Normal chest radiograph and lung function do not necessarily mean normal lungs.
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Biopsy↗
Biomedical subjects
S Shimura
Publications and source records attributed to S Shimura.
Role of cyclic ADP-ribose in ATP-activated potassium currents in alveolar macrophages.
There is growing evidence that extracellular ATP causes a dramatic change in the membrane conductance of a variety of inflammatory cells. In the present study, using the nystatin perforated patch recording configuration, we found that ATP (0.3-30 microM) induced a transient outward current in a concentration-dependent manner and that the reversal potential of the ATP-induced outward current was close to the K+ equilibrium potential, indicating that the membrane behaves like a K+ electrode in the presence of ATP. The first application of ATP to alveolar macrophages perfused with Ca2+-free external solution could induce the outward current, but the response to ATP was diminished with successive applications. Intracellular perfusion with a Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid, also diminished the response. When cyclic ADP-ribose (cADPR) was applied to the macrophage cytoplasm, a transient outward current was elicited. Thereafter, the successive outward current was inhibited, suggesting the involvement of cADPR in the response. Intracellular perfusion with inositol 1,4, 5-trisphosphate also induced a transient outward current, but the successive current was not inhibited. The ATP-induced outward current was abolished when 8-amino-cADPR (as a blocker of cADPR, 10(-6)-10(-5) M) was introduced into the cytoplasm. Homogenates of alveolar macrophages showed both ADP-ribosyl cyclase and cADPR hydrolase activities, and CD38 (ADP-ribosyl cyclase/cADPR hydrolase) expression was confirmed by reverse transcriptase-polymerase chain reaction and Western blot analyses. These results indicate that ATP activates K+ currents by releasing Ca2+ from cADPR-sensitive internal Ca2+ stores.
Adenosine Diphosphate Ribose↗
Signature current of SO2-induced bronchitis in rabbit.
To investigate abnormalities of airway epithelial ion transport underlying chronic inflammatory airway diseases, we performed electrophysiological, histological, and molecular biological experiments using rabbits exposed to SO2 as a model of bronchitis. By comparison with control, the SO2-exposed trachea exhibited decreased short circuit current (Isc) and conductance associated with increased potential difference. In normal trachea, apical ATP induced a transient Isc activation followed by a suppression, whereas the bronchitis model exhibited a prolonged activation without suppression. This pathological ATP response was abolished by diphenylamine 2-carboxylate or Cl--free bath solution. A significant increase in net Cl- flux toward the lumen was observed after ATP in our bronchitis model. Isoproterenol or adenosine evoked a sustained Isc increase in SO2-exposed, but not in normal, tracheas. The Northern blot analysis showed a strong expression of cystic fibrosis transmembrane conductance regulator (CFTR) mRNA in SO2-exposed epithelium. The immunohistochemical study revealed a positive label of CFTR on cells located luminally only in SO2-exposed rabbits. We concluded that the prolonged ATP response in our bronchitis model was of a superimposed normal and adenosine-activated current. The latter current was also activated by isoproterenol and appeared as a signature current for the bronchitis model airway. This was likely mediated by CFTR expressed in the course of chronic inflammation.
Adenosine↗
Detection of surfactant protein-A gene transcript in the cells from pleural effusion for the diagnosis of lung adenocarcinoma.
PURPOSE: To determine whether detecting surfactant protein-A (SP-A) gene transcript in the cells from pleural effusion is useful for the diagnosis of lung adenocarcinoma. PATIENTS AND METHODS: We performed reverse transcription polymerase chain reaction (RT-PCR) analysis of SP-A gene transcript in the cells of pleural effusion from 42 consecutive patients with pleural effusion, including 7 patients with primary lung adenocarcinoma before their treatments. RESULTS: A cDNA segment of SP-A was amplified from the pleural fluid cells of all patients with primary lung adenocarcinoma, indicating the presence of the SP-A gene transcript. None of the remaining patients, including those with metastatic lung adenocarcinoma, showed positive for the SP-A gene transcript. CONCLUSION: These findings indicate that RT-PCR analysis of the SP-A gene transcript in pleural effusion is useful for the diagnosis of primary lung adenocarcinoma.
Adenocarcinoma↗
ATP-induced Cl- secretion with suppressed Na+ absorption in rabbit tracheal epithelium.
The effect of extracellular ATP on ion transport of rabbit tracheal epithelium was examined using an Ussing chamber. Isoproterenol (10(-8)-10(-5) M) did not alter the electrophysiological properties across the tracheal epithelium. Apically applied ATP induced an initial transient increase in short circuit current (SCC) followed by a decline to below the prior baseline. The initial increase by ATP (10(-4) M) was significantly inhibited by a Cl(-) -channel inhibitor diphenylamine-2-carboxylate (DPC, 5 x 10(-4) M) and Cl(-) -substitution with gluconate in the bath solution, while a cystic fibrosis transmembrane regulator (CFTR) Cl(-) -channel inhibitor glibenclamide (10(-4) M), a Na(+)-channel inhibitor amiloride (10(-4) M) and a K(+) -channel inhibitor quinidine (10(-4) M) all failed to alter it. The decline in SCC by ATP was abolished by amiloride, while DPC or Cl-substitution with gluconate in the bath solution did not alter it. Ca(2+)-removal from the bath solutions did not significantly alter the initial increase nor the decline by ATP. Ionomycin (10(-5) M) induced an initial transient increase in SCC, to a degree similar to that by ATP alone. A calmodulin antagonist W-7 reduced the SCC baseline and abolished SCC increase by ATP. These findings indicate that ATP activates Ca(2+)-dependent Cl(-) -channels with an inhibition of Na -channel activity or absorption in rabbit tracheal epithelium.
Adenosine Triphosphate↗
HMT regulates histamine-induced glycoconjugate secretion from human airways in vitro.
To determine whether histamine N-methyltransferase (HMT) regulates mucus glycoprotein (MGP) secretion from airways, we examined the effect of an HMT inhibitor, SKF 91488, on MGP secretion from human airways in vitro. MGP secretion from human airway explants (with epithelium) and isolated submucosal glands was estimated by measuring trichloroacetic acid (TCA) precipitable glycoconjugates using secretory indices. Histamine induced significant MGP secretion from both explants and isolated glands. Pretreatment with SKF 91488 significantly inhibited histamine-induced secretion from explants, while it did not alter significantly the secretion from isolated glands. H1-blocker significantly reversed the inhibition by SKF 91488 of the secretion from explants, while H2-blocker abolished histamine-induced secretion from both explants and isolated glands. Prostaglandin E2 (PGE2) significantly inhibited histamine-induced secretion from isolated glands. The inhibitory action of SKF 91488 in airway explants was blocked by indomethacin and was significantly reduced by a prostanoid EP4 receptor antagonist (AH23848B). These findings suggest that HMT regulates MGP secretion from human airway submucosal glands through an interaction with epithelial cells which involves the release of PGE2.
Animals↗
Dexamethasone suppressed gene expression and production of interleukin-10 by human peripheral blood mononuclear cells and monocytes.
Interleukin-10 (IL-10) is known to inhibit T cell-mediated responses. IL-10 has also been shown to play an important pathogenetic role in allergic diseases. Glucocorticoid is known to inhibit the production and gene expression of many cytokines which induce inflammatory reactions. We examined the effect of dexamethasone on the gene expression and production of IL-10 by human peripheral blood mononuclear cells (PBMCs) and monocytes. PBMCs and monocytes from 5 healthy volunteers were incubated with or without dexamethasone for 1 h, then stimulated with 5 micrograms/ml lipopolysaccharide (LPS). Gene expression and production of IL-10 by human PBMCs were detected without stimulation and increased by LPS stimulation. Dexamethasone suppressed the gene expression and production of IL-10 by LPS-stimulated PBMCs in a dose-dependent manner by 41.6 and 61.1% at 10(-6) M, respectively. Also in monocytes, the gene expression and production of IL-10 were detected without stimulation, increased by LPS stimulation, and significantly suppressed by dexamethasone by 53.1 and 61.2% at 10(-6) M, respectively. This suppressive effect on IL-10 gene expression was not so potent compared with its effect on cytokines such as IL-5. The suppression of IL-10 production by glucocorticoid is suggested to be one of the important mechanisms by which glucocorticoids suppress allergic inflammation in the treatment of allergic diseases.
Blotting, Northern↗
Patch-clamp characterization of secretory process in human basophils.
The effects of the intracellular Ca2+ concentration ([Ca2+]i) and a nonhydrolyzable guanosine triphosphate, guanosine 5'-o-(3-thiotriphosphate) (GTP-gamma-S), on secretion were studied by a patch-clamp technique in human basophils. When 10 microM Ca2+ were applied intracellularly, the granules dispersed rapidly, moved vigorously and fused to the cell membrane in 5 min. When the cells were exposed to 2 microM [Ca2+]i and 100 microM GTP-gamma-S, the granules dispersed gradually and granule fusion continued for 7-10 min. The plasma membrane conductance did not appreciably change with either 10 microM [Ca2+]i alone or 2 microM [Ca2+]i + 100 microM GTP-gamma-S. Intracellular application of Ca2+, 1-10 microM, caused a dose-dependent increase in cell membrane capacitance, which reflects granule membrane fusion, indicating exocytosis in a Ca2+ concentration-dependent manner. The addition of 100 microM GTP-gamma-S promoted an increase in the plasma membrane capacitance at concentrations from 0.1 to 2 microM [Ca2+]i and at 2 microM [Ca2+]i the increase was 4.4 times greater than that with 2 microM [Ca2+]i alone. These results indicate that certain G protein(s) promote Ca2+-dependent exocytosis in human basophils.
Basophils↗
Significance of elevated procollagen-III-peptide and transforming growth factor-beta levels of bronchoalveolar lavage fluids from idiopathic pulmonary fibrosis patients.
Although both procollagen III aminopeptide (P-III-P) and transforming growth factor-beta (TGF-beta) are reported to be present in lung tissue and/or elevated in bronchoalveolar lavage fluid (BALF) from idiopathic pulmonary fibrosis (IPF) patients, we have little knowledge concerning the clinical significance of elevated P-III-P and TGF-beta levels in BALF. Using a radioimmunoassay, we measured P-III-P and TGF-beta in BALF from 48 IPF patients (16F and 32M, 59 +/- 2 years, mean +/- S.E.) who received BAL in our clinic over the past 13 years before glucocorticosteroid treatment. Among them, we could detect a significant amount of P-III-P (2.2 +/- 1.0 U/ml; range 0.03 to 16.5 U/ml) in BALF in 18 of the patients (5F and 13M, 58 +/- 3 years) (group B). but not (0.03 U/ml or less) in the other 30 patients (11F and 19M, 59 +/- 2 years) (group A). Lymphocyte (%) and basophil (%) in BALF from group B was much larger than that from group A (33% vs. 8%, p < 0.01). Group B showed a longer duration of onset to BAL (36 months vs. 23 months, p < 0.05). TGF-beta levels were obtained using an ELISA system kit from the same BALF samples. TGF-beta was not detected in 10 patients (100 pg/ml or less) (3F and 7M, 59 +/- 4 years) (group I), while the remaining 38 patients showed a significant amount of TGF-beta (329 +/- 44 pg/ml, range 100 to 1,360 pg/ml). The latter patients were further divided into two groups; group II 100 to 300 pg/ml (10F and 14M, 56 +/- 3 years) and group III 350 or more (3F and 11M, 63 +/- 2 years). Group III showed significantly better values in PaO2, Aa-DO2, %VC and %DLco, and smaller percentage of basophils in BALF than did groups I and/or II, whereas survival after BAL in group III was significantly shorter than in group I (31 vs. 19 months, p < 0.05). There was no significant relationship between P-III-P and TGF-beta levels in BALF. These findings suggest that elevated P-III-P level is accompanied by an increase in lymphocyte population in BALF from IPF patients, resulting in a longer duration of the disease, while elevated TGF-beta level reflects alveolar inflammation at an earlier stage of the disease which induces a progression of the disease, resulting in a shorter survival in IPF patients.
Adult↗
Serum secretory leukoprotease inhibitor levels in chronic bronchitis and Sjögren's syndrome.
Serum secretory leukoprotease inhibitor (SLPI) is synthesized and secreted by serous cells in airway glands, and the serum level is speculated to reflect airway gland hyperplasia. To test this hypothesis, we measured the serum SLPI in 38 clinically stable patients with chronic bronchitis (3F and 35M; 58 +/- 2 years, mean +/- S.E.M.) (group CB), 24 patients with Sjögren's syndrome (24F; 52 +/- 3 years) (group SG), and compared it with 12 healthy control subjects (6F and 6M; 54 +/- 3 years) (group CN) using an enzyme-linked immunosorbent assay (ELISA). The serum SLPI from group CB (105 +/- 8 ng/ml) was significantly higher than that from group CN (60 +/- 2 ng/ml) and further, it significantly correlated with sputum volume per day. Although the mean value of serum SLPI from group SG (64 +/- 5 ng/ml) was not different from that from group CN, serum SLPI significantly correlated with the duration of respiratory symptoms (cough and/or sputum) in group SG. In conclusion, serum SPLI level reflects airway gland hyperplasia, suggesting that SLPI measurement is a possible laboratory method to estimate airway glandular hyperplasia.
Bronchitis↗
[Deodorant effects of champignon extract and repressive effects on production of indole and tryptamine in vivo].
Champignon extract has potent deodorant effects, and its repressive effects on bad smells generated by the decomposition of fishery products are especially marked. Utilizing the amount of ammonical nitrogen, indoleacetic acid and tryptamine generated as the standard criteria, the deodorant effects of champingnon were evaluated. In an in vitro test, chicken liver homogenate was decomposed by incubating at 37 degrees C and with the progress of its decomposition, ammonical nitrogen was generated. Champignon extract was shown to have the ability to repress the generation of ammonical nitrogen. For an in vivo test, an excessive amount of tryptophan was orally administered to domestic rabbits resalting in an increase in blood levels of indoleacetic acid and tryptamine. Champignon extract given concomitantly rapidly reduced blood levels of the two compounds to negligible levels.
Animals↗
Bradykinin regulation of airway submucosal gland secretion: role of bradykinin receptor subtype.
To clarify the role of bradykinin receptor subtypes, we examined the effect of bradykinin on feline tracheal and human airway submucosal gland secretion using an isolated gland preparation. Bradykinin induced a significant increase in [3H]glycoconjugate secretion in a dose-dependent manner from isolated glands, which was significantly inhibited by D-Arg-(Hyp3, Thi5,8, D-Phe7)-bradykinin (the B2-receptor antagonist), whereas Des-Arg9-(Leu8)-bradykinin (B1-receptor antagonist) or indomethacin did not significantly alter it. Nitric oxide synthase inhibitor (nitro-L-arginine methyl ester) caused a significant inhibition of bradykinin-induced glycoconjugate secretion, which was reversed by the addition of L-arginine. Bradykinin evoked bidirectional current responses, and an initial inward current (Cl- current) was followed by an outward current (K+ current) of the acinar cells in a whole cell configuration by patch-clamp technique. Bradykinin induced an immediate increase in intracellular calcium concentration ([Ca2+]i) of the acinar cells followed by a prolonged plateau, and Ca2+ removal resulted in an initial increase alone. [Ca2+]i rise was significantly inhibited by the B2-receptor antagonist, whereas the B1-receptor antagonist did not significantly alter it. These findings suggest that B2-receptor stimulation and the resultant [Ca2+]i rise induced both mucus glycoprotein and electrolyte secretions, involving NO formation in airway submucosal gland cells.
Animals↗
Eosinophil adhesion to cultured airway epithelial cells from guinea pig lungs.
We examined the effects of histamine, tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), indomethacin and dexamethasone on the adherence of eosinophils to airway epithelial cells. Epithelial cells were isolated from guinea pig trachea through enzymatic digestion, and cultured until they showed confluence. Eosinophils were taken by peritoneal lavage from guinea pigs sensitized with horse serum and purified. The adhesion of eosinophils to cultured epithelial cells was examined using 51Cr. The percentage adhesion was obtained by dividing counts per minute of lysed eosinophils adhered to epithelial cells by suspended eosinophils. Histamine significantly increased the adhesion of eosinophils to epithelial cells, while TNF alpha or IFN gamma did not significantly alter the adhesion. Indomethacin significantly inhibited the adhesion of eosinophils to epithelial cells in both nontreated and histamine-induced conditions. Dexamethasone also reduced adhesion, although it did not reach statistical significance. These findings indicate that histamine induced eosinophil adherence to airway epithelial cells, suggesting a role of endogenous prostaglandins in adherence.
Animals↗
Morphologic aspects of airways of patients with pulmonary emphysema followed by bronchial asthma-like attack.
Morphometric analysis of airways was performed in autopsied lungs from four patients with pulmonary emphysema (PE) followed by bronchial-asthma (BA)-like attacks (Group PE+BA) (four males, 72 +/- 9 yr). The results were compared with those from five pulmonary emphysema patients (Group PE) (five males, age 71 +/- 4 hr), three patients with bronchial asthma (Group BA) (one female and two males, age 65 +/- 7 yr), and four control subjects with no pulmonary diseases (Group Cont) (one female, three males, age 64 +/- 4 yr). The proportion of gland area to bronchial wall (gland%), ratio of goblet-cell occupancy to the total epithelial layer (goblet%), thickness of the basement membrane, amount of intraluminal mucus (mucus occupying ratio; MOR%), and number of various cell types per square millimeter in airway walls in a section 4 microns thick were measured in central (3 to 8 mm diameter) and peripheral airways (2 mm or less diameter). Gland% for the PE+BA group was significantly greater than that for the Cont group, whereas it did not differ significantly from that of the PE or BA groups. Goblet% and thickness of the basement membrane in central and/or peripheral airways in Group PE+BA were significantly greater than those in Group Cont, whereas those in Group PE were similar to those in Group Cont. Although not statistically significant, MOR% in central and peripheral airways from Group PE+BA showed a similar value to that in Group BA, whereas MOR% in Group PE was the same as that in Group Cont. The eosinophil number in peripheral airways walls in Group PE+BA showed a similar value to that in Group BA, which was significantly greater than in Group Cont. Other cells (macrophages, lymphocytes, and neutrophils) showed similar values among Groups PE+BA, PE, and BA. The number of eosinophils in central and/or peripheral airways correlated significantly with both goblet% and BMT, whereas other cells did not. These findings indicate that the airways of Group PE+BA are morphologically similar to those of Group BA, suggesting a combination of pulmonary emphysema with bronchial asthma.
Aged↗
Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma.
The aim of this study was to elucidate the mechanism of the formation of the widespread mucous-plugging observed in autopsied lungs from patients with bronchial asthma. We performed morphometric analysis of airways of autopsied lungs from eight patients with bronchial asthma (Group BA), and compared it with those of six chronic bronchitics (Group CB) and four control patients (Control). The following parameters were measured in paraffin sections: volume proportion of bronchial glands to bronchial wall (Gland%); goblet cell granules to total epithelial layer (Goblet %); intraluminal mucus expressed as the mucus occupying ratio (MOR); volume ratio of intraluminal mucus continuous with goblet cells to total intraluminal mucus (Vc/Vtol %); and surface ratio of the contact surface of intraluminal mucus continuous with goblet cells to the total luminal surface (Sc/Stot %). Gland%, Goblet %, and MOR or inflammatory cell numbers in the airway walls both from Group BA and CB were larger than those from the Control group. However, no significant differences were observed between Group BA and CB in Gland%, Goblet %, MOR or inflammatory cell numbers, except for the eosinophil number: i.e. 23 +/- 3, 22 +/- 3 and 6 +/- 2% in Gland%; 22 +/- 9, 5 +/- 4 and 2 +/- 2% in Goblet%; 10 +/- 3, 18 +/- 3 and 0.3 +/- 0.5% in MOR; 199 +/- 68, 10 +/- 3 and 2 +/- 2 cells. mm-2 in eosinophil number of the peripheral airways from Groups BA, CB and Control, respectively. In contrast, marked and significant increases were observed both in Vc/Vtot% and Sc/Stot% in Group BA compared to Groups CB and Control both in central and peripheral airways: i.e. Vc/Vtot% in the peripheral airways was 53 +/- 5, 4 +/- 3 and 0.8 +/- 0.8% from Groups BA, CB and Control, respectively (BA vs CB or BA vs Control, p < 0.01 each). These findings suggest that the continuity of goblet cells and intraluminal mucus or lack of full release of mucus, from goblet cells, is peculiar to asthmatic airways, and may contribute to the formation of mucous-plugs.
Age Factors↗
Surfactant apoprotein-A concentration in airway secretions for the detection of pulmonary oedema.
Patients with cardiogenic pulmonary oedema expectorate foamy sputum containing surfactant, which might be expected to include surfactant apoprotein A (SP-A). SP-A is specific for lung surfactant. We have measured the SP-A concentration in airway secretions to determine whether it is useful in distinguishing pulmonary oedema from other disorders. Samples of sputum and of aspirated airway secretion were obtained from 11 patients with cardiogenic pulmonary oedema, seven patients with clinically stable congestive heart failure, five patients with adult respiratory distress syndrome (ARDS) and 20 control patients (10 intubated) with other respiratory diseases. The samples were used for the measurement of SP-A concentration by a two-site simultaneous immunoassay with monoclonal antibodies against SP-A. SP-A concentrations, measured in samples of sputum and aspirated secretions, depended on the diagnosis of the patients from which they had come. In descending order these samples came from patients with: cardiogenic pulmonary oedema (1324 +/- 197 micrograms.mL-1; n = 33); ARDS (311 +/- 47 micrograms.mL-1; n = 23); clinically stable congestive heart failure (78 +/- 10 micrograms.mL-1; n = 21); and control conditions (3.0 +/- 0.6 micrograms.mL-1; n = 30). Concentrations from disease samples did not overlap with controls. In samples from patients with cardiogenic pulmonary oedema, the SP-A concentration correlated with mean pulmonary capillary wedge pressure (PCWP) (p < 0.001; n = 39). These findings indicate that the measurement of the surfactant apoprotein A concentration in airway secretions may be useful for the detection of pulmonary oedema.
Aged↗
Diffuse alveolar hemorrhage caused by lung metastasis of ovarian angiosarcoma.
A case of diffuse alveolar hemorrhage due to lung metastasis of ovarian angiosarcoma is described. A 33-year-old woman developed persistent cough and recurrent hemoptyses with resultant anemia. Chest radiograph and computerized tomography (CT) showed diffuse and patchy shadows in both lungs with nodules in the central area of the shadows. In spite of intensive care and administration of large amounts of glucocorticoids, she died of respiratory failure 5 months after the onset of her symptoms. Histological examination by both thoracoscopic biopsy and autopsy revealed diffuse tumor emboli of disseminated angiosarcoma which originated from the right ovary and diffuse alveolar hemorrhage which appeared to be caused by the tumor emboli with resultant invasion and destruction to vascular walls. This is the first description of diffuse alveolar hemorrhage probably caused by tumor emboli of metastatic angiosarcoma.
Adult↗
Isoproterenol augments ATP-evoked Cl- secretion across canine tracheal epithelium.
Using an Ussing chamber, both the posterior epithelial membrane and cultured epithelial cell monolayers from canine trachea were used for measurements of potential difference (PD) and short circuit current (SCC). Conductance (G) was calculated as the ratio SCC/PD. Adenosine (10(-5) to 10(-3) M) failed to produce any significant increases in PD and SCC. ATP (10(-6) to 10(-4) M) produced a significant transient increase in SCC in a dose-dependent fashion, reaching a peak value within 3 min after stimulation. Isoproterenol (ISOP) at 10(-8) M itself did not significantly alter the SCC value. In both the epithelial membrane and cultured epithelial cells treated with amiloride, however, pretreatment with 10(-8) M ISOP significantly augmented the ATP-induced SCC rise, whereas G did not significantly change. These findings indicate that beta-adrenergic stimulation augments Cl- secretion induced by P2-receptor stimulation in airway epithelial cells.
Action Potentials↗