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Background: Long-acting β 2 -agonists (LABA) and leukotriene receptor antagonists (LTRA) are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. In our previous study, the Gly16Arg genotype of the β 2 -adrenergic receptor (ADRB2) gene did not influence the differential bronchodilator effect of salmeterol versus montelukast as an add-on therapy to ICS within 16 weeks of follow-up (the J-Blossom study)., Methods: We examined if genes encoding CYSLTR1, CYSLTR2, PTGER2 or PTGER4 could explain differential responses to salmeterol versus montelukast using the participants of the J-Blossom study. This study included 76 patients with mild-to-moderate asthma. The difference in peak expiratory flow (PEF) (ΔPEF, l/min) after 16 weeks of treatment with salmeterol (ΔPEFsal) versus montelukast (ΔPEFmon) was associated with the genotypes at each of 4 genes. In addition, multivariate analyses were used to identify a gene-gene interaction between ADRB2 gene and each of these 4 genes., Results: Although none of 4 genes were associated with ΔPEFsal-ΔPEFmon in the univariate analyses, multivariate analysis showed that PTGER4 gene, interacting with ADRB2 Gly16Arg, was associated with ΔPEFsal-ΔPEFmon (p=0.0032)., Conclusion: Our findings suggested that the interactions between two genetic loci at ADRB2 and PTGER4 is important in determining the differential response to salmeterol versus montelukast in patients with chronic adult asthma.

Aim: To elucidate the characteristics of patients with asthma who have specific IgE responses to inhaled allergens detected by ImmunoCAP, which is not detectable by MAST-26., Methods: A total of 168 patients with adult asthma who reside in the Kanto region were recruited. Levels of total serum IgE and allergen specific IgE antibodies towards 14 common inhaled allergens (MAST-26) were measured. Among these samples, 48 patients with no detectable allergen-specific IgE (group A) and 44 patients with strong sensitization to Dermatophagoides farinae (group B) were selected for further assessment of their sensitization to inhaled allergens such as cockroach and moth using ImmunoCAP., Results: In group A, ImmunoCAP detected specific IgE responses to some inhaled allergens in 27.1% of the patients. The strongest predictive factor for the presence of allergen-specific IgE responses detected by ImmunoCAP was elevated levels of total serum IgE (p=0.0007). In group B, the presence of IgE responses specific to cockroach or moth by ImmunoCAP were found in 27.8% or 52.3% of the patients, respectively. The predictive factor for the presence of these positive IgE responses was also elevated levels of total serum IgE (p=0.0003)., Conclusion: Asthma patients with no detectable specific IgE responses to any inhaled allergens by MAST-26 may be still sensitized to common inhaled allergens, including cockroach and moth. Thus, the presence of allergen-specific IgE responses may be re-assessed by ImmunoCAP in patients with asthma, especially when patients have higher levels of total serum IgE.

A 52-year-old man had been treated by hemodialysis because of IgA nephropathy since 1994. Gastric MALT lymphoma was diagnosed in January 2007. Radiation therapy was performed for 4 weeks (40Gy) and the response was complete remission (CR) by September 2007. He was admitted to our hospital in February 2008 because of an abnormal chest shadow. Chest CT showed multiple cystic lesions with calcification and consolidation. Transbronchial lung biopsy from the area of consolidation (left S5) showed pulmonary invasion of small lymphoid cells. PCR analysis showed clonal rearrangement of the heavy chain of the immunoglobulin gene. Accordingly, MALT lymphoma was diagnosed. Rituximab infusion was performed, because CD20 immunostaining was positive and he had been treated by hemodialysis. The abnormal chest shadow was presented since gastric MALT lymphoma was diagnosed. We considered that MALT lymphoma occurred simultaneously in the stomach and lung.

We reported a case of lung adenocarcinoma of Pancoast type that was successfully treated with chemoradiotherapy. A 66-year-old man was admitted to our hospital because of back pain. Chest computed tomography (CT) showed a Pancoast tumor on the left side. Using transbronchial needle aspiration, we diagnosed lung adenocarcinoma (cT3N0M0). The patient received chemoradiotherapy simultaneously(carboplatin AUC5 and irinotecan 60 mg/m2). There are no findings of tumor recurrence 8 years after chemoradiotherapy. This patient was successfully treated with concurrent chemoradiotherapy, which is suggested to be a useful therapy for Pancoast tumor.

Purpose: It is important to evaluate the effects of hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP), which shows predominant deposition in the lower airways, on asthmatic inflammation in the lower airways and the Quality of Life (QOL) of asthma patients, as compared with those of fluticasone propionate (FP) Diskus., Methods: Seventy-seven adult patients with mild persistent or more severe asthma who were being treated with FP for >/=3 months were randomly assigned to the HFA-BDP group and continued FP group. The differential count of eosinophils in the peripheral blood, the serum cortisol levels, and pulmonary function parameters were measured before the study and at 3 months after the start of the study treatment. The improvements in the Asthma Quality of Life Questionnaire (AQLQ) scores were also compared. Sputum samples collected by the induced expectoration method (inhalation of 10% saline for 15 min) were divided into the early-phase sputum samples obtained within 15 minutes of the inhalation and the late-phase sputum samples obtained later than 15 minutes after the inhalation, and the eosinophil count and eosinophil cationic protein (ECP) levels were measured., Results: In the HFA-BDP group (N=40), the differential count of eosinophils in the peripheral blood was significantly decreased as compared with that in the FP group (p=0.009), and the scores in all the domains of the AQLQ and the percentage improvement of the total score were significantly better as compared with those in FP group (p=0.033). The eosinophil count in the late-phase sputum samples (p=0.022) as well as the ECP level in the sputum samples showed more pronounced decreases in the HFA-BDP group as compared with those in the FP group. On the other hand, no significant changes were detected in the pulmonary function values., Conclusion: Use of the HFA-BDP preparation can more effectively suppress residual inflammation in the lower airways and significantly improve the QOL as compared with use of the FP preparation of asthma patients. Examination of induced sputum samples allows detection of changes in the peripheral airways that cannot be detected by pulmonary function testing.

Objective: Inhaled corticosteroids play a pivotal role in the treatment of asthma. To observe the mechanisms of glucocorticoids, we focused our study on the comparison of several glucocorticoids' effects on eotaxin expression in the airway epithelial cells., Methods: Airway epithelial cell line BEAS-2B was cultured in vitro. Cells were preincubated with or without glucocorticoids (becromethasone dipropionate; BDP, budesonide; BUD, fluticasone propionate; FP) and stimulated with TNFalpha and/or IL-4. Protein levels of eotaxin in the supernatants of the cultured cells were determined by ELISA., Results and Conclusions: TNFalpha and IL-4 increased the levels of eotaxin in BEAS-2B cells. Combination of these cytokines synergistically upregulated the eotaxin expression as reported previously. Each glucocorticoid significantly inhibited the expression of eotaxin protein induced with TNFalpha and IL-4 and the compared efficacy was in order of FP>BUD>BDP. FP seemed most potent and the inhibitory effect was also observed with relatively low concentration such as 10 (-10)M. Taken together, the comparison of the potency of each glucocorticoid using airway epithelial cells may reflect the efficacy of these drugs in asthmatics.

It is well known that allergic rhinitis and asthma often coexist in the same patients. Here, we investigated the influence of Japanese cedar pollinosis on the exacerbation of asthma investigated by questionnaire, daily asthma diary, and peak expiratory flow (PEF) monitoring. Furthermore, airway responsiveness to histamine before pollen season was also investigated in some patients. 333 adult patients with asthma were enrolled into the study and 116 patients (34.8%) were suffering from Japanese cedar pollinosis diagnosed by the presence of nasal allergic symptoms during pollen season and high titer of Japanese cedar-specific IgE antibody. Exacerbation of asthma symptoms, including wheezing, dyspnea, cough, and sputum, was detected in 41 of 116 patients (35.3%) during pollen season. Decrease in morning PEF more than 10% compared with the baseline values before pollen season was observed in 13 of 41 patients (11.2% of total asthmatic patients who complicated with Japanese cedar pollinosis). No significant differences in airway responsiveness to histamine and the titer of Japanese cedar-specific IgE antibodies before pollen season were observed between the patients whose asthma exacerbated and the patients whose asthma was not exacerbated. These results suggest that Japanese cedar pollinosis is one of risk factors for asthma in Japanese adult patients with asthma.

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 (p < 0.01). 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.

We have developed a tele-medicine system to monitor the airway status at home for patients with poorly controlled asthma, whereby a nurse provides instructions to individuals via the telephone to help them manage exacerbation under the supervision of their physicians. We examined the effectiveness of this system with a randomized control study. Patients with high hospitalization risk were enrolled in the study by screening patients for those with multiple previous emergency room visits and randomly assigned to either the tele-medicine or control group. After six months of participation in the program, the number of emergency room visits decreased significantly and the activities of daily living were improved in the tele-medicine group. Most of the patients in the tele-medicine group were able to continue measuring and transmitting peak expiratory flow (PEF) value successfully, and at six months had noticed an improvement in PEF. We therefore conclude that the system effectively contributes to the management of poorly controlled asthma. In addition, further consideration suggests that the reduction of emergency room visits may lead to reduction in hospitalization since we found a good correlation between number of emergency room visits and hospitalization from the studies published previously.

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.

Beta-adrenoceptor agonists have several pharmacological actions in the lung which affect airway function. They have a direct relaxant effect on human bronchial smooth muscle and several additional properties, including attenuation of mast cell mediater release, reduction in airway microvascular leakage, and inhibition of cholinergic neurotransmission within the airway, in vitro. However, direct evidence in vivo for any anti-inflammatory effects of beta-adrenocepter agonists is limited. We reported that beta-agonists (procaterol, salmeterol) inhibited significantly I. A. R. and L. A. R. Salmeterol also reduced urinary secretion of LTE4. It is suggested that beta-agonists have some of anti-allergic effects in the clinical pharmacological study. From recent clinical studies, it is recommended on demand use more than regular use of inhaled beta-agonists.

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.

We have previously demonstrated that airway responsiveness was enhanced following a late bronchial response (LBR) after an allergen challenge in ovalbumin (OA)-sensitized guinea pigs. The purpose of the present studies was to evaluate whether airway responsiveness to methacholine increased after an immediate bronchial response (IBR) and the possible involvement of the beta-adrenoceptor dysfunction in OA-sensitized guinea pigs. Guinea pigs were actively sensitized by aerosolized OA. Following OA exposure, IBR appeared. After IBR when specific airway resistance returned to the base line value, airway responsiveness to methacholine increased significantly. Before OA exposure, propranolol induced bronchoconstriction (PIB) was not provoked, however, after IBR, PIB was provoked and the guinea pigs died because of severe bronchoconstriction. These results suggest that airway responsiveness to methacholine increases significantly after IBR. Furthermore, the dysfunction of the beta-adrenoceptor may be a mechanism of this hyperresponsiveness in OA-sensitized guinea pigs.

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.

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.