Hidenori Kawakami

A Novel Prostacyclin Agonist Protects against Airway Hyperresponsiveness and Remodeling in Mice

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

Cluster analysis identifies characteristic phenotypes of asthma with accelerated lung function decline

Abstract Objective: While the majority of individuals with asthma retain normal lung function over time, some exhibit accelerated lung function decline. Preservation of lung function is an important aspect of asthma management. Whether the asthma guidelines can prevent lung function decline remains controversial. This study was performed to determine the distribution of asthmatic subjects with greater lung function decline and to identify characteristic clinical features of such subjects treated in accordance with clinical guidelines by using hierarchical cluster analysis. Methods: Eighty-six asthmatic subjects without a history of smoking were assessed with respect to eight variables selected from clinical phenotypes by using step-wise multiple regression analysis. Hierarchical cluster analysis using Ward’s method generated a dendrogram for estimation of the number of clusters within the population and the differences between them. Results: Three distinct clusters were identified. Cluster 1 (n = 40) comprised women with late-onset asthma. Cluster 2 (n = 17) comprised subjects with early-onset asthma, atopy and long disease duration. Cluster 3 (n = 29) predominantly comprised older men who had late-onset asthma, a lower prevalence of exacerbation and a lower predicted % forced expiratory volume in 1 s (FEV1) at baseline. Subjects in cluster 3 showed a mean decline in FEV1 of 69 mL/year, which was the greatest lung function decline among the three clusters. Conclusion: We identified a subgroup of patients with accelerated lung function decline despite appropriate asthma treatment based on guidelines constructed by using subjective symptoms.

IL‐17 eliminates therapeutic effects of oral tolerance in murine airway allergic inflammation

Oral tolerance is a classically used strategy for antigen‐specific systemic immunotherapy. However, the roles of IL‐17 in modification of oral tolerance are not yet understood.

Efficacy of Using the Japanese Version of the Asthma Control Test for Determing the Level of Asthma Control in Clinical Settings

BACKGROUND The Asthma Control Test (ACT) is frequently used for the evaluation of asthma control in clinical care setting because it does not require the use of pulmonary function tests, which can be difficult for general practitioners to use. However, few large-scale studies have investigated the efficacy of the Japanese version ACT (J-ACT) in actual use during clinical care. METHODS The aim of this study was to analyze the efficacy of the J-ACT in a clinical care setting. Using data from a 2008 questionnaire survey including the J-ACT by the Niigata Asthma Treatment Study Group, we compared the ACT scores of 2233 patients with respect to multiple parameters, including the severity by Japanese Society of Allergology and the attack frequency. Using the definition of asthma control partially referred to Global Initiative for Asthma (GINA) guidelines from the survey data, the accuracy screening and determination of optimal ACT cutpoints were performed by retrospective analysis. RESULTS Cronbachs α for the J-ACT was 0.785. Patients with more severe asthma and more frequent asthma attacks had lower ACT scores than did patients with less severe, less frequent attacks. The optimal ACT cutpoints were 24 for the controlled asthma and 20 for the uncontrolled asthma. CONCLUSIONS Our study, the first large-scale investigation of the efficacy of the J-ACT, determined that this evaluation tool is highly efficacious in establishing the level of asthma control. However, the determination of accurate cutpoints for the J-ACT will require more clear definitions of asthma control in future prospective studies.

A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice

Background ONO‐1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A2 (TxA2) synthase inhibitory activity. We investigated the effect of ONO‐1301 on development of airway allergic inflammation.

A single injection of a sustained-release prostacyclin analog (ONO-1301MS) suppresses airway inflammation and remodeling in a chronic house dust mite-induced asthma model

ONO-1301, a novel prostacyclin agonist with thromboxane A2 synthase inhibitory activity, is a useful agent for ameliorating airway allergic inflammation; however, its short-action feature implies a requirement for the frequent administration of this drug. Therefore, we investigated the effects of ONO-1301-loaded poly (d,l-lactic-co-glycolic acid) microspheres (ONO-1301MS; to release ONO-1301 for 3 weeks) on the airway inflammation and remodeling in chronic house dust mite (HDM)-induced model. Balb/c mice were exposed to an HDM extract intranasally for 5 days/week for 5 consecutive weeks. The mice received a single subcutaneous injection of ONO-1301MS or vehicle after 3 weeks of HDM exposure, followed by 2 additional weeks of HDM exposure. Forty-eight hours after the last HDM exposure, airway hyperresponsiveness to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised and stained to check for goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis. Mice receiving ONO-1301MS showed significantly lower airway hyperresponsiveness, airway eosinophilia, and induced T helper 2 cytokine production compared with mice receiving the vehicle. Histological findings such as goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis were decreased in ONO-1301MS-treated mice compared with vehicle-treated mice. A single administration of ONO-1301MS achieved sustained elevation of its circulating level for 3 weeks. These data suggest that a single administration of ONO-1301MS may suppress airway hyperresponsiveness, airway allergic inflammation, and development of airway remodeling in chronic HDM-induced asthma model. This agent may be effective as an anti-inflammatory and remodeling drug in the practical treatment of asthma.

Characteristics of eosinophilic and non-eosinophilic asthma during treatment with inhaled corticosteroids

Abstract Objective: Eosinophilic inflammation in the respiratory tract is a hallmark of bronchial asthma. In naïve cases, the inflammatory profile is associated with disease severity and reactivity to inhaled corticosteroids (ICS). Sustained airway eosinophilia has been reported during ICS treatment. However, the immunological characteristics of these cases are not known and it is unclear if this situation contributes to asthma control. This study was performed to determine the answer of these questions. Methods: To compare phenotypes of eosinophilic and non-eosinophilic asthma (EA and NEA, respectively) under ICS treatment, clinical data were obtained from asthmatic subjects (n = 22) and healthy controls (n = 10), and the leukocyte compositions of induced sputum and peripheral blood were determined. T lymphocyte profiles in systemic blood were assessed by flow cytometry. Results: A higher frequency of emergency room visits was observed in the NEA group, which had a higher neutrophil count relative to the total inflammatory cell population in induced sputum than the EA group (59.5 versus 36.6%; p < 0.01). The fraction of helper T (Th)17 lymphocytes as well as the ratio of Th17 to regulatory T cells (Treg) in the peripheral blood was higher in the NEA than in the EA group (0.24 versus 0.13; p < 0.05). Conclusions: Th17 were more prevalent than Treg cells in the peripheral blood of NEA patients under ICS treatment, corresponding to neutrophil-dominant airway inflammation and a severe asthmatic phenotype. Thus, an imbalance in Th17/Treg may be associated with the pathogenesis of NEA in patients undergoing ICS treatment.

Dermatomyositis with hemorrhagic myositis

A 64-year-old Japanese female, diagnosed as dermatomyositis with acute interstitial pneumonia, complained of acute abdominal pain. Computed tomography of the abdomen showed hematoma in the right retroperitoneum and left rectus-sheath. Angiogram showed multiple small aneurysms on left iliolumbar artery and a horizontal linear flush, suggesting active bleeding foci in the muscles. Although arterial embolization therapy was effective for hemostatic treatment, she died of thrombotic thrombocytopenic purpura and multiple organ failure without respiratory insufficiency. Other causes of microaneurysm, such as systemic vasculitides or infectious diseases, were excluded. We considered that this is the first case report of dermatomyositis with hemorrhagic myositis associated with small aneurysms.

Effect of ciclesonide on bronchial asthma in athletes.

Background. Although it is well established that the incidence of bronchial asthma is higher in the athlete population than in the general population, little information exists about the efficacy of treatment of bronchial asthma in the athlete population. Objectives. We conducted this study with the objective of determining the efficacy of treatment of bronchial asthma in an athlete population living in Niigata Prefecture, Japan. Methods. We conducted a retrospective study of bronchial asthma in an athlete population. Athletes diagnosed as having asthma, based on the Global Initiatives for Asthma (GINA) guidelines, who visited the Niigata Institute for Health and Sports Medicine between January 2007 and June 2008 were enrolled in this study. We compared two groups of patients, a group treated with ciclesonide (CIC) alone and another treated with montelukast alone, with the treatment duration lasting at least 3 months in both groups. The CIC or montelukast groups were compared in terms of the clinical symptoms, pulmonary function parameters, and fraction of exhaled nitric oxide (FENO). Results. There were no significant differences in the sex distribution, age, frequency of symptoms, pulmonary function parameters, or other examination data before treatment between the CIC and montelukast groups. The CIC group tended to show better symptom control and to need fewer changes of treatment than the montelukast group. While improvements of the pulmonary function parameters and FENO values were observed in the CIC group, no significant changes of these parameters were observed in the montelukast group. Conclusions. These data suggest that CIC offers greater promise for the control of asthma than montelukast in the athlete population, although further investigation is required.