Clinically remitted childhood asthma is associated with airflow obstruction in middle-aged adults.

BACKGROUND AND OBJECTIVE: While adult asthma has been shown to be a risk factor for COPD, the effect of remitted childhood asthma on adult lung function has not been clarified. The aim of this study was to examine whether remitted childhood asthma is a risk factor for airflow obstruction in a middle-aged general population. METHODS: A total of 9896 participants (range: 35-60 years) from five healthcare centres were included in the study. The participants were classified into four categories based on the presence or absence of physician-diagnosed childhood/adulthood asthma and asthma symptoms as follows: healthy controls (n = 9154), remitted childhood asthma (n = 287), adulthood-onset asthma (n = 354) and childhood-adulthood asthma (n = 101). RESULTS: The prevalence of respiratory symptoms was similar in both the participants with remitted childhood asthma and healthy controls. The prevalence of airflow obstruction (forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) < 0.7) was significantly higher in the participants with remitted childhood asthma, those with adult-onset asthma and those with childhood-adulthood asthma (5.2%, 14.4% and 16.8%, respectively) compared with healthy controls (2.2%). Multivariate logistic regression showed that remitted childhood asthma was independently associated with airflow obstruction. Among the participants with remitted childhood asthma, ever-smokers had significantly lower FEV1 /FVC than never-smokers. CONCLUSION: Clinically remitted childhood asthma is associated with airflow obstruction in middle-aged adults. Smoking and remitted childhood asthma may be additive factors for the development of airflow obstruction.

Comparison of early effects of budesonide/formoterol maintenance and reliever therapy with fluticasone furoate/vilanterol for asthma patients requiring step-up from inhaled corticosteroid monotherapy.

BACKGROUND: If asthma patients fail to achieve symptom control using a medium dose of inhaled corticosteroid (ICS) alone, addition of a long-acting ß2 agonist (LABA) is the preferred treatment. Currently, there are several combinations of ICS/LABA that are available, each of which has a different property. Here, we aimed to compare the early effects of budesonide/formoterol (BUD/FM; Symbicort(®)) for maintenance and reliever therapy (SMART) with a fixed dose of fluticasone furoate/vilanterol (FF/VI; Relvar(®)). METHODS: Inadequately controlled asthma patients (defined as having an Asthma Control Questionnaire, 5-item version [ACQ5] score≥1.5) with a fractional exhaled nitric oxide (FeNO) value > 35 ppb, who had been treated with a medium dose of ICS alone, were enrolled. Patients were randomized into two groups and treated with two inhalations twice-daily of BUD/FM 160/4.5 µg plus as-needed BUD/FM (SMART group, n = 15) or one inhalation once-daily of FF/VI 100/25 µg plus as-needed procaterol (FF/VI group, n = 15) for 4 weeks. Outcomes including FeNO, impulse oscillometry (IOS) parameters and ACQ5 scores were measured at 0, 2 and 4 weeks. RESULTS: Both groups showed improvement in airway inflammation, pulmonary function and symptoms from baseline to 2 weeks. From 2 to 4 weeks, the SMART group exhibited continuous improvement in most measured parameters, whereas improvement in the FF/VI group seemed to reach a plateau transiently. Consequently, the SMART group showed significant improvement in the FeNO, IOS parameters (resonance frequency and integrated area of low frequency reactance) and ACQ5 score as compared with the FF/VI group at 4 weeks. CONCLUSION: As compared with the FF/VI group, the SMART group achieved a greater improvement in FeNO, small airway parameters regarding IOS and ACQ score, in patients with airway inflammation and uncontrolled symptoms treated with a medium dose of ICS alone. In this 4-week study, these two ICS/LABA combination therapies showed different treatment outcomes; they must be investigated further to clarify suitable patient characters and the long term efficacies for each combination.

Effect of increasing respiratory rate on airway resistance and reactance in COPD patients.

BACKGROUND AND OBJECTIVE: Airway resistance and reactance measured by forced oscillometry have been used to measure the severity of airway obstruction in chronic obstructive pulmonary disease (COPD) patients. The aims of this study were to assess the effects of tachypnoea on airway resistance and reactance and to correlate these with the severity of dyspnoea. We also evaluated the effects of short-acting ß2-agonist (SABA) on these measurements. METHODS: Airway resistance and reactance were measured with an impulse oscillation system (IOS) in 20 COPD and 10 control participants during resting respiration and metronome-paced breathing at 20, 30 and 40 tidal breaths/min. The same measurements were made for COPD patients after SABA inhalation. Dyspnoea was evaluated using the modified Medical Research Council (MRC) scale. RESULTS: In patients with COPD, higher respiratory rates increased expiratory and inspiratory resistance at 5 Hz (R5), the difference in respiratory resistance at 5 Hz and 20 Hz (R5-R20), resonant frequency and decreased expiratory reactance. The decreases in expiratory reactance from 20 to 40 tidal breaths/min were significantly correlated with MRC scores. SABA inhalation significantly reduced the effect of increased respiratory rate on the reactance measurements. CONCLUSIONS: Characteristic changes in IOS measurements, particularly expiratory reactance, induced by increased respiratory rates, were correlated with severity of dyspnoea in COPD patients during their daily lives. IOS and paced breathing may be useful for assessing breathlessness in COPD.

Effects of a 6-month nurse-led self-management program on comprehensive pulmonary rehabilitation for patients with COPD receiving home oxygen therapy.

PURPOSE: This study was to examine the effectiveness of a nurse-led 6-month comprehensive pulmonary rehabilitation program for stage IV chronic obstructive pulmonary disease patients receiving home oxygen therapy. DESIGN: A controlled clinical study was performed. METHODS: Face-to-face and telephone interviews were conducted with the intervention group, whereas conventional education was given to the control group. FINDINGS: Fifteen participants were analyzed in each group. There were no improvements in physiological outcomes; however, the severity of dyspnea, social activity, and walking distance significantly improved in the intervention group, and consequently quality of life was improved. Three patients in the intervention group received treatment for cold-like-symptoms but did not require hospitalization. However, five patients in the control group received treatment for cold-like-symptoms and two required hospitalization. CONCLUSIONS: The findings demonstrate that our program contributes to patients' learning of self-management skills and significantly improves dyspnea, social activity level, walking distance, and overall quality of life.

Elevated serum IgE against MGL_1304 in patients with atopic dermatitis and cholinergic urticaria.

BACKGROUND: MGL_1304 secreted by Malassezia globosa is contained in human sweat and induces histamine release from basophils in patients with atopic dermatitis (AD) at a high positive rate. The aims of this study were to establish the enzyme-linked immunosorbent assay (ELISA) measuring specific immunoglobulins against MGL_1304 and to investigate the levels of these immunoglobulins in sera of patients with various allergic diseases. METHODS: Purified MGL_1304 from human sweat (QRX) and recombinant MGL_1304 (rMGL_1304) were prepared for ELISA. To quantify the amount of MGL_1304-specific immunoglobulins, the standard serum was created by pooling sera of 20 patients with AD whose basophils released histamine in response to QRX. A monoclonal antibody which exhibited the highest neutralizing ability against QRX was established as Smith-2, and used as a capture antibody for the assay of QRX-specific IgE. A total of 156 subjects [normal controls (n = 23), AD (n = 63), cholinergic urticaria (CU) (n = 24), bronchial asthma (n = 32), and allergic rhinitis (n = 14)] were enrolled in this study. RESULTS: ELISA methods to quantify the specific IgE, IgG and IgG4 against MGL_1304 in sera were successfully established. Levels of QRX-specific IgE in sera of patients with AD and CU were significantly higher than those of normal controls. Moreover, the levels of QRX-specific IgE and rMGL_1304-specific IgE in patients with AD were significantly correlated with their disease severities. CONCLUSIONS: These ELISA methods to quantify the specific immunoglobulins against MGL_1304 are easy and useful means to assess allergy to MGL_1304. MGL_1304 contained in sweat is an important antigen for patients with AD and CU.

[Clinical effects of budesonide/formoterol combination drug in elder patients with asthma compared with budesonide plus tulobuterol patch combination treatment].

BACKGROUND AND AIMS: Tulobuterol patch (Tulo) is often used for treatment of elder patient with asthma in Japan. However, there is no evidence either ICS plus Tulo or ICS/LABA combination is better for elder patient. METHODS: Elder patients with asthma (aged≥ 70, n=17) who had treated with budesonide (BUD) 400 µg/day plus Tulo 2 mg/day, were randomly assigned either to change control medication to budesonide/formoterol combination (BUD/FM) 320/9 µg/day or to keep BUD plus Tulo treatment for 12 weeks. RESULTS: At week 4 and week 12, the BUD/FM group showed significant increase in lung function (FEV1, %FEV1) and mini AQLQ score compared with the BUD plus Tulo group. The BUD/FM group also showed decrease in Tumor Necrosis Factor-alpha level in exhaled breath condensate at week 12. No adverse event was observed in both groups. CONCLUSION: In elder patients with asthma, treatment with BUD/FM does not have any clinical disadvantage and may provide better efficacy in lung function, QOL, and possibly anti-inflammation compared with BUD plus Tulo treatment.

Association Between Patient Preference for Inhaler Medications and Asthma Outcomes.

Purpose: Asthma guidelines recommend considering the patient preference to optimize medication choices. Patient preference for inhaler medication may affect asthma outcomes, but evidence regarding this is lacking. This study investigated the associations between patient preference for inhaler medications and asthma outcomes. Patients and Methods: A multicenter questionnaire survey was conducted among 351 adult patients with asthma treated with regular inhaled corticosteroids. Agreement between patients' preferences and current medication was evaluated using two questions: matched preference was defined as patients answering that the current inhaler medication was the most preferred treatment and they were satisfied with it. Mismatched preference was defined as when patients reported that the current inhaler medication was not the most preferred treatment and/or they were not satisfied with it. We investigated the factors associated with patient preference for asthma inhaler medications. Results: In total, 269 (76.6%) patients were classified into the matched preference group and 82 (23.4%) patients into the mismatched preference group. Multivariate analyses showed that matched preference was independently associated with higher asthma control test scores (P<0.001), fewer exacerbations (P=0.009), less regular oral corticosteroid use (P=0.009), and better inhaler adherence (P=0.006) than the mismatched preference group. In subgroup analysis, younger age was associated with matched preference in patients using dry powder inhalers but not in those using pressurized metered dose inhalers. Conclusion: The use of preference-matched inhaler medication was associated with better asthma outcomes. Evaluation of patients' preference for inhaler medication might provide useful information for individualized treatment with asthma inhaler medications.

Intra-airway administration of small interfering RNA targeting plasminogen activator inhibitor-1 attenuates allergic asthma in mice.

Recent studies suggest that plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of the fibrinolytic system, may promote the development of asthma. To further investigate the significance of PAI-1 in the pathogenesis of asthma and determine the possibility that PAI-1 could be a therapeutic target for asthma, this study was conducted. First, PAI-1 levels in induced sputum (IS) from asthmatic subjects and healthy controls were measured. In asthmatic subjects, IS PAI-1 levels were elevated, compared with that of healthy controls, and were significantly higher in patients with long-duration asthma compared with short-duration asthma. PAI-1 levels were also found to correlate with IS transforming growth factor-ß levels. Then, acute and chronic asthma models induced by ovalbumin were established in PAI-1-deficient mice and wild-type mice that received intra-airway administrations of small interfering RNA against PAI-1 (PAI-1-siRNA). We could demonstrate that eosinophilic airway inflammation and airway hyperresponsiveness were reduced in an acute asthma model, and airway remodeling was suppressed in a chronic asthma model in both PAI-1-deficient mice and wild-type mice that received intra-airway administration of PAI-1-siRNA. These results indicate that PAI-1 is strongly involved in the pathogenesis of asthma, and intra-airway administration of PAI-1-siRNA may be able to become a new therapeutic approach for asthma.

KL-6 concentration in pulmonary epithelial lining fluid is a useful prognostic indicator in patients with acute respiratory distress syndrome.

BACKGROUND: KL-6 is a mucin-like glycoprotein expressed on the surface of alveolar type II cells. Elevated concentrations of KL-6 in serum and epithelial lining fluid (ELF) in patients with acute respiratory distress syndrome (ARDS) have been previously reported; however, kinetics and prognostic significance of KL-6 have not been extensively studied. This study was conducted to clarify these points in ARDS patients. METHODS: Thirty-two patients with ARDS who received mechanical ventilation under intubation were studied for 28 days. ELF and blood were obtained from each patient at multiple time points after the diagnosis of ARDS. ELF was collected using a bronchoscopic microsampling procedure, and ELF and serum KL-6 concentrations were measured. RESULTS: KL-6 levels in ELF on days 0 to 3 after ARDS diagnosis were significantly higher in nonsurvivors than in survivors, and thereafter, there was no difference in concentrations between the two groups. Serum KL-6 levels did not show statistically significant differences between nonsurvivors and survivors at any time point. When the highest KL-6 levels in ELF and serum sample from each patient were examined, KL-6 levels in both ELF and serum were significantly higher in nonsurvivors than in survivors. The optimal cut-off values were set at 3453 U/mL for ELF and 530 U/mL for serum by receiver operating characteristic (ROC) curve analyses. Patients with KL-6 concentrations in ELF higher than 3453 U/mL or serum concentrations higher than 530 U/mL had significantly lower survival rates up to 90 days after ARDS diagnosis. CONCLUSIONS: ELF and serum KL-6 concentrations were found to be good indicators of clinical outcome in ARDS patients. Particularly, KL-6 levels in ELF measured during the early period after the diagnosis were useful for predicting prognosis in ARDS patients.

Association of airway inflammation with asthma control level evaluated by the asthma control test.

BACKGROUND: The association between airway inflammation and asthma control level is not clear at present. OBJECTIVE: This study aimed to explore the association by using induced sputum and asthma control status as determined by the Asthma Control Test (ACT). We also evaluated the association between the scores for each ACT question item and eosinophilic or neutrophilic airway inflammation. METHODS: The ACT and sputum induction were performed at the same time. Associations between total scores or scores for each question item and sputum eosinophil or neutrophil counts were examined. The study was approved by an Institutional Review Board. RESULTS: Of the 101 patients with chronic asthma enrolled, data from 98 (controlled n = 66, uncontrolled n = 32) were analyzed [60.0 years (43.0-68.0) M:F = 34:64]. Current control status determined by the ACT was not significantly associated with eosinophilic or neutrophilic inflammation. Among the ACT items, only nocturnal symptoms were associated with sputum eosinophils: patients with a positive answer to the question had significantly higher eosinophil counts than patients with a negative answer [5.4 (2.2-17.6) versus 2.1 (0.7-7.3), respectively, p = 0.08]. Furthermore, significant correlation was found between eosinophil counts and the scores for nocturnal symptoms (rs = -0.218 p = 0.031). On the other hand, patients with rescue use of a short-acting b2-agonist (SABA) had significantly higher sputum neutrophil counts than non-SABA users [73.4 (52.8-83.4) versus 61.0 (36.3-74.8), respectively, p = 0.031]. The other ACT items were not significantly associated with sputum neutrophils. The neutrophil count correlated significantly with the frequency of rescue SABA use (rs = -0.218 p = 0.031). CONCLUSIONS: Asthma control level evaluated by the ACT was not associated with airway eosinophilic or neutrophilic inflammation. However, the frequency of nocturnal symptoms was associated with sputum eosinophilia, and the frequency of rescue SABA use was associated with sputum neutrophilia.

Levels of surfactant proteins A and D and KL-6 are elevated in the induced sputum of chronic obstructive pulmonary disease patients: a sequential sputum analysis.

BACKGROUND: Recent clinical studies have suggested that serum surfactant protein (SP) A, SP-D and Krebs von den Lungen-6 (KL-6) are potential biomarkers for interstitial lung diseases. Serum levels of SP-A and SP-D have also been found to be elevated in chronic obstructive pulmonary disease (COPD), but their significance has not been evaluated or compared in induced sputum samples obtained directly from the airways. OBJECTIVE: A sequential sputum analysis was conducted to assess the value of SP-A, SP-D and KL-6 levels in COPD. METHODS: The study material consisted of induced sputum samples from 61 subjects, 28 with COPD and 33 with prolonged cough (cough lasting >3 weeks and normal spirometry). Sputum was collected in 3 fractions (3 periods of 5 min each). Sputum levels of these proteins were measured, and receiver operating characteristic curve analysis was carried out to evaluate the sensitivity, specificity and area under the curve (AUC) for each fraction. RESULTS: The levels of SP-A, SP-D and KL-6 were higher in patients with COPD than in those with prolonged cough in each of the fractions. Sputum levels of these proteins correlated inversely with obstruction and positively with ageing, smoking history, sputum macrophages and eosinophils. Sputum fractionation had a relatively minor effect on the levels and AUC of these proteins. CONCLUSION: Sequential sputum analysis from 3 consecutive fractions indicated a significant difference in the levels of SP-A, SP-D and KL-6 between COPD and prolonged cough. However, sputum fractionation itself had a relatively minor effect on the levels of these proteins.

Chronic hepatitis C virus infection is associated with more severe asthma.

BACKGROUND: Chronic hepatitis C virus (HCV) infection causes intra- and extra-hepatic complications. The elimination of HCV has been reported to be beneficial for asthmatic patients with HCV infection. Therefore, we hypothesized that chronic HCV infection might be associated with the severity of asthma. METHODS: Asthmatic patients were prospectively enrolled from 13 outpatient settings. Hepatitis B surface (HBs) antigen and HCV-RNA were measured at the time of enrollment and evaluated along with the clinical characteristics of the patients including the age, sex, duration of asthma, atopic status, smoking history, and treatment step according to the Global Initiative for Asthma guideline. RESULTS: Of 1327 asthmatic patients, 1258 patients (94.8%) were treated with inhaled corticosteroids, 18 patients were positive for HBs antigen (1.4%), and 32 patients (2.4%) were positive for HCV-RNA. When compared with HCV-RNA-negative patients, HCV-RNA-positive patients required significantly more drugs for the treatment of asthma. No such relationship was observed in patients with positive HBs antigen. A multivariate logistic regression analysis showed that the male sex, a long duration of asthma, status as a current smoker, and HCV-RNA positivity were independently associated with more severe asthma. CONCLUSIONS: These results suggest that chronic HCV infection is an independent factor that predisposes asthmatic patients to more severe asthma. The evaluation of chronic HCV infection may be helpful for the management of severe asthmatic patients without obvious factors associated with severe asthma.

Regression of a primary pulmonary adenocarcinoma after zoledronic acid monotherapy.

Bisphosphonates are widely used for the treatment of metastatic skeletal tumors and hypercalcemia resulting from malignant tumors. Zoledronic acid (ZOL), a third-generation bisphosphonate agent, was recently demonstrated to show synergistic antitumor activity of ZOL when combined with chemotherapy in lung cancer patients. However, whether ZOL exerts direct antitumor activity on lung cancer remains unclear. Here, we report an atypical case encountered while treating a 57-year-old woman with pulmonary adenocarcinoma and multiple metastases of the liver, left adrenal gland, and bone. The nonskeletal lesions, consisting of the primary lesion and hepatic metastasis, regressed after treatment with ZOL alone. We believe this case demonstrates a possible antitumor effect of ZOL against lung cancer.

Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis.

BACKGROUND AND AIM: There is a growing body of evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. In fact, PAI-1 knockout mice are protected from bleomycin-induced pulmonary fibrosis. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA (siRNA) targeting PAI-1 (PAI-1-siRNA) limits the development of bleomycin-induced pulmonary fibrosis. METHODS: Lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) were stained for PAI-1. The distribution of siRNA in the lung, the PAI-1 level in bronchoalveolar (BAL) fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of PAI-1-siRNA in a mouse model of bleomycin-induced pulmonary fibrosis. The effect of PAI-1-siRNA on the epithelial to mesenchymal transition (EMT) was also evaluated using a mouse lung epithelial cell line, LA-4. RESULTS: PAI-1 was overexpressed in the hyperplastic type 2 pneumocytes lining the honeycomb lesions of patients with IPF. The single intranasal instillation of PAI-1-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of PAI-1-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the PAI-1 level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor beta (TGFbeta) in LA-4 cells was inhibited by transfection with PAI-1-siRNA. CONCLUSIONS: The direct suppression of PAI-1 in the lung by the intrapulmonary administration of PAI-1-siRNA attenuated the development and progression of pulmonary fibrosis. The inhibition of EMT may be, at least in part, involved in this effect.

Productive cough is an independent risk factor for the development of COPD in former smokers.

UNLABELLED: The presence of productive cough was an independent risk factor for the development of COPD in Japanese men, particularly former smokers. Stage 0 disease, as defined in GOLD 2001 guidelines, is relevant for the identification of subjects at risk of developing COPD. BACKGROUND AND OBJECTIVE: It has yet to be determined whether the presence of productive cough is a risk factor for the development of COPD. The aim of the present study was to obtain more information on this potential association in Japanese men. METHODS: Seven hundred and eighty-three men with normal spirometry who did not have respiratory disease were recruited. The subjects were divided into three groups: group A, non-smokers; group B, those with a positive smoking history without productive cough; and group C, those with a positive smoking history and productive cough. The incidence rates of COPD were compared among the three groups and the relative risks for the development of COPD were assessed. RESULTS: During the mean follow-up period of 33.6+/-20.4 months, 19 (2.4%) subjects developed COPD. The incidence rate of COPD was significantly higher in group C than in group B (10.1 vs 2.2%, P=0.003). A multivariate analysis of data for all subjects, current smokers and former smokers revealed that productive cough was an independent risk factor for the development of COPD in all subjects and former smokers but not in current smokers. CONCLUSIONS: Productive cough was an independent risk factor for the development of COPD in Japanese men. In particular, former smokers who complain of this symptom should be regarded as being at high risk for the development of COPD. The data suggested that stage 0 disease, as defined in the Global Initiative for Chronic Obstructive Lung Disease 2001 guidelines, is relevant for the identification of subjects at risk of developing COPD.

Airflow limitation in smokers is associated with subclinical atherosclerosis.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality from cardiovascular disease. Although a close association between COPD and atherosclerosis has been speculated, such scientific information is limited. OBJECTIVES: To evaluate subclinical atherosclerosis in smokers with airflow limitation. METHODS: The subjects of this study were healthy middle-aged men. Smokers with airflow limitation (n = 61) and age-matched control smokers (n = 122) and control never-smokers (n = 122) without airflow limitation were included in the present study. Subjects with diabetes, acute infection, and respiratory disease other than COPD were excluded beforehand. All subjects underwent chest radiogram, spirometry, blood sampling, and carotid ultrasonography. We determined carotid intima-media thickness and focal atheromatous plaque as indicators of subclinical atherosclerosis. MEASUREMENTS AND MAIN RESULTS: Mean carotid intima-media thickness was greater in smokers with airflow limitation than in control smokers (P < 0.01) and control never-smokers (P < 0.005). Focal carotid plaque was significantly more prevalent in smokers with airflow limitation than in control never-smokers (P < 0.005). Multivariate analyses showed significant associations between thickened intima-media thickness and decreased percent predicted FEV(1) (P = 0.001) and between plaque and log(10) C-reactive protein (P = 0.013) independent of age, pack-years of smoking, body mass index, peripheral mean arterial pressure, heart rate, glucose, and low-density lipoprotein cholesterol. CONCLUSIONS: Smokers with airflow limitation had exaggerated subclinical atherosclerosis. This study suggests that middle-aged men who are susceptible to COPD may also be susceptible to vascular atherosclerosis by smoking, and atherosclerotic change starts early in the disease process of COPD.

Suplatast tosilate prevents bleomycin-induced pulmonary fibrosis in mice.

Increasing evidence suggests that the development of pulmonary fibrosis is a T helper (Th) 2-mediated process. Suplatast tosilate is a Th2 cytokine inhibitor that is widely used as an asthma controller in Japan. Therefore, we hypothesized that suplatast tosilate might have an inhibitory effect on the development of pulmonary fibrosis. To investigate this effect, suplatast tosilate was administered to mice after the intratracheal instillation of bleomycin (BLM). The effect of suplatast tosilate was studied by analysis of bronchoalveolar lavage (BAL) fluid and a hydroxyproline assay. We found that the treatment of mice with suplatast tosilate significantly reduced the degree of pulmonary fibrosis. Because a significantly elevated Th2 response was not detected in the C57BL/6 mice after BLM administration, the effect of suplatast tosilate on Th2 cytokines could not be demonstrated. Interestingly, however, the up-regulation of the monocyte chemoattractant protein (MCP)-1 levels in the BAL fluid was found to be suppressed. Following these results, we also demonstrated that suplatast tosilate effectively inhibited the production of MCP-1 in alveolar macrophages (AMs). These findings suggest that suplatast tosilate has both anti-inflammatory and antifibrotic effects, which were associated with a suppressed MCP-1 expression in AMs. Thus, suplatast tosilate, which is already widely used in Japan, may warrant further consideration as a potentially useful treatment for pulmonary fibrosis.

Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis.

BACKGROUND: Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling. Our previous study suggested that SOCS1 regulates collagen synthesis by lung fibroblasts, suggesting a role of SOCS1 in the pathophysiology of pulmonary fibrosis. OBJECTIVES: We sought to investigate the role of SOCS1 in pulmonary inflammation and fibrosis in vivo. METHODS: SOCS1-haplodeficient mice treated with bleomycin (BLM) were evaluated for pulmonary inflammation and fibrosis compared with wild-type mice. The human study group was composed of 18 patients with interstitial lung disease. Lung specimens obtained by means of open lung biopsy were investigated to determine whether the severity of fibrosis was associated with decreased SOCS1 expression. Finally, we further analyzed the effect of exogenous SOCS1 on BLM-induced lung injury based on adenoviral SOCS1 gene transfer to the lung. RESULTS: SOCS1-haplodeficient mice treated with BLM showed markedly enhanced pulmonary inflammation and fibrosis compared with wild-type mice. Using human lung specimens, we found that SOCS1 mRNA levels inversely correlated with duration of the disease. SOCS1 expression was significantly less in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) compared with that in non-IPF patients. Moreover, SOCS1 expression was significantly less in severe fibrotic lesions (lower lobe) than in less fibrotic lesions (upper lobe). Adenoviral SOCS1 gene transfer to murine lungs significantly decreased lymphocytic inflammation, pulmonary fibrosis, and mortality because of BLM-induced lung injury. Exogenous SOCS1 inhibited expression of various cytokines, including TNF-alpha, which might play a key role. CONCLUSIONS: These results suggest that SOCS1 might act as a suppressor for pulmonary fibrosis. SOCS1 might be a target of IPF treatment.

Effects of the addition of Beta2-agonist tulobuterol patches to inhaled corticosteroid in patients with asthma.

BACKGROUND: Whether the additive effects of the tulobuterol patch (TP), the world's first transdermal beta2-agonist preparation, are useful in asthma patients receiving inhaled corticosteroid (ICS) is unclear. To examine the add-on effects of TP on bronchial hyperresponsiveness and reduction of the percentage of sputum eosinophils, and to compare add-on effects of TP, slow-release theophylline (SRT), and a leukotriene receptor antagonist (LTRA) in patients with asthma receiving ICS. METHODS: Study 1: We randomly allocated 24 patients with asthma receiving ICS alone in equal numbers to either control treatment (ICS alone at conventional doses) or TP treatment (ICS at conventional doses plus TP at 2mg/day). Following a 2-week observation period, patients received the allocated drug regimens for 4 weeks. Methacholine challenge test and measurement of percentage of eosinophils in hypertonic saline-induced sputum were performed before and after the treatment period. Study 2: We compared add-on effects of TP, SRT, and LTRA in 65 patients with asthma receiving ICS alone, using spirometry and peak expiratory flow (PEF). Participants in these studies had experienced decrease in morning PEF to <80% of the predicted value at least twice a week. RESULTS: Study 1: In the TP group, improvement of bronchial hyperresponsiveness and decrease in percentage of sputum eosinophils both indicated a statistically significant difference (p < 0.01, and p < 0.05, respectively). These findings were not observed in the control group. Study 2: forced expiratory volume in 1 second (FEV(1)) and PEF markedly increased after treatment with TP compared with treatment with SRT or LTRA. CONCLUSIONS: These findings suggest that TP can be used as a long-term add-on controller for patients with asthma receiving ICS.