Eosinophilic bronchitis is an important cause of chronic cough.
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Asthma↗
Biomedical subjects
M Fujimura
Publications and source records attributed to M Fujimura.
Effect of losartan, a type 1 angiotensin II receptor antagonist, on bronchial hyperresponsiveness to methacholine in patients with bronchial asthma.
It is unclear whether angiotensin II receptors are involved in bronchial hyperresponsiveness in asthmatic patients. We examined the effect of losartan, a specific angiotensin II type 1 (AT1) receptor antagonist, on bronchial responsiveness to inhaled methacholine in eight patients with stable asthma. Bronchial responsiveness to methacholine, assessed as the concentration of methacholine producing a 20% fall in FEV(1) (PC(20)-FEV(1)) and a 35% fall in standardized partial expiratory flow at 40% of FVC (PC(35)-PEF(40)), was measured on two occasions 2 wk apart. Losartan (50 mg once a day) or a placebo was orally administered for 1 wk before methacholine provocation test in a double-blind, randomized, crossover fashion. Although the PC(20)-FEV(1) values after placebo (2.037 [geometric standard error of the mean, GSEM = 0.210] mg/ml) and losartan (2.098 [GSEM, 0.239] mg/ml) were identical (p = 0.840), the geometric mean PC(35)-PEF(40) values significantly (p = 0.034) increased from 0.258 (GSEM, 0.156) mg/ml with placebo to 0.456 (GSEM, 0.186) mg/ml with losartan. We conclude that AT1 receptors are involved in bronchial hyperresponsiveness in asthmatic patients. This is the first report demonstrating the involvement of AT1 receptors in bronchial asthma.
Adult↗
Type 1 angiotensin II receptor antagonism reduces antigen-induced airway reactions.
Although the renin-angiotensin system is activated in patients with asthma during severe acute attacks and angiotensin II has been shown to cause bronchoconstriction in patients with asthma, the role of angiotensin II in patients with asthma is unclear. We investigated the effects of two specific antagonists at type 1 and type 2 angiotensin II receptors, candesartan cilexetil (TCV-116) and PD123319, on antigen-induced airway reactions in guinea pigs. Sixty minutes after intraperitoneal administration of candesartan cilexetil (0.1, 1.0, or 10 mg/kg) or PD123319 (30 mg/kg), animals received an antigen challenge. Airway responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)). Differential cell counts in bronchoalveolar lavage fluids (BALF) were measured 24 h after antigen challenge. Candesartan cilexetil did not inhibit antigen-induced bronchoconstriction in sensitized guinea pigs or alter PC(200) in nonsensitized guinea pigs. Antigen inhalation significantly increased bronchoconstrictor responses to methacholine and increased airway accumulation of eosinophils; both responses showed dose-dependent prevention by candesartan but not by PD123319. These results indicate that endogenous angiotensin II promotes antigen-induced airway hyperresponsiveness and eosinophil accumulation by acting at type 1 receptors.
Angiotensin Receptor Antagonists↗
A case of cigarette smoking-induced acute eosinophilic pneumonia showing tolerance.
It has been proposed that acute eosinophilic pneumonia (AEP), which is characterized by the absence of recurrence, is associated with cigarette smoking (CS), because Japanese patients with AEP are young and have a high incidence of short-term smoking history. However, there has been no direct evidence that CS causes AEP. We hypothesized that tolerance might develop against repeated resumption of smoking cigarettes in CS-induced AEP cases. In this connection, we challenged a patient with CS-induced AEP with repeated resumption of CS, and it was demonstrated that CS induced AEP in conjunction with tolerance to repeated resumption of smoking.
Acute Disease↗
Acute eosinophilic pneumonia caused by cigarette smoking.
It has been suggested that acute eosinophilic pneumonia (AEP) is associated with cigarette smoking because in Japan, the patients with AEP are young and have a high incidence of short-term smoking history. However, there has been no direct evidence to support that cigarette smoke causes AEP. Herein is reported the first case showing the direct evidence and a long-term clinical course of cigarette smoking-induced AEP, in which tolerance to repeated resumption of smoking cigarettes might have occurred. We should pay attention to the history of cigarette smoking in seeing patients with AEP, especially in young patients.
Adult↗
[Multiple Aspergillus brain abscesses complicated by bronchial asthma].
A 35-year-old man was hospitalized for the treatment of severe asthma attack. His condition improved with intensive steroid chemotherapy under artificial ventilation. On the 12th hospital day, he was taken off respirator support but lost consciousness afterward. Computed tomography of the brain disclosed multiple hypodense lesions with bleeding. T1-weighted magnetic resonance imaging disclosed low-intensity lesions containing high-intensity areas. T2-weighted images showed heterogeneous high-intensity lesions. The autopsy specimen demonstrated multiple brain abscesses. Histologic examination revealed branching fungal hyphae in abscess walls and also extending through arterial walls with emboli. These findings yielded a diagnosis of multiple Aspergillus infarct abscesses of the brain.
Adult↗
Effect of thromboxane synthase inhibitor, CS-518, on propranolol-induced bronchoconstriction in guinea pigs.
Beta-adrenoreceptor antagonists, such as propranolol, can provoke severe bronchoconstriction in asthmatic subjects. Recently we developed an animal model of propranolol-induced bronchoconstriction and investigated the involvement of chemical mediators in this reaction. The purpose of this study was to elucidate the role of thromboxane A2 in the development of propranolol-induced bronchoconstriction after allergic bronchoconstriction. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride and were then artificially ventilated. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. A potent and selective thromboxane A2 synthase inhibitor, CS-518, in doses of 0.01, 0.1 and 1 mg/kg and vehicle were administered intravenously 15 min after the antigen challenge. Another study was performed in naive guinea pigs; ascending doses of methacholine (12.5, 25, 50, 100 and 200 microg/ml) were inhaled for 20 sec at 5-min intervals, 10 min after intravenous administration of CS-518. Propranolol inhaled 20 min after the antigen challenge caused bronchoconstriction in sensitized guinea pigs. CS-518 administered 15 min after the antigen challenge significantly inhibited propranolol-induced bronchoconstriction in a dose-dependent manner, while CS-518 did not influence the dose-dependent response to inhaled methacholine in naive guinea pigs. We conclude that thromboxane A2 contributes to the development of propranolol-induced bronchoconstriction following allergic reaction in our guinea pig model.
Adrenergic beta-Antagonists↗
[A case of adenocarcinoma complicated with massive leukocytosis and hypercalcemia].
A 66-year-old man was admitted to our hospital complaining of non-productive cough and low-grade fever. Chest X-ray examination revealed a mass shadow in the right hilum. Transbronchial lung biopsy of the tumor mass yielded a diagnosis of adenocarcinoma. Despite repeated chemotherapy using CDDP and VDS, metastasis to the right adrenal gland and right femur occurred, and was accompanied by hypercalcemia and hypophosphatemia. Serological study revealed elevated levels of PTH-rP and G-CSF. Six months after adenocarcinoma was diagnosed, multiple skin metastases of the cancer were observed. Immunohistochemical staining for PTH-rP and G-CSF indicated that production of cytokines had caused a paraneoplastic syndrome including hypercalcemia and leukocytosis. It appeared that the elevation of G-CSF was induced by IL-6 produced from PTH-rP in cancer tissue. Documentation of similar cases is required.
Adenocarcinoma↗
Comparison between tidal breathing and dosimeter methods in assessing cough receptor sensitivity to capsaicin.
OBJECTIVE: Dosimeter method and tidal breathing method have been used to assess cough sensitivity to inhaled capsaicin, a C-fibre ending stimulator. The aim of the present study was to evaluate the repeatability of and the agreement between the two methods. METHODOLOGY: Cough threshold, the lowest concentration of capsaicin causing five or more coughs, was measured twice 1-3 weeks apart by each method in 26 normal subjects. Increasing concentrations of capsaicin were inhaled by a single breath in the dosimeter method or by 15 s tidal breathing in the tidal breathing method in 1 min intervals. RESULTS: Coefficients of repeatability of the cough threshold measurement were 1.89 and 2.71 doubling concentration in the tidal breathing method and the dosimeter method, respectively, suggesting good repeatability in the cough threshold measurement by both methods. The cough threshold was significantly (P < 0.0001) greater by 1.75 doubling concentration on the dosimeter method than the tidal breathing method. The coefficient of agreement between the two methods was 2.53 doubling concentration. Five subjects complained of burning sensation in the throat in the dosimeter method but no patient complained about the tidal breathing method (P < 0.05). CONCLUSIONS: Although the agreement between the two methods was considered to be good, higher concentrations of capsaicin solution were required to determine the cough threshold in the dosimeter method, resulting in an unpleasant sensation in the throat.
Administration, Inhalation↗
Neuroprotective effects of an antioxidant in cortical cerebral ischemia: prevention of early reduction of the apurinic/apyrimidinic endonuclease DNA repair enzyme.
We examined the effects of the free radical scavenger, 21-aminosteroid, on apurinic/apyrimidinic endonuclease (APE/Ref-1) protein expression and subsequent infarction volume after photothrombotic cortical cerebral ischemia in mice. Immunohistochemistry and Western blot analysis showed a significant reduction in APE/Ref-1 expression 6 and 24 h after ischemia in untreated animals, whereas in drug-treated animals the reduction was much less at the same time points. The administration of 21-aminosteroid significantly decreased subsequent infarction volume 3 days after ischemia. These data suggest that 21-aminosteroid prevents the early decrease of APE/Ref-1 expression, thereby reducing cortical infarction after photothrombotic cerebral ischemia.
Animals↗
Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia.
Release of cytochrome c from mitochondria to the cytosol is a critical step in apoptotic cell death after focal cerebral ischemia. The relationship among cytochrome c release, selective vulnerability, and delayed death of hippocampal CA1 neurons after transient global ischemia was examined. Global ischemia was induced by 10 min of bilateral common carotid artery occlusion and hypotension in rats. Cytosolic expression of cytochrome c was evaluated by immunohistochemistry and Western blotting. Apoptosis after global ischemia was also characterized by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) staining and DNA gel electrophoresis. Immunohistochemistry showed cytosolic cytochrome c-positive cells exclusively in the CA1 subregion of the hippocampus as early as 2 hr after ischemia. Double fluorescent immunostaining confirmed that CA1 neurons and a small number of astrocytes expressed cytochrome c. Western blot analysis revealed a band (15 kDa) of cytochrome c in the cytosolic fraction and a corresponding decrease in the mitochondrial fraction. A significant number of TUNEL-positive cells appeared only in the CA1 pyramidal cell layer of the hippocampus, and DNA gel electrophoresis showed a significant amount of DNA fragmentation 3-5 d after ischemia. Our data provide the first evidence that cytochrome c was released to the cytosol from mitochondria in CA1 neurons after global ischemia and that the release preceded DNA fragmentation. These findings suggest cytochrome c involvement in the delayed death of hippocampal CA1 neurons in rats after transient global ischemia.
Animals↗
Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion.
Blood-brain barrier (BBB) disruption is thought to play a critical role in the pathophysiology of ischemia/reperfusion. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that can degrade all the components of the extracellular matrix when they are activated. Gelatinase A (MMP-2) and gelatinase B (MMP-9) are able to digest the endothelial basal lamina, which plays a major role in maintaining BBB impermeability. The present study examined the expression and activation of gelatinases before and after transient focal cerebral ischemia (FCI) in mice. Adult male CD1 mice were subjected to 60 min FCI and reperfusion. Zymography was performed from 1 to 23 h after reperfusion using the protein extraction method with detergent extraction and affinity-support purification. MMP-9 expression was also examined by both immunohistochemistry and Western blot analysis, and tissue inhibitors to metalloproteinase-1 was measured by reverse zymography. The BBB opening was evaluated by the Evans blue extravasation method. The 88-kDa activated MMP-9 was absent from the control specimens, while it appeared 3 h after transient ischemia by zymography. At this time point, the BBB permeability alteration was detected in the ischemic brain. Both pro-MMP-9 (96 kDa) and pro-MMP-2 (72 kDa) were seen in the control specimens, and were markedly increased after FCI. A significant induction of MMP-9 was confirmed by both immunohistochemistry and Western blot analysis. The early appearance of activated MMP-9, associated with evidence of BBB permeability alteration, suggests that activation of MMP-9 contributes to the early formation of vasogenic edema after transient FCI.
Animals↗
Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts.
Because few previous studies have shown the immunohistochemical localization of tryptophan 5-hydroxylase (TPH) in the gastrointestinal tract, we developed a specific antibody against TPH purified from mouse mastocytoma P-815 and stained human and rat gastrointestinal tracts. The specificity of the antibody was examined by Western blotting and by immunohistochemistry in brain sections. Human ileum and colon specimens, rat stomach, duodenum, jejunum, ileum and colon specimens, with and without colchicine treatment were prepared for immunohistochemistry. Immunoelectron microscopic double staining of TPH and serotonin/chromogranin A and immunofluorescence double staining of TPH and serotonin were performed to identify the cell types. Epithelial enterochromaffin (EC) cells, mast cells in the lamina propria and submucosa, and varicose fibers in the submucosa and muscle layer showed positive immunoreactivity in all segments examined from human and normal rat specimens. In colchicine-treated rat specimens, nerve cell bodies in the myenteric plexus were stained. Because the antibody does not cross react with tyrosine hydroxylase as defined in Western blotting or brain sections, these positive structures may contain TPH. The present results show evidence that EC cells, mast cells, and nerve cell bodies and fibers in the gastrointestinal tracts of both the human and the rat contain TPH and therefore may have the ability to synthesize serotonin from tryptophan.
Animals↗
Release of mitochondrial cytochrome c and DNA fragmentation after cold injury-induced brain trauma in mice: possible role in neuronal apoptosis.
Recent studies have shown that release of mitochondrial cytochrome c is a critical step in the apoptosis process. In this study, we examined the subcellular distribution of the cytochrome c protein after cold injury (CI), in which apoptosis is assumed to participate. Western blotting and immunohistochemistry showed cytosolic cytochrome c as early as 1 h after CI, and correspondingly, there was a reduction in mitochondrial cytochrome c after injury. Neuronal distribution of cytosolic cytochrome c was shown by double staining with a neuronal nuclear marker by immunohistochemistry. A significant amount of DNA laddering was detected 4 h after CI, and increased in a time-dependent manner. These data suggest that early cytochrome c release from mitochondria may contribute to apoptosis induction after traumatic brain injury.
Animals↗
Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice.
Recent studies have shown that release of mitochondrial cytochrome c is a critical step in the apoptosis process. We have reported that cytosolic redistribution of cytochrome c in vivo occurred after transient focal cerebral ischemia (FCI) in rats and preceded the peak of DNA fragmentation. Although the involvement of reactive oxygen species in the cytosolic redistribution of cytochrome c in vitro has been suggested, the detailed mechanism by which cytochrome c release is mediated in vivo has not yet been established. Also, the role of mitochondrial oxidative stress in cytochrome c release is unknown. These issues can be addressed using knock-out mutants that are deficient in the level of the mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD). In this study we examined the subcellular distribution of the cytochrome c protein in both wild-type mice and heterozygous knock-outs of the Mn-SOD gene (Sod2 -/+) after permanent FCI, in which apoptosis is assumed to participate. Cytosolic cytochrome c was detected as early as 1 hr after ischemia, and correspondingly, mitochondrial cytochrome c showed a significant reduction 2 hr after ischemia (p < 0.01). Cytosolic accumulation of cytochrome c was significantly higher in Sod2 -/+ mice compared with wild-type animals (p < 0.05). N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone (z-VAD.FMK), a nonselective caspase inhibitor, did not affect cytochrome c release after ischemia. A significant amount of DNA laddering was detected 24 hr after ischemia and increased in Sod2 -/+ mice. These data suggest that Mn-SOD blocks cytosolic release of cytochrome c and could thereby reduce apoptosis after permanent FCI.
Amino Acid Chloromethyl Ketones↗
CD38 disruption impairs glucose-induced increases in cyclic ADP-ribose, [Ca2+]i, and insulin secretion.
Increases in [Ca2+]i in pancreatic beta cells, resulting from Ca2+ mobilization from intracellular stores as well as Ca2+ influx from extracellular sources, are important in insulin secretion by glucose. Cyclic ADP-ribose (cADPR), accumulated in beta cells by glucose stimulation, has been postulated to serve as a second messenger for intracellular Ca2+ mobilization for insulin secretion, and CD38 is thought to be involved in the cADPR accumulation (Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054). Here we created "knockout" (CD38(-/-)) mice by homologous recombination. CD38(-/-) mice developed normally but showed no increase in their glucose-induced production of cADPR in pancreatic islets. The glucose-induced [Ca2+]i rise and insulin secretion were both severely impaired in CD38(-/-) islets, whereas CD38(-/-) islets responded normally to the extracellular Ca2+ influx stimulants tolbutamide and KCl. CD38(-/-) mice showed impaired glucose tolerance, and the serum insulin level was lower than control, and these impaired phenotypes were rescued by beta cell-specific expression of CD38 cDNA. These results indicate that CD38 plays an essential role in intracellular Ca2+ mobilization by cADPR for insulin secretion.
ADP-ribosyl Cyclase↗
Inflammatory malignant fibrous histiocytoma of the ovary producing interleukin-6: A case report.
OBJECTIVE: Inflammatory malignant fibrous histiocytoma (IMFH) is composed of fibroblastic and histiocytic elements with a marked inflammatory cell infiltrate. The authors examined the case of a 43-year-old woman with IMFH of the ovary. METHODS: The serum interleukin-6 (IL-6) levels were examined and immunohistochemical analysis of the tumor was performed using monoclonal antibodies against lysozyme, alpha 1-antitripsin, vimentin, and IL-6. RESULTS: The patient had marked general inflammatory reactions of fever (38.0 degrees C), leukocytosis with 78.3% neutrophils, elevated CRP (23.5 mg/dl), and accelerated ESR (166 mm/h). The serum IL-6 concentration was 499 pg/ml. The right ovary was occupied by the solid tumor, composed of both fibrous and histiocytic elements with a marked inflammatory cell infiltrate. These inflammatory reactions disappeared after surgical resection and recurred when the tumor reappeared. The immunohistochemical staining of lysozyme, alpha 1-antitrypsin, vimentin, and IL-6 was localized to the malignant cells, suggesting their histiocytic origin. CONCLUSIONS: This is the first case of IMFH of the ovary producing IL-6. Expression of IL-6 in the IMFH may account for both the local and the systemic inflammatory effects of tumors with these morphological features.
Adult↗
Changes in number of serotonin-containing cells and serotonin levels in the intestinal mucosa of rats with colitis induced by dextran sodium sulfate.
The role of serotonin in the pathogenesis of inflammatory bowel disease has not been fully studied. We examined the changes in the serotonin level and the density of serotonin-containing enterochromaffin (EC) and mast cells in the intestinal mucosa of dextran sodium sulfate (DSS)-induced colitis in rats. Rats were treated with 1.5% DSS for 1 month. Serotonin levels were biochemically measured and the density of epithelial EC cells and mucosal mast cells was quantified by serotonin immunohistochemistry. DSS caused malnutrition due to chronic diarrhea. Infiltrated inflammatory cells were microscopically observed in the colonic wall with intact epithelium. The serotonin content in the mucosa/submucosa tissue was increased in the proximal and distal colon in DSS-treated rats, compared to that in control rats. The density of EC cells in the epithelium also increased in the proximal and distal colon in DSS-treated rats. In contrast, the density of mast cells in the lamina propria dramatically increased in the distal, but not in the proximal colon in DSS-treated rats. This discrepancy implies the serotonin released from EC cells and from mast cells may play different roles in the pathogenesis of DSS-induced colitis.
Animals↗