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There are only a few reports of the use of impulse oscillation system (IOS) for the evaluation of COPD treatment. In this study, we applied IOS and spirometry to evaluate the effectiveness of fluticasone propionate and salmeterol (SFC) combined with tiotropium (TIO) in COPD patients. Following a 4-week run-in period with TIO (18 μg once daily) treatment, COPD patients were randomized to SFC (250/50 μg twice daily; SFC + TIO group, n = 25), or TIO alone (TIO group, n = 31). Pulmonary functions were recorded by IOS and spirometry before and after the study period. The SFC + TIO group showed significant improvements in inspiratory resistance at 5 Hz and resonant frequency, as well as in FVC and FEV1, after the 12-week treatment (p

Increased expression of IL-17F has been noted in the airway of asthmatic patients, but its role in asthma has not been fully elucidated. Insulin-like growth FACTOR-I (IGF-I) is known to be involved in airway remodelling and inflammation, while its regulatory mechanisms remain to be defined.To further clarify the biological function of IL-17F, we investigated whether IL-17F is able to regulate the expression of IGF-I in bronchial epithelial cells.Bronchial epithelial cells were stimulated with IL-17F in the presence or absence of T-helper type 2 cytokines. Various kinase inhibitors were added to the culture to identify the key signalling events leading to the expression of IGF-I, in conjunction with the use of short interfering RNAs (siRNAs) targeting mitogen- and stress-activated protein kinase (MSK) 1, p90 ribosomal S6 kinase (p90RSK), and cyclic AMP response element-binding protein (CREB).IL-17F significantly induced IGF-I gene and protein expression, and co-stimulation with IL-4 and IL-13 augmented its production. MAP kinase kinase (MEK) inhibitors and the Raf1 kinase inhibitor significantly inhibited IGF-I production, and the combination of PD98059 and Raf1 kinase inhibitor showed further inhibition. Overexpression of Raf1 and Ras dominant-negative mutants inhibited its expression. MSK1 inhibitors significantly blocked IL17F-induced IGF-I expression. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked its expression.In bronchial epithelial cells, IL-17F is able to induce the expression of IGF-I via the Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB pathway in vitro.

Respiratory virus is one of the most common causes of airway inflammation, but its pathogenic mechanisms are not well understood. Eotaxin is a potent eosinophil chemoattractant and is a selective agonist for C-C chemokine receptor 3 (CCR3). Although it has recently been demonstrated that epithelial cells express eotaxin, both in vivo and in vitro, there are few data concerning the expression in viral infection.We hypothesized that eotaxin may play an important role in attracting inflammatory cells into the airway after viral infection and analysed whether viral infection induces eotaxin in nasal epithelial cells in vitro.Nasal epithelial cells obtained from polypectomy for nasal polyp were infected with influenza virus A (subtype H3N2). The cells and supernatants were collected 8, 24 and 48 h after infection. Eotaxin mRNA was analysed by RT-PCR. Eotaxin concentration in the supernatants was analysed by enzyme-linked immunosorbent assay. We also examined a blocking assay to analyse the intervention of pro-inflammatory cytokines, TNF-alpha and IL-1beta in eotaxin production induced by influenza virus.The results showed that eotaxin was expressed constitutively in uninfected cells, but was up-regulated for both mRNA and protein levels in infected cells. Blocking experiments using anti-TNF-alpha and anti-IL-1beta antibodies showed no effects of these agents on the level of eotaxin. In addition, UV-inactivated virus did not enhance the expression of eotaxin.These results suggest that influenza virus A infection in nasal epithelial cells stimulates the expression of eotaxin, and may play an important role in the pathogenesis of airway inflammation by inducing eotaxin.

Viral infection is one of important factors to cause the exacerbation of bronchial asthma. We have investigated 167 adults of asthmatics to clarify the correlation between viral infection and exacerbation of asthma. Patients were classified to four group by the symptoms of common cold and asthma attack. Furthermore, we have examined Picornavirus and Human rhino virus RNA from throat gargles of patients using RT-PCR (reverse transcription--polymerase chain reaction) method. Forty of 65 (61.5%) asthmatics with common cold revealed asthma attack and common cold was significantly associated with acute exacerbation of asthma (p0.01). We identified Picornavirus RNA, which include 113 of Human rhino virus serotypes and enterovirus, from the samples of 16 of 52 (30.8%) patients who had acute exacerbation. It was significantly higher than the detection rate of viral RNA from patient without asthma attack. Furthermore, we analyzed Human rhino virus RNA from the same samples by RT-PCR and 93.7% of Picornavirus were identified as Human rhino virus. Taken together, these findings suggest that common cold is significantly associated with the exacerbation of bronchial asthma. Human rhino virus infection might be one of important virus in this procedure.

We examined an effectiveness of a new asthma telemedicine system in reducing hospitalizations using a multi-site randomized control study. In this program, a nurse under physician supervision monitors the patient's airway status at home and provides instructions to individuals via the telephone, helping them manage exacerbations as well as reinforcing proper use of a zone-controlled management plan. Patients with a high risk for hospitalization were screened based on the numbers of emergency room visits and hospitalizations found in a previous study and randomly assigned to either the telemedicine or control group. After a six-month study period, an 83% reduction in hospitalization was demonstrated in the telemedicine group versus the control group, with a P value of 0.01. Improvement of peak expiratory flow and symptoms were also shown in the study group. We conclude that the key success factors in home asthma management for poorly controlled asthma patients are early detection of exacerbations through daily peak flow monitoring, compliance with prescribed daily prophylactic anti-inflammatory steroid medications, and immediate action as specified by a zone-controlled action plan upon the first signs of deterioration.

Bronchial asthma is characterized as a chronic inflammation of the airway infiltrated by eosinophils, lymphocytes, and neutrophils. ICAM-1 expression on airway epithelium facilitates adhesion between these inflammatory cells and bronchial epithelial cells, and induces the activation of inflammatory cells. ICAM-1 expression was affected by various cytokines, such as IL-17. IL-17 is a novel cytokine released by CD4+ activated memory T cells. In this study, we examined the effect of IL-17 on ICAM-1 expression by RT-PCR and flow cytometry. Human bronchial epithelial cells, NCI-H 292 cells, were stimulated with IL-17 (100 ng/ml) and/or IFN-gamma (100 U/ml). ICAM-1 was expressed constitutively. IL-17 alone did not enhance ICAM-1 expression on NCI-H 292 cells. However, IL-17 synergistically enhanced ICAM-1 expression induced by IFN-gamma. These results suggest that IL-17 has an effect on ICAM-1 expression of bronchial epithelial cells in airway inflammation.

Theophylline has been used as a bronchodilator in acute and chronic asthma management but recent evidences suggest that it has anti-inflammatory effects. Therefore, we investigated the therapeutic effect of slow-release theophylline in mild to moderate asthmatic patients. Symptomatic 19 patients with mild asthma who were treated with inhaled beta 2-agonist alone, and 17 subjects with moderate asthma who were treated with moderate dose of inhaled corticosteroid (beclomethasone dipropionate, BDP, 400-800 micrograms/day) were enrolled to the present study. After two-week run-in period, slow-release theophylline was administered for six to eight weeks and asthma symptoms, respiratory function, airway inflammation evaluated by the inhalation of hypertonic saline, and airway reactivity to histamine were investigated during observation period and after treatment. Asthma symptom score was significantly improved after theophylline treatment in both groups. Morning peak expiratory flow was significantly elevated but FEV1 was not significantly improved by the additional treatment with slow-release theophylline in both groups. Significant decreases in the percentages of total and EG2 + eosinophils in induced sputum demonstrated that slow-release theophylline has anti-inflammatory effect in patients with asthma despite the treatment with inhaled corticosteroid. Because recent reports suggest that theophylline may act as an anti-inflammatory drug even in low dose concentration, we also investigated the effect of plasma theophylline concentration on the airway inflammation. Patients were divided into two groups by the plasma concentration of theophylline, more than 10 micrograms/mL which is necessary to dilate airway and below 10 micrograms/mL, referred to as low dose concentration of theophylline. The results suggest that the administration of slow-release theophylline significantly decreased the percentages of both total and EG2 + eosinophils in induced sputum in both concentration groups. However, airway reactivity to histamine did not significantly change by the treatment. Taken together, we conclude that low dose treatment of slow-release theophylline has an anti-inflammatory effect and treatment with slow-release theophylline alone or the additional use with inhaled corticosteroid is an effective therapy for the management of mild to moderate asthma.

We studied the chemotactic activity of isolated human peripheral eosinophils toward leukotriene (LT) E4. We obtained eosinophil suspensions by the method of CD16 negative selection. Eosinophil chemotactic activities toward platelet activating factor (PAF, 10(-6) M) and LTE4 (10(-7) M, 10(-6) M, 10(-5) M) were studied using a modified Boyden Chamber method. Eosinophils migrated significantly toward PAF and LTE4 (10(-7) M, 10(-6) M). The chemotactic activity toward LTE, was most potential at 10(-6) M. These results suggest that LTE4 is an eosinophil chemoattractant.

The clinical study and in vitro study used with leukocytes were made of a case of food-dependent exercise-induced anaphylaxis induced by shrimp. A 26-year-old man experienced anaphylactic reaction of nasal obstruction, face edema and dyspnea while running 90 minutes after eating shrimp. He experienced similar episodes two years ago in his past history. IgE-RAST was positive for shrimp. Anaphylactic reaction and elevation of plasma histamine levels were verified by exercise challenge test after eating 100 g shrimp. At the same time, we verified the dedine of plasma cAMP levels after eating shrimp. In leukocyte stimulating test used with shrimp antigen, histamine level elevations, which were lower compared with calcium ionophore A23187 (Ca I 10(-6) M) stimulation, were recognized in dose dependent manner in this patient. But in normal subject, histamine level elevations were not recognized. We diagnosed him food-dependent exercise-induced anaphylaxis. It was suggested that there was relation between histamine release and decline of cAMP levels of plasma after eating shrimp in this case.

Viral infection induces airway inflammation. It is possible that bronchial epithelium derived chemokine contributes to the migration and accumulation of inflammatory cells in the airway viral infection. We infected bronchial epithelial cells with influenza virus and analysed mRNA expression and production of RANTES. The expression of mRNA and the production of RANTES were detected in infected cells using RT-PCR method and ELISA.

Bronchial asthma is characterized as a chronic inflammation of the airway that causes an infiltration of lymphocytes and eosinophils. Cell to cell interaction or cell to tissue interaction is essential for infiltration of eosinophils to underlying tissues. These phenomena are closely related to the expression of intercellular adhesion molecule-1 (ICAM-1). Inhalation of steroids, such as beclomethasone dipropionate, is commonly used to cure airway inflammation. In this study, we investigated the effect of cytokines on ICAM-1 expression on human bronchial epithelial cell lines, NCI-H292. Moreover, the effect of dexamethasone on ICAM-1 expression stimulated by IL-1 beta, TNF-alpha and IFN-gamma was observed. Treatment with IL-1 beta, TNF-alpha and IFN-gamma dose-dependently increased ICAM-1 expression on NCI-H292 cells. Inhibitory effects were exerted by dexamethasone on ICAM-1 expression in cells stimulated by IL-1 beta and IFN-gamma in a dose-dependent manner, but not in cells stimulated by TNF-alpha. These results suggest that the inhibition of ICAM-1 expression could be related to the pharmacological action of steroid drugs.

Inflammation of mucosa and epithelial damage the of bronchi are characteristic pathological features of asthma. Infiltration of T lymphocytes and eosinophils followed by their activation and release of cytokines seems to be a contributing process. We studied the interaction of interleukin 2 (IL-2) and interleukin 5 (IL-5), cytokines which act on eosinophils, using human peripheral lymphocytes. We found that cyclosporin A (CyA) inhibited the IL-5 production from human peripheral lymphocytes induced by IL-2 stimulation. Human peripheral lymphocytes were isolated from healthy volunteers and bronchial asthma patients with mild eosinophilia. Lymphocyte cultures stimulated with IL-2 were cultured at 37 degrees C in a humidified atmosphere of 5% CO2 in air. After 72 hours' incubation, the proliferative response of the lymphocytes was examined by [3H]thymidine uptake, and at the same time IL-5 in the supernatant of the culture medium was assayed by ELISA. The lymphocytes proliferated on IL-2 stimulation in all cases; IL-5 was detected in 3 out of 9 healthy volunteer cases and 7 out of 11 asthma patient cases. CyA added at the beginning of incubation inhibited both of these responses in a dose-dependent manner.

An (125I) iodohydroxybenzyl pindolol (125IHYP) binding inhibition assay was performed. Various dilutions (1:5-1:500) of sera from asthmatics and controls were incubated with canine lung membranes for 60 minutes at 30 degrees C. 125IHYP was added to the membranes for 30 minutes at room temperature in the presence and absence of 10 microM 1-propranolol, and the samples were washed through a Gelman (Type A-E) glass fiber filter using a washing buffer. Radio activity was measured with Aloka gamma counter. In the presence of various serum dilutions from asthmatics, 125IHYP specific bindings of 0.16 fmol to 4.38 fmol were measured. 125IHYP binding was inhibited in a dose-related and nonspecific manner. Serum, albumin, L-histidine and L-cysteine also inhibited 125IHYP specific binding to beta-receptors. Percentages of inhibition of serum from asthmatics on 125IHYP specific finding to beta-receptors were -17.6% to +9.3%, which were compared with identical dilutions of control serum. There was no significant difference in 125IHYP binding inhibition assay between asthmatics and controls. From these results, development of autoantibody to beta-adrenergic receptors could not be detected in this study.

Ten patients with allergic asthma were studied to compare the inhibitory effects of ketotifen and disodium cromoglycate on bronchial responses, especially the late asthmatic response, induced by house dust allergen in bronchial provocation tests. In the first study, types of bronchial response to house dust challenge were classified from peak expiratory flow rate measurements made at intervals after the test. Nine patients showed dual asthmatic response (immediate with isolated late response) and 1 patient showed isolated late asthmatic response. The tests were treated at 1-week intervals, patients having been premedicated from the night before the test with either ketotifen (3 X 2 mg oral doses) or disodium cromoglycate (3 X 40 mg by inhalation). The results showed that both drugs produced significant protection against the immediate bronchial response and that ketotifen was at least as effective as disodium cromoglycate in inhibiting the late asthmatic response.

A sulpyrin inhalation test was given to 13 patients with aspirin-induced asthma (AIA) and 8 patients with non-aspirin-induced asthma (non-AIA) to observe the changes in plasma histamine levels before and after challenges. The respiratory function (FEV1.0) was measured before and after sulpyrin inhalation. A decrease of more than 20% the initial value (basal value) was defined as a positive response. Plasma histamine was determined by high-performance liquid chromatography (HPLC). In 11 patients with AIA, a positive response was observed (SIT positive), with a fall of FEV1.0 to 63.70 +/- 4.87% of the basal value. In 2 patients with AIA and 8 patients with non-AIA, no positive response was observed (SIT negative). In patients with SIT positive, plasma histamine levels increased significantly from 0.61 +/- 0.06 ng/ml before challenges to 1.34 +/- 0.22 ng/ml after challenges (p less than 0.01). No significant changes of plasma histamine occurred in the SIT negative patients. These results suggest that mast cells play some role in the mechanism of the development of aspirin-induced asthma.