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S Tsujimura,
H Nakamura,
I Sato,
K Tsuduki,
T Shirahata,
S Yoshida,
S Chubachi,
M Miyazaki,
H Aoki, M Nakamura,
S Takahashi,
T Nakajima,
N Minematsu,
H Tateno,
K Asano
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ABSTRACT: Spirometry is practically the only tool to evaluate pulmonary functions. Other automatic systems comparable to spirometry are expected. A fiber-grating (FG) vision sensor is a non-contact respiratory monitoring system to detect changes in volumes by measuring the movement of laser spots on the body surface. We examined the contributions of the FG sensor to evaluating pulmonary functions. The FG sensor showed a linear correlation with spirometry in tidal volumes (TV) obtained from five controls (R = 0.98, P < 0.0001). We also showed agreement of TV between the two devices using Bland-Altman analysis. TV measured by the FG sensor were reproducible and applicable to distinct subjects. To detect airway obstruction, we performed forced expiration in controls (n = 16) and chronic obstructive pulmonary disease (COPD) patients (n = 18) with the FG sensor and spirometry. Forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity in COPD patients were lower than those in controls by the FG sensor. In addition, prolonged expiration in natural breathing by the FG sensor was related to airflow limitation by spirometry. The FG sensor was helpful to measure volume changes and to evaluate pulmonary functions in controls and patients with COPD. Its upcoming clinical applications are promising for simplicity and feasibility.
Physiological Measurement 10/2011; 32(10):1701-13. · 1.68 Impact Factor
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ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is a disease in which the airways and tiny air sacs (alveoli) inside the lungs are partially obstructed or destroyed. The result is labored breathing. There are varying degrees of this illness, and different names for them, but it all comes back to damaged airways and air sacs. Emphysema is what occurs as more and more of the walls between air sacs get destroyed. Instead of having lots of little sacs, the sacs break up and what is left are larger sacs. These bigger sacs have less surface area for the exchange of oxygen and carbon dioxide than the tiny ones. Poor exchange of oxygen and carbon dioxide causes shortness of breath. At present, diagnosis of emphysema is done by using spirometry, X-rays, spiral chest CT-scan, bronchoscopy, pulse oximetry and arterial blood gas sampling. This paper proposes a computer-aided diagnostic system for emphysema that segments the lungs into multiple square regions and classifies the segmented regions into 5 classes of severity. The proposed algorithm is divided into three stages: 1. digital image processing, 2. feature extraction, and 3. classification using neural network (NN). The aim of this paper is to analyze the severity of the lungs region by region along with NN classification.
SICE, 2007 Annual Conference; 10/2007
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ABSTRACT: The whole gene deletion CYP2A6*4, the defect of the main nicotine oxidase, contributes to limiting lifelong and daily cigarette consumption. However, the effects on smoking habits of CYP2A6*7 and *9, two major functional polymorphisms common in Asian populations, have not been reported. The present study examined the relationship between polymorphisms *4, *7 and *9 with the smoking habits of 200 Japanese smokers who visited the Keio University Hospital (Tokyo, Japan). The allele frequencies of *1 (wild type), *4, *7 and *9 were 52, 17, 11 and 20%, respectively. When the three polymorphisms were considered simultaneously, the percentages of homozygous wild type, heterozygote, and homozygous mutants and compound heterozygotes were 26.0, 52.5 and 21.5%, respectively. Homozygous mutants and compound heterozygotes (n = 43) smoked fewer cigarettes daily than heterozygotes (n = 105) and homozygous wild-type individuals (n = 52). Smokers with *7/*7, *9/*9 or *7/*9 had lower daily cigarette consumption than smokers with *1/*1. In conclusion, polymorphisms *4, *7 and *9 of CYP2A6 were detected in approximately three out of four Japanese smokers, and their daily cigarette consumption was genetically modulated by these functional polymorphisms.
European Respiratory Journal 03/2006; 27(2):289-92. · 5.89 Impact Factor
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ABSTRACT: Our understanding of asthma severity was advanced by the identification of biomarkers which account for differences in lung function impairment. We tried to examine the effects of corticosteroid treatment on known correlates of asthma severity including peripheral eosinophil counts, total IgE, IL-5, and eotaxin Levels in plasma. We compared these biomarkers among groups of stable asthmatics categorized by the dose of corticosteroid (N: steroid-free, n = 25; L: low-dose inhaled, n = 27; MH: medium or high-dose inhaled, n= 19; O: inhaled plus oral, n= 8). Next we compared these markers and peak expiratory flow rate (PEFR) in unstable asthmatics before and after treatment with steroids (n = 22). Eotaxin levels in the O group were higher than those in the N and MH groups (P < 0.05). Logistic regression analysis demonstrated that plasma eotaxin level was correlated with the severity of asthma defined by treatment intensity (P = 0.01) and % FEV1 (P = 0.04) while the other markers were not. Eotaxin levels did not change after steroid treatment in unstable patients, whereas eosinophil counts decreased in parallel with PEFR. Among biomarkers of asthma severity studied, plasma eotaxin level was not significantly affected by corticosteroid treatment, and was associated with the severity even in the presence of steroid therapy.
Respiratory Medicine 08/2004; 98(8):782-90. · 2.47 Impact Factor
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ABSTRACT: In comparison with neutrophil-mediated lung diseases, such as acute respiratory distress syndrome, the involvement of IL-8 in lymphocyte-mediated lung diseases has not been fully investigated. Several reports have shown a slight increase in bronchoalveolar lavage fluid (BALF) IL-8 in patients with hypersensitivity pneumonitis (HP) and sarcoidosis (SAR), but the source of the IL-8 has not been clarified. In the present study, the in vivo production of IL-8 by alveolar macrophages (AMs) is examined in these patients by analyzing the cell-associated IL-8, using the flow cytometric method adopted previously. The IL-8 levels in the epithelial lining fluid (ELF) were also assessed. Initially, slight, but significant, increased levels of ELF IL-8 in HP and SAR were confirmed. Using flow cytometric analysis, a significant increase was found in the cell-associated IL-8 of the freshly isolated AMs in HP, but not in SAR, indicating in vivo production of IL-8 by AMs in HP. The cell-associated IL-8 of the AMs cultured with or without lipopolysaccharide was also analyzed. However, in contrast to previous findings in patients with idiopathic pulmonary fibrosis, no differences were found between SAR and HP patients and control subjects. Based on these findings, it is speculated that ELF IL-8 levels are slightly increased in HP and SAR, and they may contribute to the accumulation of neutrophils and possibly lymphocytes. However, the source of IL-8 may be different and AMs are the candidate source of IL-8 in HP, but not in SAR. The flow cytometric method may be useful in assessing cytokines production by AMs.
Scandinavian Journal of Clinical and Laboratory Investigation 02/2004; 64(3):237-43. · 1.38 Impact Factor
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ABSTRACT: Nicotine is responsible for smoking dependence and is mainly metabolised by CYP2A6. Several types of genetic polymorphism of CYP2A6 have been reported, but their relation to smoking habit and chronic obstructive pulmonary disease (COPD) phenotypes has not been fully clarified.
203 current or ex-smokers (lifelong cigarette consumption (CC) >/=10 pack years) with subclinical and established COPD phenotypes were clinically evaluated and pulmonary function tests and a chest CT scan were performed (smoker group). The non-smoker group consisted of 123 healthy volunteers. CYP2A6 genotypes were determined in both groups.
The percentage of subjects with a CYP2A6del allele (genotype D) was lower in heavy smokers (20.5%, n=88, CC >/=60 pack years) than in light smokers (37.4%, n=115, CC 10-59 pack years, chi(2)=6.8, p=0.01) or non-smokers (36.1%, n=122, chi(2)=6.0, p=0.01); lower in ex-smokers (20.7%, n=111) than in current smokers (41.3%, n=92, chi(2)=10.1, p<0.01); and lower in smokers with a high LAA (low attenuation area) score on the chest CT scan (18.4%, n=76, LAA >/=8.0) than in those with a low LAA score (37.0%, n=127, LAA <8.0, chi(2)=7.8, p<0.01).
Subjects with the CYP2A6del allele tend not to be heavy habitual smokers but can be light habitual smokers. The CYP2A6del polymorphism may inhibit smokers from giving up smoking, but appears to function as a protective factor against the development of pulmonary emphysema independent of smoking habit.
Thorax 07/2003; 58(7):623-8. · 6.84 Impact Factor
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ABSTRACT: Protease-antiprotease imbalance due to genetic variation may be responsible for the development of pulmonary emphysema induced by smoking. Since matrix metalloproteinases (MMPs) have recently been suggested to play important roles in the pathogenesis of pulmonary emphysema, the association between the functional polymorphism of MMP-9 (-1562C/T) and the development of pulmonary emphysema was examined in 110 smokers and 94 nonsmokers in Japan. The T allele frequency was higher in subjects with distinct emphysema on chest CT-scans (n = 45) than in those without it (n = 65) (0.244 vs 0.123, P = 0.02). Logistic regression analysis demonstrated that the T allele is a risk factor for smoking-induced emphysema (odds ratio = 2.69, P = 0.02). DL(CO)/VA was lower (P = 0.02) and emphysematous changes were more conspicuous (P = 0.03) in subjects with C/T or T/T (n = 35) than in those with C/C (n = 75). These results suggest that the polymorphism of MMP-9 acts as a genetic factor for the development of smoking-induced pulmonary emphysema.
Biochemical and Biophysical Research Communications 12/2001; 289(1):116-9. · 2.48 Impact Factor
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ABSTRACT: Eotaxin, a CC chemokine expressed in the asthmatic lung, has been associated with impaired lung function. The role of its variant form is unknown.
The purpose of this study was to detect the population frequency and effects of a known single-nucleotide polymorphism in the eotaxin gene in which a threonine residue (THR(23)) is substituted for the wild-type alanine (ALA(23)) at the 23rd amino acid at the terminus of the peptide leader sequence.
We measured eotaxin protein secretion in 293 cells transfected with expression vectors and in PBMCs obtained from individuals bearing the alternative forms of the gene. A case-control study of plasma eotaxin levels and eosinophil counts, a comparison of baseline lung function by genotype in a population of 806 subjects with asthma, and a comparison of the allele frequency with a nonasthmatic population were performed.
Human 293 cells and PBMCs with THR(23) variant eotaxin secreted significantly less eotaxin protein than did ALA(23)-bearing cells. In the case-control study, THR(23)-THR(23) individuals had lower plasma levels of eotaxin (310 [240-350] vs 420 [270-700] pg/mL; P < .05) and eosinophil counts (120 [5-220] vs 190 [110-470] cells/microL; P < .05) than ALA(23)-ALA(23) subjects; heterozygous subjects had intermediate levels. Higher levels of lung function were associated with THR(23) eotaxin (percent of predicted FEV(1), 65% +/- 3.5% [THR(23)-THR(23)] vs 58% +/- 0.9% [THR(23)-ALA(23)] and 56% +/- 0.5% [ALA(23)-ALA(23)]; P < .05).
The THR(23) variant is associated with both decreased eosinophil counts and higher levels of lung function in subjects with asthma.
Journal of Allergy and Clinical Immunology 12/2001; 108(6):946-53. · 11.00 Impact Factor
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ABSTRACT: To investigate the mechanisms of eosinophil recruitment in allergic airway inflammation, we examined the effects of interleukin (IL)-4, a Th2-type cytokine, on eotaxin and monocyte chemoattractant protein-4 (MCP-4) expression in human peripheral blood mononuclear cells (PBMCs; n = 10), in human lower airway mononuclear cells (n = 5), in the human lung epithelial cell lines A549 and BEAS-2B, and in human cultured airway epithelial cells. IL-4 inhibited eotaxin and MCP-4 mRNA expression induced by IL-1 beta and tumor necrosis factor-alpha in PBMCs but did not significantly inhibit expression in epithelial cells. Eotaxin and MCP-4 mRNA expression was not significantly induced by proinflammatory cytokines in lower airway mononuclear cells. IL-1 beta-induced eotaxin and MCP-4 protein production was also inhibited by IL-4 in PBMCs, whereas IL-4 enhanced eotaxin protein production in A549 cells. In contrast, dexamethasone inhibited eotaxin and MCP-4 expression in both PBMCs and epithelial cells. The divergent effects of IL-4 on eotaxin and MCP-4 expression between PBMCs and epithelial cells may create chemokine concentration gradients between the subepithelial layer and the capillary spaces that may promote the recruitment of eosinophils to the airway in Th2-type responses.
AJP Lung Cellular and Molecular Physiology 12/2001; 281(5):L1288-302. · 3.66 Impact Factor
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ABSTRACT: Chronic eosinophilic pneumonia (CEP) is characterized by chronic or recurrent pulmonary infiltrates with eosinophils, but the precise mechanism of eosinophil accumulation has not been fully elucidated. Eotaxin is one of the CC chemokines that selectively recruits eosinophils and contributes to the pathogenesis of allergic airway diseases including asthma, but its roles in pathogenesis of CEP have not been fully elucidated. The authors measured concentrations of eotaxin and other CC chemokines, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted, macrophage inflammatory protein-1alpha, and the eosinophil activating Th2 cytokine interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid from CEP patients (n=11), and compared these concentrations with those from control subjects (n = 6). The eotaxin (904 +/- 203 versus 29 +/- 7 pg x mL(-1), p = 0.0001), MCP-1 (194 +/- 57 versus 15 +/- 2 pg x mL(-1), p < 0.05), and IL-5 (7.8 +/- 2.0 versus 2.7 +/- 0.6 pg x mL(-1), p < 0.05) levels were significantly higher for cases with CEP in comparison to those serving as controls. Proportions of eosinophil and lymphocyte counts were greater in BAL fluid from CEP patients. Eotaxin and IL-5 levels correlated with the proportion of eosinophils in BAL fluid from CEP patients. MCP-1 correlated with the relative lymphocyte numbers. In short, eotaxin, interleukin-5, and monocyte chemoattractant protein-1 levels were higher in the BAL fluid of CEP patients and these levels may contribute to eosinophil and lymphocyte recruitment and activation in the airways as found with this disorder.
European Respiratory Journal 06/2001; 17(5):962-8. · 5.89 Impact Factor
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ABSTRACT: Expression of pulmonary eotaxin protein and mRNA was determined in six subjects with atopic asthma and five nonatopic normal subjects. Levels of eotaxin expression and eosinophil mobilization were compared before and after segmental allergen challenge in subjects with atopic asthma. In the absence of allergen challenge, we found significantly higher levels of eotaxin in the bronchoalveolar lavage (BAL) fluid of subjects with asthma than in that of normal subjects (25 +/- 3 versus 15 +/- 2 pg/ml, p < 0.05). BAL eotaxin levels increased after segmental allergen challenge in all six subjects with atopic asthma tested, with a mean increase from 22 +/- 4 to 53 +/- 10 pg/ml (p = 0.013). Segmental allergen challenge was associated with a significant increase in the percentage of BAL macrophages and eosinophils that were immunopositive for eotaxin. Eotaxin mRNA was detectable by northern analysis in BAL cells exclusively from allergen-challenged segments. Allergen- induced increases in eotaxin levels were strongly associated with increases in BAL eosinophil recovery (r(2) = 0.88, p = 0.0036). Segmental allergen challenge also increased eotaxin expression in airway epithelial and endothelial cells obtained by endobronchial biopsy. These findings demonstrate, for the first time, that the airways of subjects with allergic asthma respond to allergen by increasing eotaxin expression. The tissue loci of eotaxin expression, the levels of eotaxin recovered in BAL fluid, and the association of eotaxin levels with eosinophil mobilization suggest either that eotaxin plays a mechanistic role in allergen-induced airway eosinophilia or that it serves as a biomarker for the causal mechanisms.
American Journal of Respiratory and Critical Care Medicine 06/2001; 163(7):1669-75. · 11.08 Impact Factor
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A Ishizaka,
M Watanabe,
T Yamashita,
Y Ogawa,
H Koh,
N Hasegawa, H Nakamura,
K Asano,
K Yamaguchi,
M Kotani,
T Kotani,
H Morisaki,
J Takeda,
K Kobayashi,
S Ogawa
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ABSTRACT: A noninvasive bronchoscopic microsampling (BMS) probe was developed to sample biochemical constituents of the epithelial lining fluid in small airways.
Observational, controlled study.
Intensive care unit of academic medical center. PATIENTS AND PROCEDURE: BMS was applied in a control group of seven patients who had hemoptysis or small solitary peripheral nodules but no hypoxemia or other signs of acute inflammation and in four patients with acute respiratory distress syndrome (ARDS), to test whether BMS can ascertain the presence of acute pulmonary inflammation without complications.
Complications, including a significant decrease in arterial oxygen saturation, were observed neither during nor after BMS. In the ARDS group, albumin, lactate dehydrogenase, interleukin-6, basic fibroblast growth factor, and neutrophil elastase concentrations in epithelial lining fluid were significantly higher (p <.0001, p =.012, p <.0001, p <.0001, and p <.0001, respectively) than in the control group. Serial BMS was safely performed in one patient with ARDS, allowing us to observe a correlation between changes in the concentration of inflammation-related biochemical markers and clinical course of the disease.
These results suggest that BMS is safe and useful to monitor pulmonary biochemical events in ARDS.
Critical Care Medicine 04/2001; 29(4):896-8. · 6.33 Impact Factor
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ABSTRACT: Eotaxin is an asthma-related C-C chemokine that is produced in response to interleukin-1beta (IL-1beta). We detected an increase in newly transcribed eotaxin mRNA in IL-1beta-stimulated airway epithelial cells. Transient transfection assays using promoter-reporter constructs identified a region as essential for IL-1beta-induced increases in eotaxin transcription. Using site-directed mutagenesis, we found that a nuclear factor-kappaB (NF-kappaB) site located 46 bp upstream from the transcriptional start site was both necessary and sufficient for IL-1beta induction of reporter construct activity. Electrophoretic mobility shift assay demonstrated that IL-1beta-stimulated airway epithelial cells produced p50 and p65 protein that bound this site in a sequence-specific manner. The functional importance of the NF-kappaB site was demonstrated by coexpression experiments in which increasing doses of p65 expression vector were directly associated with reporter activity exclusively in constructs with an intact NF-kappaB site (r(2) = 0.97, P = 0.002). Moreover, IL-1beta-induced increases in eotaxin mRNA expression are inhibited by inhibitors of NF-kappaB. Our findings implicate NF-kappaB and its binding sequence in IL-1beta-induced transcriptional activation of the eotaxin gene.
AJP Lung Cellular and Molecular Physiology 01/2001; 279(6):L1058-65. · 3.66 Impact Factor
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B Lamkhioued,
E A Garcia-Zepeda,
S Abi-Younes, H Nakamura,
S Jedrzkiewicz,
L Wagner,
P M Renzi,
Z Allakhverdi,
C Lilly,
Q Hamid,
A D Luster
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ABSTRACT: Chemokines are chemotactic cytokines that play an important role in recruiting leukocytes in allergic inflammation. Monocyte chemoacctractant protein (MCP)-4 is a CC chemokine with potent chemotactic activities for eosinophils, monocytes, T lymphocytes, and basophils and therefore represents a good candidate to participate in allergic reactions. To determine if MCP-4 plays a role in asthma, we have investigated the expression of MCP-4 messenger RNA (mRNA) and protein in the airways of patients with asthma and normal control subjects by in situ hybridization and immunohistochemistry. We found that MCP-4 mRNA and protein was significantly upregulated in the epithelium and submucosa of bronchial biopsies and in the bronchoalveolar lavage (BAL) cells of patients with asthma compared with normal control subjects (p < 0. 01). In addition, MCP-4 protein was significantly elevated in the BAL fluid of patients with atopic asthma when compared with normal control subjects (p < 0.01) and there was a significant correlation between MCP-4, eotaxin, and eosinophils. In support of our in situ findings demonstrating MCP-4 expression in epithelial cells and mononuclear cells in vivo, we have found that MCP-4 expression can be induced in these cells in vitro by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Interferon-gamma (IFN-gamma) acted synergistically with TNF-alpha and IL-1beta in the induction of mRNA MCP-4 mRNA expression in A549 cells, whereas the glucocorticoid dexamethasone diminished the cytokine-induced expression of MCP-4. Our findings demonstrate that MCP-4 is upregulated in the airways of patients with asthma and suggest that MCP-4 plays a role in the recruitment of eosinophils into the airways of patients with asthma.
American Journal of Respiratory and Critical Care Medicine 08/2000; 162(2 Pt 1):723-32. · 11.08 Impact Factor
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ABSTRACT: We performed an association study of plasma eotaxin levels, eosinophil counts, total IgE levels, asthma diagnosis, and lung function in an ethnically diverse and geographically dispersed population. We studied 515 asthmatic and 519 normal subjects, none of whom was taking inhaled or oral corticosteroids. Logistic regression analysis demonstrated a direct relationship between asthma diagnosis and eotaxin levels (p < 0.0001). The odds of an asthma diagnosis increased with eotaxin quartile, with the highest quartile having an odds ratio of 5.4 (95% CI 3.2 to 9.2, p < 0.001) compared with the lowest eotaxin quartile. Eotaxin levels were inversely related to lung function (p < 0.001), with the mean percent predicted FEV(1) in the highest eotaxin quartile being 13.5 percentage points (SEM 2.1, p < 0.001) less than that in the lowest quartile. Plasma eotaxin levels were associated with asthma and inversely related to lung function independent of age, race, sex, or smoking status. When combined with eosinophil counts and IgE levels, eotaxin levels contributed to the odds of an asthma diagnosis and of impaired lung function. Our results are the first to associate eotaxin levels with asthma diagnosis and compromised lung function in a large geographically and ethnically diverse population.
American Journal of Respiratory and Critical Care Medicine 01/2000; 160(6):1952-6. · 11.08 Impact Factor
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ABSTRACT: The eosinophil chemotactic and activating effects of eotaxin and the known association of eosinophils with asthma suggest that eotaxin expression is increased during asthma exacerbations.
We sought to determine whether plasma eotaxin levels are elevated in patients presenting for emergency treatment of acute asthma and to correlate eotaxin levels with disease activity and responses to treatment.
A case-control study of plasma eotaxin levels was performed in the 46 patients who presented for emergency asthma treatment and 133 age-, sex-, and ethnicity-matched subjects with stable asthma.
Plasma eotaxin levels were significantly higher in 46 patients with acute asthma symptoms and airflow obstruction (520 pg/mL [250, 1100 pg/mL]; geometric mean [-1 SD, +1 SD]) than in 133 subjects with stable asthma (350 pg/mL [190, 620 pg/mL]; P =.0008). Among the patients with emergency asthma flares, those who responded to asthma treatment with an increase in peak expiratory flow rate by an amount equal to at least 20% of their predicted normal value had lower eotaxin levels than those who did not (410 pg/mL [210, 800 pg/mL] and 660 pg/mL [300, 1480 pg/mL], respectively; P =.04).
These findings imply that eotaxin either is mechanistically involved in acute asthma or serves as a biomarker for activity of the CCR3 receptor ligand system, which is functionally linked to asthma.
Journal of Allergy and Clinical Immunology 11/1999; 104(4 Pt 1):786-90. · 11.00 Impact Factor
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H Nakamura,
S Fujishima,
T Inoue,
Y Ohkubo,
K Soejima,
Y Waki,
M Mori,
T Urano,
F Sakamaki,
S Tasaka,
A Ishizaka,
M Kanazawa,
K Yamaguchi
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ABSTRACT: The clinical and immunoregulatory effects of long-term macrolide antibiotic therapy for patients with chronic lower respiratory tract infections (CLRTI) were investigated. Clinical parameters and neutrophil chemotactic mediators in the epithelial lining fluid (ELF) of CLRTI patients (n = 10) were examined before and after 3 months oral administration of roxithromycin (RXM). The in vitro effects of RXM were also examined on the release of these mediators from alveolar macrophages (AM) and neutrophils. Arterial oxygen tension (p<0.05), vital capacity (VC) (p<0.001), %VC (p<0.05) and forced expiratory volume in one second (p<0.01) were improved after RXM treatment, but airway bacteria were not eradicated. Among the mediators, the levels of interleukin (IL)-8, neutrophil elastase (NE) and leukotriene B4 (LTB4) were higher in ELF than in plasma of CLRTI patients and they decreased after RXM treatment (n = 7, p<0.05 for each). RXM concentrations were significantly increased in the bronchoalveolar lavage cells of the treated patients. In in vitro experiments, RXM showed inhibitory effects on IL-8 release from AM and neutrophils. In conclusion, interleukin-8, neutrophil elastase and leukotriene B4 contribute to the neutrophilic inflammation in the airways of chronic lower respiratory tract infection patients and the clinical effects of roxithromycin may, in part, be attributable to the suppression of excess release of the chemotactic mediators from inflammatory cells.
European Respiratory Journal 07/1999; 13(6):1371-9. · 5.89 Impact Factor
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ABSTRACT: Regulation of eotaxin expression was investigated in U-937 cells, a human monocyte-like cell line. Eotaxin mRNA was induced by tumor necrosis factor-alpha (TNF-alpha; 0.1-100 ng/ml) and phorbol 12-myristate 13-acetate (PMA; 0.01-1 microM). PMA-induced eotaxin mRNA expression was of greater magnitude and was maximal at a later time point than TNF-alpha-induced expression (16 h vs. 2 h after stimulation), which was consistent with eotaxin protein expression detected by immunocytochemistry. Dexamethasone (0.01-10 microM) decreased eotaxin mRNA expression in both TNF-alpha- and PMA-stimulated U-937 cells. PMA-induced eotaxin mRNA expression was inhibited by cycloheximide (10 microg/ml), whereas TNF-alpha-induced expression was not. The protein kinase C (PKC) inhibitor staurosporine (10-50 nM) inhibited PMA-induced eotaxin mRNA expression, whereas TNF-alpha-induced expression was enhanced by this reagent. These results suggest that eotaxin expression can be induced by more than one mechanism: the PMA-triggered pathway is mediated by PKC activation and requires new protein synthesis, whereas the TNF-alpha-triggered pathway is independent of PKC and protein synthesis. TNF-alpha- and PMA-induced pathways are both associated with nuclear factor-kappaB, because its binding activity was enhanced in the presence of these stimuli, and both pathways were limited by its inhibitor, diethyldithiocarbamate.
The American journal of physiology 10/1998; 275(3 Pt 1):L601-10.
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ABSTRACT: We examined the expression of interleukin (IL)-8 receptors (Rs), type A (IL-8-RA) and type B (IL-8-RB), on peripheral blood and bronchoalveolar lavage (BAL) fluid neutrophils; we also examined IL-8 and other chemoattractants in the epithelial lining fluid (ELF) of patients with chronic lower respiratory tract infection (CLI) to elucidate the in vivo regulation of IL-8Rs. Neutrophils were stained with monoclonal antibodies specific for IL-8-RA and IL-8-RB. We detected higher levels of IL-8 (81.6 +/- 25.4 ng/ml, mean +/- SE), leukotriene (LT) B4, and IL-1 beta in the ELF of the CLI patients than in their serum (P < 0.05). The expression of IL-8Rs on BAL neutrophils was significantly lower than that on peripheral blood neutrophils (P < 0.01 for both). In vitro analysis showed that low-level IL-8 (50 ng/ml) alone did not affect IL-8R expression but that it was downregulated by high-level IL-8 (500 ng/ml) alone and by low-level IL-8 in combination with LTB4 or IL-1 beta. Staurosporine reduced the downmodulation by low-level IL-8 plus LTB4 or IL-1 beta but not by high-level IL-8 alone. We speculate that pulmonary IL-8-RA and IL-8-RB may have been downmodulated by the combined effect of local chemoattractants through, in part, a protein kinase C-dependent mechanism.
The American journal of physiology 09/1997; 273(3 Pt 1):L618-25.
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ABSTRACT: Eotaxin is a potent and specific eosinophil chemoattractant that is mobilized in the respiratory epithelium after allergic stimulation. Pulmonary levels of eotaxin mRNA are known to increase after allergen exposure in sensitized animals. In this study we demonstrate that TNF alpha and IL-1beta induce the accumulation of eotaxin mRNA in the pulmonary epithelial cell lines A549 and BEAS 2B in a dose-dependent manner. Cytokine-induced A549 cell mRNA accumulation was maximal at 4 h and was significantly enhanced when the cells were costimulated with IFNgamma. TNFalpha- and IL-1beta-induced increases in eotaxin mRNA were diminished in a dose-dependent manner by the glucocorticoid dexamethasone and were augmented by the protein synthesis inhibitor cycloheximide. Cytokine-induced increases in eotaxin mRNA expression correlated with increased eotaxin protein production and secretion, and dexamethasone inhibition of cytokine-induced eotaxin mRNA augmentation was associated with diminished eotaxin protein secretion. These findings, together with the known kinetics of TNF alpha and IL-1beta mobilization in asthmatic airways and the potent eosinophil chemotactic effects of eotaxin, define a mechanism linking inflammatory cytokine mobilization to eosinophil recruitment that may be relevant to the pathogenesis of asthma.
Journal of Clinical Investigation 05/1997; 99(7):1767-73. · 15.39 Impact Factor
