[Effect of macrolide antibiotics on MUC5AC production in human bronchial epithelial cells].
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Anti-Bacterial Agents↗
Biomedical subjects
A Nagai
Publications and source records attributed to A Nagai.
Cystatin C and cathepsin B in CSF from patients with inflammatory neurologic diseases.
BACKGROUND: In CSF, proteolytic enzymes are believed to have crucial roles in the initiation and progression of inflammatory neurologic diseases (IND). Cystatin C, a major cysteine protease inhibitor in CSF, is tightly bound to cathepsin B and H. OBJECTIVE: To determine if cystatin C is involved in the disease process of IND, the authors measured the cystatin C concentration by ELISA method and cathepsin B and H activities in the CSF of patients with acute IND. METHODS: Cystatin C concentration and cathepsin B and H activities were measured in CSF samples taken from patients during the acute phase of their disease. Subjects studied were 8 patients with Guillain-Barré syndrome (GBS), 5 with chronic inflammatory demyelinating polyneuropathy (CIDP), 12 with MS, 16 with aseptic meningitis, 15 with neurodegenerative diseases as disease controls, and 35 healthy controls. RESULTS: A significant decrease in CSF cystatin C level was seen in the patients with GBS, CIDP, and MS compared to the control subjects. High cathepsin B activity, but not cathepsin H activity, was also observed in the patients with GBS, CIDP, and MS. CONCLUSION: Cystatin C levels in CSF measured by ELISA may help the physician recognize GBS, CIDP, and MS. Decreased levels of cystatin C may be related to the high levels of cathepsin B activity seen in the CSF of patients with GBS, CIDP, and MS.
Adult↗
Cardioprotective effect of TY-12533, a novel Na(+)/H(+) exchange inhibitor, on ischemia/reperfusion injury.
The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro derivative of TY-12533) and cariporide on the platelet Na(+)/H(+) exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533, TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before ischemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).
Aconitine↗
Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Tokyo Joshi-Idai Asthma Research Group.
BACKGROUND: Th2 cytokines play an important part in the pathogenesis of asthma. Our aim was to study the effect of suplatast tosilate, a selective Th2 cytokine inhibitor, on asthma control and asthma exacerbations during reduction of inhaled corticosteroid dose in patients with steroid-dependent asthma. METHODS: 85 patients with moderate to severe asthma taking high doses (> or = 1500 microg per day) of inhaled beclometasone dipropionate, were assigned suplatast tosilate (100 mg three times daily) or placebo for 8 weeks in a double-blind, randomised, parallel-group, multicentre trial. During the first 4 weeks, other medications remained unchanged (add-on phase); during the next 4 weeks, the doses of beclometasone were halved (steroid-reduction phase). Main outcome measures were pulmonary function, asthma symptoms, and use of beta2-agonists. FINDINGS: Data were available from 77 patients. During the add-on phase, suplatast tosilate treatment, compared with placebo, was associated with higher forced expiratory volume in 1 s (mean difference between groups for changes from baseline at week 4, 0.20 L [95% CI 0.16-0.24], p=0.043), morning peak expiratory flow (18.6 L/min [14.1-23.1], p=0.037), and less diurnal variation in peak expiratory flow rate, asthma symptom scores (7.1 [6.6-7.6], p=0.029), and serum concentrations of eosinophil cationic protein and IgE. In the steroid-reduction phase, pulmonary function, asthma symptoms, and use of beta2-agonist deteriorated significantly more in the placebo group than in the suplatast group. INTERPRETATION: Treatment with a Th2 cytokine inhibitor in steroid-dependent asthma improves pulmonary function and symptom control, and allows a decrease in dose of inhaled corticosteroid without significant side-effects. Some improvements in pharmacokinetics are, however, needed.
Administration, Inhalation↗
A Japanese propositus with D-- phenotype characterized by the deletion of both the RHCE gene and D1S80 locus situated in chromosome 1p and the existence of a new CE-D-CE hybrid gene.
In a family study of a Japanese propositus with the D-- phenotype, the serological data of her D-- phenotype and those of her parents were discrepant. Gene analysis of the propositus showed a gross deletion of the RHCE gene and a new rearrangement of RHCE to yield the CE-D-CE hybrid. It was demonstrated that the hybrid CE-D-CE gene consisted of exon 1 from the RHCE gene, followed by exons 3 to 7 from the RHD gene and exons 8 to 10 from the RHCE gene. However, whether or not exon 2 of the RHD or the RHCE gene was contained in the CE-D-CE gene remained unclear. Moreover, spacer analysis between both RH genes and the family study suggested that the D-- gene complex from the paternal and maternal sides consisted of only the CE-D-CE hybrid gene and a single RHD gene, respectively. For the purpose of confirming the parent-child relationship, a paternity test using DNA fingerprint and polymerase chain reaction (PCR) analysis at the D1S80 locus were performed. DNA fingerprints with two kinds of DNA minisatellite probes (33.15 and 33.6) confirmed that the parent-child relationship in the D-- propositus was compatible. However, in the present case, at the D1S80 locus, the PCR product derived from the mother was lacking, thereby negating a parent-child relationship. It is probable that the RH genes and D1S80 locus exist in close proximity, because they are situated in chromosomes 1p 34.3-36.1 and 1p 36.1-36.3, respectively. These data suggested that at the stage of gametogenesis, both the RHCE gene and the D1S80 locus from the maternal side may have been deleted, thereby producing the D-- gene complex.
Chimera↗
Inhibition of airway smooth muscle tone by Chinese herbal medicines.
The aim of the present study was to elucidate whether Chinese traditional herbal drugs, Gorei-San (TJ-17) and Toki-Shakuyaku-San (TJ-23), affect airway smooth muscle tone and, if so, to determine what the mechanism of action is. Rabbit tracheal segments were isolated and the contractile responses to electrical field stimulation and acetylcholine were measured before and after the application of TJ-17 or TJ-23 under isometric conditions in vitro. Ouabain-sensitive rubidium-86 (86Rb) uptake by tissues in response to each drug was also measured. Each herbal medicine attenuated the contractile responses to electrical field stimulation and acetylcholine in a concentration-dependent manner, the maximal inhibition of acetylcholine-induced contraction being 37.5+/-4.9% for TJ-17 and 42.4+/-5.3% for TJ-23 (p<0.05 for each). These effects were not altered by mechanical removal of the epithelium, indomethacin, the nitric oxide synthase inhibitor NG -nitro-L-arginine methyl ester, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor adenosine 3'5'-cyclic monophosphorothioate (Rp-cAMPS), the cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor KT5823, or the calcium (Ca2+)-activated potassium (K+) channel inhibitor charybdotoxin, but were greatly inhibited in the presence of the sodium (Na+)-K+ adenosine triphosphatase (ATPase) inhibitor ouabain. Incubation of tissues with TJ-17 and TJ-23 dose dependently increased ouabain-sensitive 86Rb uptake. The results of the study suggest that both Gorei-San and Toki-Shakuyaku-San reduce airway smooth muscle tone via a postjunctional mechanism probably through stimulation of the sodium pump and the subsequent hyperpolarization/repolarization of the cell membrane. These effects may contribute to the antiasthmatic properties of these herbal medicines.
Acetylcholine↗
Ginsenoside-induced relaxation of human bronchial smooth muscle via release of nitric oxide.
Ginsenoside, an extract of Panax ginseng, is an essential constituent of anti-asthmatic Chinese herbal medicine. To elucidate whether ginsenoside affects airway smooth muscle tone and, if so, what the mechanism of action is, we studied relaxant responses of human bronchial strips under isometric condition in vitro, and directly measured the release of nitric oxide (NO) by an amperometric sensor for this molecule. Addition of ginsenoside relaxed the tissues precontracted with acetylcholine in a dose-dependent manner, the maximal relaxation and the ginsenoside concentration required to produce 50% relaxation being 67+/-8% and 210+/-29 microg ml(-1), respectively. The relaxant responses to ginsenoside were inhibited by N(G)-nitro-L-arginine methylester (L-NAME) and removal of the epithelium, but not by N(G)-nitro-D-arginine methylester (D-NAME) or tetrodotoxin. This inhibitory effect of L-NAME was reversed by L-arginine but not by D-arginine. Addition of ginsenoside to the medium containing bronchial tissues dose-dependently increased NO-selective electrical current, and this effect was greatly attenuated by the epithelial removal or Ca(2+)-free medium. Ginsenoside also increased tissue cyclic GMP contents, an effect that was abolished in the presence of L-NAME. It is concluded that ginsenoside induces relaxation of human bronchial smooth muscle via stimulation of NO generation predominantly from airway epithelium and cyclic GMP synthesis. This action might account for the anti-asthmatic effect of Panax ginseng.
Bronchi↗
Angio-oedema in a neonate with IgG antibodies to parvovirus B19 following intrauterine parvovirus B19 infection.
We report a neonate with angio-oedema following fetal hydrops caused by maternal parvovirus B19 infection. Levels of complement components, including total haemolytic complement activity and C1 inhibitor concentration, were within normal ranges in cord blood. Neonatal angio-oedema might be included in the clinical spectrum of parvovirus B19 infection in pregnancy.
Adult↗
Anion channels modulate store-operated calcium influx in human microglia.
Recent work from this laboratory has demonstrated that purinergic-mediated depolarization of human microglia inhibited a store-operated pathway for entry of Ca2+. We have used Fura-2 spectrofluorometry to investigate the effects on store-operated Ca2+ influx induced by replacement of NaCl with Na-gluconate in extracellular solutions. Three separate procedures were used to activate store-operated channels. Platelet activating factor (PAF) was used to generate a sustained influx of Ca2+ in standard physiological saline solution (PSS). The magnitude of this response was depressed by 70% after replacement of PSS with low Cl- PSS. A second procedure used ATP, initially applied in Ca2+-free PSS solution to deplete intracellular stores. The subsequent perfusion of PSS solution containing Ca2+ resulted in a large and sustained entry of Ca2+, which was inhibited by 75% with low Cl- PSS. The SERCA inhibitor cyclopiazonic acid (CPA) was used to directly deplete stores in zero-Ca2+ PSS. Following the introduction of PSS containing Ca2+, a maintained stores-operated influx of Ca2+ was evident which was inhibited by 77% in the presence of the low Cl- PSS. Ca2+ influx was linearly reduced with cell depolarization in elevated K+ (7.5 to 35 mM) suggesting that changes in external Cl- were manifest as altered electrical driving force for Ca2+ entry. However, 50 mM external KCl effectively eliminated divalent entry which may indicate inactivation of this pathway with high magnitudes of depolarization. Patch clamp studies showed low Cl-PSS to cause depolarizing shifts in both holding currents and reversal potentials of currents activated with voltage ramps. The results demonstrate that Cl- channels play an important role in regulating store-operated entry of Ca2+ in human microglia.
Adenosine Triphosphate↗
Effect of inhaled indomethacin in asthmatic patients taking high doses of inhaled corticosteroids.
BACKGROUND: Cyclooxygenase products of arachidonic acid may play a part in bronchoconstriction and airway inflammation in asthma. OBJECTIVE: We sought to determine the effect of inhaled indomethacin on asthma control and asthma exacerbations during reduction of inhaled corticosteroids in patients with moderate-to-severe steroid-dependent asthma. METHODS: We conducted a double-blind, randomized, parallel-group, multicenter study in 38 patients with asthma taking high doses (> or =1500 microg/d) of beclomethasone dipropionate (BDP). After a run-in period, patients were assigned inhaled indomethacin (50 mg/d) or placebo for 6 weeks, during which the daily doses of BDP were reduced to half at week 2 and then to one third of the baseline dose at week 4. RESULTS: Data were available from 34 patients. After the reduction of BDP doses, FEV(1), peak expiratory flow, asthma symptoms, and exhaled nitric oxide concentrations deteriorated in both treatment groups, but these effects were less pronounced in the indomethacin group compared with the placebo group. During the 6-week treatment period, 89% of the patients receiving placebo had relapse of asthma, whereas only 38% of those receiving inhaled indomethacin did so (P =.003). CONCLUSION: Inhalation of indomethacin can reduce asthma exacerbations induced by reduction of high-dose inhaled corticosteroid in steroid-dependent asthma.
Administration, Inhalation↗
Morphological changes in rat lung after long-term exposure to diesel emissions.
Wistar rats were exposed for 24 mo to diesel emissions containing a low (0.2 ppm, 0.21 mg/m(3)), medium (1.04 ppm, 1.18 mg/m(3)), or high (2.96 ppm, 3.05 mg/m(3)) concentration of NO(2) and particles, or diesel emissions containing a medium (1.12 ppm, 0.01 mg/m(3)) concentration of NO(2) without particles. At 6-mo intervals during the exposure period, rats were autopsied, and their lungs were prepared for light- and electron-microscopic examination. Morphological evaluations included examination for hyperplasia of airway goblet cells, shift in the types of glycoprotein of intracellular mucus granules in goblet cells, infiltration of inflammatory cells in the airways, enlargement of the cross-sectional area of an alveolus as a parameter of air space enlargement, and development of alveolar holes, which is considered to be an early hallmark of alveolar destruction. The number of goblet cells with acid-form mucus granules increased with the exposure concentration and time; however, goblet cells did not show any hyperplastic changes. Furthermore, inflammatory cells such as alveolar macrophages, mast cells, plasma cells, neutrophils, and lymphocytes infiltrated the airways and the alveoli, and showed some cell-to-cell contact. Although no significant enlargement of the air space of the lungs was seen in any exposure group, the number of alveolar holes was significantly higher in the high-concentration group in comparison with the control group at each exposure time, and also increased in other exposure groups, even in the low-concentration group at certain exposure times. Morphological changes in the lungs were mild even in the animals exposed to the highest levels of diesel emissions for 24 mo. Elimination of particles from diesel emissions led to reduced morphological changes such as a decreased shift in the types of glycoprotein of mucus granules in goblet cells, decreased infiltration of inflammatory cells in the lungs, and reduced anthracosis.
Animals↗
Impairment of airway mucociliary transport in patients with sinobronchial syndrome: role of nitric oxide.
Nitric oxide (NO) produced within the respiratory tract can stimulate ciliary motility of airway epithelial cells and hence mucociliary transport. In this study, to determine the role of NO in mucociliary dysfunction in sinobronchial syndrome (SBS), we measured NO concentrations in the exhaled air by chemiluminescence analyzer and nasal clearance time (NCT) by saccharin test. Exhaled NO concentrations in patients with SBS were 39% of those in healthy nonsmokers and 55% of those in healthy smokers. The patients also showed prolonged NCT compared with healthy subjects, and there was a significant negative correlation between exhaled NO concentrations and NCT. Furthermore, concentrations of chloride (Cl) in the sputum supernatant were higher in SBS patients than in healthy subjects, and there was a significant negative correlation between sputum Cl concentrations and exhaled NO concentrations. These results suggest that airway mucociliary clearance is impaired in patients with SBS and that this impairment might result from the reduced production of NO and the impaired availability of the molecule in the mucociliary apparatus.
Adult↗
Fetal death from abruptio placentae associated with incorrect use of a seatbelt.
A female driver, 24 weeks pregnant, was wearing a three-point seatbelt in the manner usual for nonpregnant women, when her automobile collided head-on with another vehicle. A cardiotocographic examination after the accident revealed the fetus to be alive. Five days after the accident, however, a cardiotocographic examination showed fetal death. At that time, a transverse ecchymotic band on the lower abdominal wall that had not been observed at the first examination was noticed. Eight days after the accident, the mother delivered a macerated female fetus. At autopsy, the baby showed no abnormality, but there was a hematoma on the placental surface toward the uterus. These results suggest that the fetus died of abruptio placentae associated with incorrect placement of the lap belt.
Abruptio Placentae↗
Traumatic rupture of the basilar artery: report of two cases and review of the literature.
Two cases of traumatic rupture of the basilar artery are reported. In the first case, severe basal subarachnoid hemorrhage (SAH) due to a complete transverse tear of the basilar artery was observed in a 53-year-old restrained male driver who was involved in a head-on collision while intoxicated and drowsy. He lost consciousness shortly after the accident and was admitted to hospital in cardiopulmonary arrest. Intensive resuscitative therapies produced cardiac response, but he died 50 minutes after the accident. The ethanol concentration in his blood and urine was 0.35 and 0.55 mg/ml, respectively. In the second case, SAH due to a similar tear of the basilar artery was observed in a 47-year-old man who received several fist blows to the face while intoxicated. He suddenly lost consciousness after the final blow and was admitted to hospital in cardiopulmonary arrest. Intensive resuscitative therapies produced cardiac response, but he died 6 hours after the event. In these cases, the mechanism of the traumatic rupture of the basilar artery is thought to be overstretching due to hyperextension of the head, and intoxication, drowsiness, or both may have interfered with the decedents' ability to protect themselves; thus, the hyperextension of the head may have been rather forceful.
Accidents, Traffic↗
Identification of the origin of a vesical mass occurring after cadaveric renal transplantation using short tandem repeat markers.
We report a case of polypoid cystitis in a 54-year-old female occurring 4 years after cadaveric kidney transplantation. Endoscopic exploration revealed a polypoid tumor near the stoma opened for the transplanted ureter. The diagnosis of polypoid cystitis was confirmed histopathologically. Genotyping of cells from the tumor with polymorphic short tandem repeat (STR) and amelogenin loci revealed that the tumor contained alleles from both the donor and recipient. Molecular genetic analysis provided strong evidence that the tumor cells arose from the donor tissue.
Cadaver↗
The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice.
Recent studies suggest that Fas-Fas-ligand (FasL) interactions play an important role in the development of lung injury and fibrosis. However, evidence to support this concept is still indirect. To determine whether Fas-FasL interaction is required for the development of bleomycin-induced pulmonary fibrosis in mice, we used Fas-deficient (lpr) and FasL-deficient (gld ) mice as animal models. After intratracheal instillation of bleomycin, we examined the lungs of mice through bronchoalveolar lavage, histologic studies, DNA nick-end labeling, and hydroxyproline assay. The development of cellular infiltrates, bronchiolar and alveolar epithelial apoptosis, and fibrosis following bleomycin instillation in the lungs in lpr mice and gld mice was similar to their development in wild-type mice. The results of this study show that bleomycin-induced pulmonary fibrosis does not require Fas-FasL interaction, and that epithelial cell apoptosis after bleomycin exposure is mediated by Fas-independent pathways.
Animals↗
Macrolide antibiotics inhibit nitric oxide generation by rat pulmonary alveolar macrophages.
There is evidence that macrolide antibiotics are effective in the treatment of chronic airway inflammatory diseases, probably through actions other than their antibacterial properties. In order to determine whether macrolides affect the nitric oxide-generating system in the respiratory tract, rat pulmonary alveolar macrophages (PAMs) were studied in vitro. The release of NO was assessed by direct measurement with a specific amperometric sensor for this molecule, and the expression of type II NO synthase (NOS) messenger ribonucleic acid (mRNA) was determined by Northern blotting. Incubation of PAMs with lipopolysaccharide from Escherichia coli and recombinant human interferon-gamma caused release of NO, which was accompanied by induction of type II NOS mRNA. The release of NO was reduced by coincubation of cells with the macrolides erythromycin, clarithromycin and josamycin in a concentration-dependent manner, the maximal inhibition being 73+/-10, 81+/-6 and 84+/-9%, respectively, but was not altered by amoxycillin or cefaclor. These macrolides likewise inhibited the induction of type II NOS mRNA, whereas no inhibitory effects were observed with amoxycillin or cefaclor. These results suggest that macrolide antibiotics specifically inhibit type II NO synthase gene expression and consequently reduce NO production by rat pulmonary alveolar macrophages, which might result in attenuation of airway inflammation.
Amoxicillin↗
Inhaled indomethacin in bronchorrhea in bronchioloalveolar carcinoma: role of cyclooxygenase.
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Adenocarcinoma, Bronchiolo-Alveolar↗