection period (PEP, the time interval from the onset of QRS to the onset of systolic wave) and regional ejection time (ET). Left ventriculography was obtained before and 3 months after coronary angioplasty to assess regional wall motion. Improvement of abnormal wall motion was observed in 19 patients (group P) but not in 11 (group N). Group P had significantly larger S and smaller PEP/ET than group N during DOB stress, although there were no significant differences in these indices between the groups at baseline. As a consequence, group P had a significantly larger percent change in S and a smaller percent change in PEP/ET than group N (164+/-39 vs 117+/-20% and 88+/-17 vs 116+/-29%, respectively, p < 0.01). It is suggested that the quantitative measurement of longitudinal systolic velocities during DOB stress by DTI is useful for the precise assessment of myocardial viability.

Adult↗
PubMed1999

Intracoronary flecainide induces ST alternans and reentrant arrhythmia on intact canine heart: A role of 4-aminopyridine-sensitive current.

BACKGROUND: The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia. METHODS AND RESULTS: A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 microg. kg-1. min-1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7+/-3.4 mV; mean+/-SEM) was significantly greater than that in disopyramide or lidocaine (0. 9+/-0.4 and 0.8+/-0.2 mV, P<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in STa and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those. CONCLUSIONS: Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP-sensitive current such as Ito or Isus may play an important role on this phenomenon.

4-Aminopyridine↗
PubMed1999

Ultrasonic assessment of vascular complications in coronary angiography and angioplasty after transradial approach.

The transradial approach has currently been accepted as an alternative entry method for coronary angiography and angioplasty. Vascular complications of this method were evaluated by 2-dimensional echo and color Doppler ultrasonic studies in 162 patients before, early (2+/-2 [mean+/-SD] days), and late (95+/-29 days) after catheterization. Mean age was 64+/-10 years, and 103 were men. Coronary angioplasty was performed in 59 patients (79 lesions) with angiographic success in 92%. Early after the procedure, segmental stenosis was noted in 35 patients (22%) and no flow in 15 patients (9%). Late after the procedure, segmental stenosis was noted in 2, diffuse stenosis in 36 (22%), and no flow in 8 (5%) patients. The cessation of radial artery pulse was unpalpable in only 2% of cases, whereas radial flow by color Doppler was undetectable in 9% early after the procedure. Late after the procedure, recanalization was observed in 60% of these occluded cases. Thirty-three of 86 patients (38%) with no flow or diffuse stenosis had radial artery diameters smaller than the sheath diameter, and 11 of 76 patients (14%) had radial artery diameters larger than the sheath diameter (p <0.01). Multivariate analysis revealed risk factors for vascular complications: (1) Radial artery diameter before the procedure was one of the significant and independent determinants of no flow both early (p = 0.06) and late (p = 0.004) after the procedure. (2) The difference in radial artery diameter and sheath size was related to the occurrence of diffuse stenosis late after the procedure (p = 0.003). (3) Diabetes mellitus was related to no flow (p = 0.05) or diffuse stenosis (p = 0.11) late after the procedure. Thus, ultrasonic evaluation of the radial artery was useful in selecting both an access route and an appropriate size of the sheath to determine early and late vascular complications.

Angioplasty, Balloon, Coronary↗
PubMed1999

Inhibitory effect of TS-962 on the formation of early atherosclerotic lesions in high fat-fed hyperlipidemic hamsters.

The hypocholesterolemic and anti-atherosclerotic effect of TS-962, a specific ACAT inhibitor, was investigated in a hamster model fed a high fat diet containing 10% coconut oil and 0.05% cholesterol. Lipid accumulated atherosclerotic lesions were detected by using oil red O staining in the lesion-prone aortic arch. A high dose, estimated to be 15 mg/kg, of TS-962 decreased serum cholesterol to normal levels with reduction of liver cholesterol contents below normal levels, and as a consequence, entirely inhibited the lipid accumulation in the aortic arch. Furthermore, a low dose, estimated to be 1.5 mg/kg, of TS-962 remarkably inhibited aortic lipid accumulation by 73% compared with the control group, without changing either serum cholesterol level or liver cholesterol content. These findings suggest that TS-962 is effective in the primary prevention of atherosclerosis by directly suppressing the formation of foam cells in arteries.

Acetamides↗
PubMed1999

Progressive bronchial obstruction associated with toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is an acute life-threatening condition, characterized by erosion of the mucous membranes, extensive detachment of the epidermis, and severe constitutional symptoms. Pulmonary complications of TEN are reported as rare, but are one of the most common causes of death. Our report focuses on an unusual case of toxic epidermal necrolysis which showed multiple bronchial obliteration during the chronic phase of the disease. Biopsied tissue of the obliterated bronchi demonstrated non-specific granulation. To improve the obliterated ventilatory function, we tried to reopen the bronchial obliteration using a balloon catheter under the guidance of fibreoptic bronchoscopy, however rapid restenosis of the bronchi ensued.

Adult↗
PubMed1999

Lung adenocarcinoma in lymphocytic interstitial pneumonitis associated with primary Sjögren's syndrome.

We experienced a rare case of lung adenocarcinoma associated with lymphocytic interstitial pneumonitis caused by primary Sjögren's syndrome. A 78-year-old woman was referred to our hospital because of progressive sicca syndrome and nodular opacities in the right lower lobe on chest radiograph. This patient was diagnosed as primary Sjögren's syndrome by a labial gland biopsy and classical clinical features including xerophthalmia, xerostomia and immunoserological findings. Pathological findings including immunohistochemical studies in a surgically resected lung revealed adenocarcinoma in lymphocytic interstitial pneumonitis associated with primary Sjögren's syndrome. There was no evidence of malignant lymphoma in the lymph nodes or resected lung tissue. Pulmonary involvement of Sjögren's syndrome is now regarded both clinically and histopathologically as a wide spectrum of lymphoproliferative disorders ranging from benign to malignant. However, lung cancer associated with primary Sjögren's syndrome, as in our case, has apparently not been reported previously.

Adenocarcinoma, Papillary↗
PubMed1999

Relation between activation sequence fluctuation and arrhythmogenicity in sodium-channel blockades.

To examine the correlation between activation sequence fluctuation and arrhythmogenicity, we investigated temporal changes in the activation sequence by measuring activation times [negative first derivative of voltage over time (-dV/dt) in QRS] from the entire heart in 18 dogs. The heart was paced by constant atrial stimulation. The character of the activation sequence fluctuation was established by a principal component analysis, in which the first principal component was defined as a stable component of the sequence and the second or third component as a fluctuated component. Steady state contained 2.2 +/- 0.6% (percent total principal component, mean +/- SD) of fluctuated components, which appeared in a beat-by-beat manner (activation sequence alternans). Activation sequence alternans was observed only during flecainide administration and not during lidocaine or disopyramide administration. Fluctuated components at a high dose of flecainide significantly increased (3.3 +/- 0.8%). Ventricular fibrillation ensued in all dogs (n = 6) exposed to flecainide after an increase in activation sequence alternans. In conclusion, flecainide evoked local activation sequence alternans. This phenomenon correlated with the occurrence of ventricular fibrillation.

Animals↗
PubMed1999

Circulating leptin in patients with chronic obstructive pulmonary disease.

Unexplained weight loss is common in patients with chronic obstructive pulmonary disease (COPD). Since leptin, an obesity gene product, is known to play important roles in the control of body weight and energy expenditure, we investigated serum leptin levels, along with circulating tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor (sTNF-R55 and -R75) levels, in 31 patients with COPD and 15 age-matched healthy controls. The body mass index (BMI) and percent body fat (%fat) were significantly lower in the COPD patients than in the healthy controls (BMI = 18.1 +/- 2.7 kg/m2 versus 22.8 +/- 2.2 kg/m2 [mean +/- SD]; p < 0.0001; %fat = 16.9 +/- 5.8% versus 24.3 +/- 4.9%; p < 0.001). Serum leptin levels were significantly lower in the COPD patients than in the healthy controls (1.14 +/- 1.17 ng/ml versus 2.47 +/- 2.01 ng/ml; p < 0.05). In contrast, serum TNF-alpha levels (6.59 +/- 1.92 pg/ml versus 5.41 +/- 1.60 pg/ml; p < 0.05), plasma sTNF-R55 (1.16 +/- 0.47 ng/ml versus 0.67 +/- 0.13 ng/ml; p < 0.0001) and sTNF-R75 (3.65 +/- 1.29 ng/ml versus 2.25 +/- 0.43 ng/ml; p < 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. Importantly, circulating leptin levels (log transformed) did correlate well with BMI and %fat, but not with TNF-alpha or with sTNF-R levels in the COPD patients. These data suggest that circulating leptin is independent of the TNF-alpha system and is regulated physiologically even in the presence of cachexia in patients with COPD.

Adipose Tissue↗
PubMed1999

Hydrogen peroxide enhances shedding of type I soluble tumor necrosis factor receptor from pulmonary epithelial cells.

Reactive oxygen intermediates (ROIs) are among the important mediators in the pathogenesis of lung diseases in which tumor necrosis factor (TNF) plays a pivotal role. However, the effects of ROIs on the TNF- TNF receptor system remain unclear. Effects of hydrogen peroxide on the shedding of soluble tumor necrosis factor receptor (sTNF-R) were investigated in a pulmonary epithelial cell line (A549) using enzyme-linked immunoassay. A549 cells spontaneously released type I sTNF-R (sTNF-RI) into the culture medium. Hydrogen peroxide accelerated the release of sTNF-RI from the A549 cells time- and dose- dependently. Stimulated release of sTNF-RI by hydrogen peroxide or phorbol myristate acetate (PMA) was inhibited by pretreatment with the intracellular hydroxyl radical scavengers dimethyl sulfoxide and dimethyl thiourea. A synthetic metalloproteinase inhibitor (KB-R8301) inhibited not only spontaneous release of sTNF-RI but also shedding enhanced by hydrogen peroxide and PMA. Preincubation with a protein kinase C inhibitor, calphostin C, downregulated the hydrogen peroxide- or PMA-induced shedding of sTNF-RI. Neither genistein, a tyrosine kinase inhibitor, nor H-89, a protein kinase A inhibitor, inhibited shedding of sTNF-RI by hydrogen peroxide and PMA. Although the surface expression of TNF-R assessed by 125I-TNF specific binding was decreased in the presence of hydrogen peroxide or PMA, TNF-RI mRNA transcript levels remained unchanged. These results show that hydrogen peroxide is involved in the activation of metalloproteinase and protein kinase C responsible for the shedding of sTNF-RI. Accordingly, ROIs may alter TNF action by enhanced shedding of sTNF-RI and reducing its surface receptor expression.

Cell Line↗
PubMed1999

Anti-inflammatory cytokine profile in human heart failure: behavior of interleukin-10 in association with tumor necrosis factor-alpha.

Proinflammatory cytokines, i.e., tumor necrosis factor-alpha (TNFalpha), participate in the development and the progression of congestive heart failure (CHF). On the other hand, an anti-inflammatory cytokine may neutralize the proinflammatory cytokines of CHF. Interleukin-10 (IL-10) is known to suppress the synthesis of proinflammatory cytokines. IL-10 and the IL-10 receptor system was investigated in comparison with the behavior of TNFalpha in 68 patients with various causes of CHF (mean age: 61 years) and in 31 normal subjects (61 years). The circulating IL-10 level was higher in CHF patients than in normal subjects (p<0.05). The TNFalpha level was higher in CHF patients than in control subjects (p<0.005). The ratio of IL-10 to TNFalpha tended to be higher in control subjects than in patients with CHF (p = 0.09). With lipopolysaccharide treatment, the release of IL-10 was more enhanced from mononuclear leukocyte of patients with CHF than from control subjects (p<0.05). The expression of the IL-10 receptor estimated by flow cytometry of mononuclear leukocytes was higher in the CHF patients than in the normal subjects. The IL-10/IL-10 receptor system was activated, at least partly, to downregulate an excess of TNFalpha in patients with advanced CHF. IL-10 may be an important inherent component of the cytokine network of CHF.

Adult↗