[Effects of macrolide antibiotics on iNOS gene expression and NO production by alveolar macrophages].
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Animals↗
Biomedical subjects
J Tamaoki
Publications and source records attributed to J Tamaoki.
[Effects of macrolide antibiotics on neutrophil infiltration into the airway mucosa and ICAM-1 expression].
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Animals↗
[Effects of macrolides on intracellular Ca2+ response by airway epithelium].
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Ampicillin↗
[A case of pulmonary eosinophilic granuloma undergoing spontaneous remission].
A case of pulmonary eosinophilic granuloma that underwent spontaneous remission is presented. A 23-year old man presented with dry cough and fever. Chest X-ray film revealed diffuse reticulo-nodular infiltrates in the middle and upper lung fields. Chest CT and HRCT showed multiple cystic lesions with thick walls and small nodules predominantly in the inner zone. Based on radiographic findings, pulmonary eosinophilic granuloma was suspected. Bronchoalveolar lavage cell data showed lymphocyte and eosinophil alveolitis with no increase of CD 1 lymphocytes. The symptoms and radiographic findings improved markedly within 4 months after the onset of symptoms without treatment and upon cessation of smoking. Chest CT and HRCT showed that the cystic walls were thinner and that the small nodules had decreased. Thoracoscopic lung biopsy revealed granulomatous lesions consisting of CD 1 and S-100 protein positive histiocytes with infiltration of eosinophils and fibrous lesions. Pulmonary eosinophilic granuloma was diagnosed. There has been no recurrence for 1 year.
Adult↗
[Airway hypersecretion and mucociliary dysfunction in asthma].
Mucociliary transport function can be determined by ciliary motility of airway epithelial cells, the amount and physicochemical properties of airway surface fluid, and the airway integrity. Mucus glycoprotein is released from submucosal glands and goblet cells in response to a variety of stimuli and, on other hand, water is secreted by airway epithelial cells through the movement of electrolytes. Marked airway goblet cell hyperplasia has been found in patients who died of severe asthma, indicating that goblet cell hypersecretion may play a significant role in the formation of mucus plugs in the respiratory tract. Goblet cell secretion is regulated by autonomic nerves and various chemical mediators associated with asthma. Antigen challenge causes an increase in mucus discharge from goblet cells in ovalbumin-sensitized animals, and this effect can be greatly inhibited by an histamine H2-receptor antagonist. Similarly, histamine released by antigen challenge stimulates airway epithelial Cl secretion and, hence, water secretion toward the airway lumen. There is ample evidence that mucociliary clearance is impaired in patients with asthma, which results in deterioration of airflow limitation. The precise mechanism for this impairment remains uncertain, but bronchospasm and the increased mucus secretion induced by peptide leukotrienes may be involved.
Animals↗
[Regulation and pathophysiology of airway secretion].
Although excessive production of sputum is one of the characteristic features of acute and chronic respiratory infections, bronchiectasis, diffuse panbronchiolitis, chronic bronchitis and asthma, pathophysiological mechanisms underlying airway hypersecretion remain uncertain. The increase in intraluminal mucus may lead to impairment of airway mucociliary clearance and deterioration of bronchial obstruction. Airway surface fluid is composed of mucus glycoprotein released from submucosal glands and goblet cells and water from airway epithelial cells, and the secretory function can be regulated by autonomic nervous system and a variety of chemical mediators. It is thus important to select mucoregulating drugs after understanding the mechanisms of hypersecretion and impaired mucociliary transport under individual conditions.
Anti-Bacterial Agents↗
[Effect of adenosine and its analogues on microvascular leakage in the rat trachea].
We examined the effects of adenosine and its analogues on vascular permeability in rat trachea using Evans blue dye as a marker for plasma leakage. Inhalation of N6-2-(4-aminophenyl) ethyladenosine (APNEA), a specific A 3 receptor agonist, increased microvascular leakage in a dose-dependent manner, but adenosine, [R]-N6-(1-Methyl-2-phenylethyl) adenosine (R-PIA), aspecific A 1 receptor agonist, and 5'-(N-ethyl-carboxamide) adenosine (NECA), a specific A 2 receptor agonist, had no effect. Inhalation of capsaicin increased vascular permeability in a dose-dependent manner. Pretreatment with NECA (10-1000 nmol/kg, i.v.) but not adenosine (100 nmol/kg i.v.), R-PIA (100 nmol/kg, i.v.) or APNEA (100 nmol/kg, i.v.) inhibited microvascular leakage produced by capsaicin aerosol (3 x 10(-5) M) in a dose-dependent manner. However, NECA (10-100 nmol/kg, i.v.) failed to inhibit substance P aerosol (10(-4) M)-induced extravasation of the dye. These findings suggest that stimulation of adenosine A 3 receptors produces airway vascular permeability, and that A 2 receptors inhibit neurogenic plasma extravasation, presumably by inhibiting the release of tachykinins from sensory nerves.
Adenosine↗
[Effect of salbutamol on proliferation of human bronchial epithelial cells: role of MAP kinase].
To determine whether stimulation of beta-adrenoceptors affects proliferation of airway epithelial cells and, if so, whether activation of mitogen-activated protein kinase (MAPK) is involved, we studied cultured human bronchial epithelial (16-HBE) cells in vitro. The 16-HBE cells were grown to subconfluence in 96-well plates, and their growth was inhibited by incubation in serum-free medium for 72 h. The cells were ten incubated in the presence of saltbutamol (SAL, 10(-7) M), a specific beta(2)-adrenoceptor agonist. Proliferation of the cells was evaluated by MTT assay and total DNA content, and activation of MAPK was assessed by immunocytochemistry and Western blotting for phosphorylated MAPK (phospho-MAPK). Immunocytochemistry and immunoblots demonstrated that phospho-MAPK was expressed within minutes of SAL exposure. This effect of SAL was as potent as that of 10% serum, and was greatly inhibited by treatment with propranolol. These results suggest that SAL is a potent mitogen of airway epithelial cells and that its effect may be exerted by beta(2)-adrenocepter-mediated activation of MAPK.
Adrenergic beta-2 Receptor Agonists↗
[Relaxation of canine pulmonary arteries caused by stimulation of atypical beta-adrenergic receptors].
To examine possible contributions of beta(3)-adrenoceptors to catecholamine-induced pulmonary vasodilation, we studied isolated canine pulmonary arterial segments under isometric conditions. Addition of beta-adrenoceptor agonists produced a concentration-dependent relaxation of tissues precontracted with 50 mM KCl; the rank order of potency was isoproterenol (ISO, 1) > salbutamol (SAL, 0.97) > selective beta(3)-adrenoceptor agonists CL 316243 (CL, 0.87) and BRL 37344 (BRL, 0.86). Relaxant responses to SAL were competitively antagonized by the beta(2)-adrenoceptor antagonist ICI 118551 and the pA2 value was 6.67 +/- 0.21 (mean +/- SE), whereas the response to CL was weekly antagonized only by a high concentration of ICI 118551 (10(-5) M) and the apparent pA2 value was 5.24 when alpha-and beta(1)-adrenergic receptors were blocked. By contrast, the atypical beta-adrenoceptor antagonist cyanopindolol antagonized CL-induced relaxation in a competitive manner; the pA2 value was 6.71 +/- 0.12, which was lower than that with salbutamol (p < 0.05). Intracellular cyclic AMP levels were increased in a contraction-dependent manner by CL. These results suggest that beta(3)-adrenoceptors may exist in canine pulmonary arterial smooth muscle and that stimulation of this atypical receptor causes vasodilation through a cyclic AMP-dependent pathway.
Adrenergic beta-Agonists↗
[Effect of heparin on airway goblet cell secretion in sensitized guinea pigs].
Heparin and related proteoglycans are released from mast cells and possess anti-inflammatory and anti-complement activities. To elucidate whether heparin affects goblet cell secretion in asthmatic airways and, if so, what the mechanism of action is, we studied guinea pigs sensitized with ovalbumin (OVA) by determining the mucus score (MS) of tracheal goblet cells stained with Alcian blue and PAS. Inhalation of OVA caused a rapid decrease in MS in a dose-dependent manner, with the maximal decrease being from 545 +/- 26 to 192 +/- 35 (p < 0.001), indicating an increase in goblet cell mucus discharge. This effect was selectively inhibited by the histamine H2 receptor blockade with cimetidine. Prior inhalation of heparin inhibited OVA-induced goblet cell secretion in a dose-dependent fashion, but had no effect on histamine-induced goblet cell secretion. The OVA-induced histamine release from the tracheal tissue was likewise inhibited by heparin. These results suggest that allergic challenge stimulates airway goblet cell secretion mainly through the release of histamine and the concomitant activation of histamine H2 receptors on goblet cells, and that heparin protects against this effect by inhibiting the histamine release from mast cells.
Animals↗
Histamine H2 receptor-mediated airway goblet cell secretion and its modulation by histamine-degrading enzymes.
BACKGROUND: Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions. METHODS: We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge. RESULTS: Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity. CONCLUSION: These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.
Amine Oxidase (Copper-Containing)↗
Role of Ca(2+)-activated K+ channel in epithelium-dependent relaxation of human bronchial smooth muscle.
1. To elucidate whether K+ channels play a role in the action of epithelium-dependent bronchodilatation, we studied responses in human bronchial strips in the presence of indomethacin and NG-nitro-L-arginine methylester under isometric conditions, in vitro. 2. Mechanical removal of the epithelium increased the contractile responses to acetylcholine; the pD2 values increased from 5.0 +/- 0.2 to 5.9 +/- 0.3 (P < 0.001). This potentiation was abolished by iberiotoxin but not by apamin or glibenclamide. 3. In cascade bioassay, application of the bathing medium from dispersed, bronchial epithelial cells to epithelium-denuded bronchial strips decreased acetylcholine-induced contraction by 44 +/- 6%. This effect was reduced to 10 +/- 3% (P < 0.01) when the epithelial cells were pretreated with iberiotoxin, and to 4 +/- 1% (P < 0.001) when the epithelial cells were incubated with Ca(2+)-free medium containing [1,2-bis(2) aminophenoxy] ethane N,N,N',N'-tetraacetic acid-acetomethoxy ester. 4. In contrast, the bronchodilator effect of the medium bathing epithelial cells was not altered by the direct addition of iberiotoxin to epithelium-denuded tissues. 5. These results suggest that the Ca(2+)-activated K+ channel may play a role in the synthesis and/or release of smooth muscle relaxing factor, which is neither nitric oxide nor a cyclo-oxygenase product, from airway epithelial cells.
Acetylcholine↗
Role of Na(+)-K+ ATPase in cyclic GMP-mediated relaxation of canine pulmonary artery smooth muscle cells.
1. Sodium-potassium adenosine triphosphate (Na(+)-K+ ATPase) plays a role in the regulation of vascular tone, but contribution of this enzyme to intravasodilator-induced pulmonary vasodilation remains uncertain. We thus studied the interaction between guanosine 3':5'-cyclic monophosphate (cyclic GMP) and Na(+)-K+ ATPase in smooth muscle cells isolated from canine pulmonary artery. 2. To assess the contractile properties, changes in smooth muscle cell length were determined microscopically. Application of potassium chloride (KCl) shortened the cell length, an effect which was reduced by sodium nitroprusside and 8-bromo-cyclic GMP in a concentration-dependent manner. Pretreatment of cells with the cyclic GMP-dependent kinase inhibitor KT 5823 (2 microM) abolished the effects of sodium nitroprusside and 8-bromo-cyclic GMP. 3. Ouabain (0.3 microM) did not alter the KCl-induced muscle shortening, but inhibited the relevant responses to sodium nitroprusside and 8-bromo-cyclic GMP. 4. Incubation of smooth muscle cells with sodium nitroprusside concentration-dependently increased intracellular cyclic GMP levels and ouabain-sensitive 86Rb uptake, and these values were significantly correlated. In the presence of KT 5823, sodium nitroprusside increased cyclic GMP levels but did not alter ouabain-sensitive 86Rb uptake. 5. These results suggest that there is a link between accumulation of intracellular cyclic AMP and activation of sarcolemmal Na(+)-K+ ATPase in pulmonary artery smooth muscle cells and that this link may be involved in the sodium nitroprusside-induced pulmonary vasodilatation.
Animals↗
Effect of adenosine on adrenergic neurotransmission and modulation by endothelium in canine pulmonary artery.
To determine the effect of adenosine on adrenergic neurotransmission in pulmonary vasculature and its modulation by endothelial cells, we studied canine pulmonary arteries under isometric conditions in vitro. Adenosine decreased the contractile responses to electrical field stimulation but had no effect on those to norepinephrine. This inhibitory effect was concentration dependent, with a rank order of potency of NECA > 2-chloroadenosine > adenosine >> APNEA (an A3-adenosine-receptor agonist) > CGS-21680 (an A2a agonist) > CCPA (an A1 agonist). Adenosine reduced the electrical field stimulation-evoked 3H overflow in superfused pulmonary artery previously soaked in [3H]norepinephrine. Pretreatment with the adenosine uptake blocker dipyridamole or the adenosine deaminase inhibitor deoxycoformycin enhanced the adenosine action, and this enhancement was not observed in the endothelium-denuded tissues. Adenosine deaminase activity was found in endothelial cells. Therefore, adenosine inhibits norepinephrine release via an A2b-receptor mechanism, an effect that may be modulated by uptake and metabolism by endothelial cells.
Adenosine↗
Lipopolysaccharide-induced goblet cell hypersecretion in the guinea pig trachea: inhibition by macrolides.
We studied the effects of macrolides on lipopolysaccharide (LPS)-induced airway goblet cell secretion in the guinea pig trachea. The goblet cell secretion was assessed in histological sections of the tracheal mucosa stained with alcian blue and periodic acid Schiff by arbitrarily determining mucus score, which is inversely related to the magnitude of mucus discharge. Inhalation of Escherichia coli LPS (5 mg/kg) caused a time-dependent decrease in mucus score, with the maximal response being from 542 +/- 49 to 92 +/- 20 arbitrary units (P < 0.001) after 3 h, which was accompanied by an increase in the number of neutrophils in the tracheal mucosa. The LPS-induced mucus discharge was inhibited by oral clarithromycin and erythromycin in a dose-dependent manner (5 and 10 mg/kg), whereas amoxicillin and cefaclor had no effect. Each dose of clarithromycin and erythromycin, but not amoxicillin or cefaclor, likewise attenuated the LPS-induced recruitment of neutrophils. These results suggest that LPS stimulates goblet cell secretion and neutrophil accumulation in the airways and that macrolides may be of value in protecting against neutrophil-associated airway hypersecretion.
Animals↗
Invasive thymoma with CD4+CD8+ double-positive T cell lymphocytosis.
Lymphocytosis in the peripheral blood is a very rare manifestation of thymoma. A 45-year-old man presented with a giant mediastinal mass involving pleural dissemination and peripheral T cell lymphocytosis. Biopsy of the mediastinal mass revealed invasive thymoma, and two-color analysis of peripheral lymphocytes showed a marked increase in CD4+CD8+ double-positive cells. Both thymoma and lymphocytosis were improved by a combination of chemotherapy and mediastinal irradiation.
CD4 Antigens↗
Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group.
To test whether the leukotriene antagonist ONO-1078 (pranlukast) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid, we conducted a randomized, double-blind, placebo-controlled study in 79 asthma patients requiring high doses (1,500 microg/d or more) of inhaled beclomethasone dipropionate (BDI) for clinical control (duration of asthma, 11.0 +/- 3.1 yr; duration of BDI treatment, 0.5 +/- 0.3 yr; FEV1 percentage of predicted, 80.7 +/- 2.0%). After a 2-wk run-in period, the doses of BDI were halved, while the patients were assigned to receive orally ONO-1078, 450 mg twice daily, or placebo. In the placebo group FEV1 decreased by 0.33 +/- 0.20 L after 6 wk (p < 0.001). Likewise, morning and evening PEF decreased by 46 +/- 7 L/min and 18 +/- 6 L/min, respectively. By contrast these variables were sustained above baseline in the ONO-1078 group. The number of daytime and nighttime asthma symptoms and the use of beta2-agonist increased in the placebo group, whereas they remained unchanged in the ONO-1078 group. In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased (p = 0.007 and p = 0.025, respectively), compared with no change in the ONO-1078 group. Therefore, the leukotriene antagonist ONO-1078 prevents the asthma deterioration provoked by a 6-wk reduction of the dose of inhaled BDI into half.
Administration, Inhalation↗
Increased oxidative metabolism in cow tracheal epithelial cells cultured at air-liquid interface.
Airway epithelial cells cultured at the air-liquid interface possess highly differentiated functions and structures compared with the cells cultured under immersion. We examined the oxidative metabolism and glycolysis in cow tracheal epithelial cells on Days 3, 6, 10, and 13, cultured under three different conditions: (1) immersion culture on porous filters with apical and basolateral feeding (IM), (2) air-exposed culture on porous filters with basolateral feeding, i.e., air-liquid interface culture (AI), and (3) conventional immersion culture in plastic dishes with apical feeding (DI). Lactate production was less in AI than in IM and DI on Day 3 through Day 13, whereas cellular adenosine triphosphate content and basal O2 consumption were greater. Ouabain-sensitive and ouabain-insensitive O2 consumption, and the uncoupled O2 consumption were also greater in AI. Cytosolic lactate dehydrogenase activities on Day 10 were lower in AI, whereas alpha-ketoglutarate dehydrogenase activities were higher. The increased oxidative metabolism in AI was more pronounced at the late phase of culture (Days 10 and 13). In contrast, glycolysis remained elevated during the experiment in IM and DI. These data suggest that (I) AI begins to promote oxidative metabolism from growth phase by the provision of adequate oxygenation, and then further shifts to oxidative metabolism with differentiation; and (2) apical feeding may be responsible for the disturbance of the development of the oxidative metabolism.
Adenosine Triphosphate↗