Yasuyuki Sano

Inducible Expression of a Th2-Type CC Chemokine Thymus- and Activation-Regulated Chemokine by Human Bronchial Epithelial Cells

CCR4 is now known to be selectively expressed in Th2 cells. Since the bronchial epithelium is recognized as an important source of mediators fundamental to the manifestation of respiratory allergic inflammation, we studied the expression of two functional ligands for CCR4, i.e., macrophage-derived chemokine (MDC) and thymus- and activation-regulated chemokine (TARC), in bronchial epithelial cells. The bronchial epithelium of asthmatics and normal subjects expressed TARC protein, and the asthmatics showed more intense expression than the normal subjects. On the other hand, MDC expression was only weakly detected in the asthmatics, but the intensity was not significantly different from that of normal subjects. Combination of TNF-α and IL-4 induced expression of TARC protein and mRNA in bronchial epithelial A549 cells, which was slightly up-regulated by IFN-γ. The enhancement by IFN-γ was more pronounced in bronchial epithelial BEAS-2B cells, and a maximum production occurred with combination of TNF-α, IL-4, and IFN-γ. On the other hand, MDC was essentially not expressed in any of the cultures. Furthermore, expressions of TARC protein and mRNA were almost completely inhibited by glucocorticoids. These results indicate that the airway epithelium represents an important source of TARC, which potentially plays a role via a paracrine mechanism in the development of allergic respiratory diseases. Furthermore, the beneficial effect of inhaled glucocorticoids on asthma may be at least in part due to their direct inhibitory effect on TARC generation by the bronchial epithelium.

Increased levels of a TH2‐type CC chemokine thymus and activation‐regulated chemokine (TARC) in serum and induced sputum of asthmatics

Background: Cytokines liberated by TH2 cells play crucial roles in the pathogenesis of bronchial asthma. Recent studies have demonstrated that CC chemokine receptor (CCR)4 is preferentially expressed by TH2 cells. These facts suggest possible involvement of two CCR4‐specific ligands i.e., thymus and activation‐regulated chemokine (TARC) and macrophage‐derived chemokine (MDC), in the pathogenesis of bronchial asthma via recruitment of TH2 cells to inflammatory sites. We investigated the levels of TARC and MDC in the serum and induced sputum of asthmatics.

Eotaxin in induced sputum of asthmatics: relationship with eosinophils and eosinophil cationic protein in sputum.

Background: Eosinophilic inflammation is a crucial aspect of allergic diseases such as bronchial asthma. An eosinophil‐active chemokine, eotaxin, may play a role in the pathogenesis of the tissue eosinophilia accompanying asthma.

Gene‐expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin‐intolerant asthma

Background Aspirin‐intolerant asthma (AIA) is a subtype of asthma induced by non‐steroidal anti‐inflammatory drugs and characterized by an aggressive mucosal inflammation of the lower airway (asthma) and the upper airways (rhinitis and nasal polyp). The lower airway lesion and the nasal polyp in AIA are postulated to have common pathogenic features involving aspirin sensitivity that would be reflected in the gene expression profile of AIA polyps.

Can Mycobacterium tuberculosis infection prevent asthma and other allergic disorders

It is generally considered that tuberculosis (TB) is a disease which upregulates Th1 cell function. There is a hypothesis that infection of Mycobacterium tuberculosis may prevent allergic disorders such as bronchial asthma. However, our clinical experience of patients with TB somewhat conflicts this hypothesis. Hence, we investigated Th1/Th2 balance in the peripheral blood of patients with active TB by measuring serum levels of IgE antibody and by intracellular cytokine assay. We found that serum levels of IgE in the patients with active TB were significantly higher than in those with lung cancer or with COPD. In the TB patients, titers of IgE tended to correlate with disease severity. Intracellular cytokine assay demonstrated that IFN-γ-positive cells were significantly decreased in the patients with active TB compared to normal controls. The ratio of IFN-γ-positive (Th1-like)/IL-4-positive (Th2-like) cells was remarkably reduced in the TB patients (p < 0.0001). This ratio showed a significant negative correlation with erythrocyte sedimentation rate and with C-reactive protein. Therapy against TB for 2–3 months did not result in significant changes of the Th1/Th2 ratio. These findings suggest that infection of M. tuberculosis does not systematically upregulate Th1 cells in some patients, and is unlikely to prevent allergic disorders like asthma.

Aminophlline is effective on acute exacerbations of asthma in adults–objective improvements in peak flow, spirogram, arterial blood gas measurements and lung sounds

Second Department of Medicine, Teikyo University School of Medicine, *Clinical Research Center for Allergy and Rheumatology. National Sagamihara Ho.spital. f Section of Allergy and Respiratory Medicine. Doai Memorial Hospital IMat.sunwra Clinic and Research institute for Asthma and Imtnunological Diseases, l^Fourth Department of Medicine, Nippon Medical School, and ^International Medical Center of Japan, Tokyo, Japan

Effect of inhaled corticosteroid on an immunoreactive thymus and activation-regulated chemokine expression in the bronchial biopsies from asthmatics

Background:  Bronchial asthma is characterized by airway inflammation, notably because of eosinophils and T cells. Thymus and activation‐regulated chemokine (TARC) is known to selectively attract Th2 cells, and is increased in response to interleukin (IL)‐4 and IL‐13, which share a common receptor, IL‐4 receptor alpha (IL‐4Rα). While corticosteroids have proven, very effective in modifying airway inflammation, the effect of corticosteroids on TARC in asthmatics has been little studied.

The Efficacy and Tolerability of Intravenous Montelukast in Acute Asthma Exacerbations in Japanese Patients

Objectives. In Japan, the Asthma Prevention and Management Guidelines recommend nebulized β-agonists, IV (intravenous) drip corticosteroids, as well as IV drip aminophylline for acute asthma treatment. However, current treatment for acute asthma provides inadequate benefit for some patients. We evaluated the efficacy and safety of IV montelukast added to standard therapy in Japanese patients with acute asthma exacerbations. Methods. This multicenter, randomized, double-blind, parallel-group study compared IV montelukast 7 mg, 14 mg, and placebo in Japanese patients with acute asthma exacerbations (N = 242). Fifteen- to sixty-five-year-old patients with acute asthma were treated with standard care during a screening period that lasted ≤60 minutes. Patients with FEV1 (forced expiratory volume in 1 second) ≤70 predicted were randomly allocated to one of three treatment groups. The primary end point was the time-weighted average change in FEV1 from baseline over 60 minutes [ΔFEV1 (0–60 minutes)] after study drug administration. Secondary end points included the time-weighted average change in FEV1 over 20, 40, and 120 minutes [ΔFEV1 (0–T min)]. Results. IV montelukast 7 mg was significantly more effective than placebo for the time-weighted average ΔFEV1 (0–60 minutes) [least squares (LS) mean 0.09 L vs. 0.01 L; p < .05]. IV montelukast 14 mg was also more effective than placebo (LS mean 0.17 L; p < .001). Similar improvements in time-weighted average [ΔFEV1 (0–T min)] were seen at all time points (all p < .05). Both doses of IV montelukast demonstrated a significant increase in average ΔFEV1 compared with placebo within 10 minutes of administration (p < .001 to p < .01). The tolerability of IV montelukast was similar to that of placebo. Conclusion. IV montelukast was significantly more effective than placebo in the improvement of ΔFEV1 in Japanese patients, suggesting its role as an adjunctive therapy to existing guideline recommendations.

Progress in suplatast tosilate research.

The therapeutic strategy for bronchial asthma has made dramatic advances over the past dozen years. In particular, inhaled corticosteroids have contributed most to improve the control of this disease, and nowadays many asthmatic patients can lead a much better daily life than before through the use of this inhaled regimen [1–5]. However, it took many years until inhaled corticosteroids, with anti-inflammatory effects but no acute bronchodilatory effects, became recognized as being central in the treatment of persistent asthma. ‘Asthma is a disease derived from airway allergic inflammation; broncho-constriction is a secondary phenomenon of the disease.’ This concept of the disease has become widely accepted only recently [6]. Suplatast tosilate is an anti-asthma agent defined as a ‘Th2 cytokine inhibitor’ in ‘Asthma Prevention and Management Guidelines 2006, Japan’ [7]. However, the detailed mechanism of the action of this medicine is yet to be elucidated. In the present issue of the journal, Tanaka and colleagues [8] reported that suplatast tosilate indeed affected dendritic cells, thereby exerting its anti-asthma effect, providing a new perspective for treatment of asthmatics. Sympathomimetic drugs and xanthines used to play a major role in the treatment for asthmatics, but today it has changed dramatically. Despite recent scientific progress, the mechanism of the action of xanthines has not been fully elucidated, although a study has shown that xanthines have the efficacy of anti-inflammatory drugs [9]. The manner in which theophylline affects eosinophils and T cells [10], and shows such anti-inflammatory effects at concentrations lower than those required for bronchodilation, is interesting [11]. Today, highly potent inhaled corticosteroids and longacting b-2 agonists (LABA) are available for asthmatics. Nowadays, the inhaled LABA and corticosteroid combination therapy has become a trend for the treatment of asthma. Together with topical short-acting b-2 agonist used on demand, it is possible to treat a considerable number of patients. However, these therapies are still insufficient to manage all cases of asthma. Most corticosteroids were already synthesized in the 1940s and 1950s and used as if they were magic remedies. Indeed, corticosteroids have a strong anti-inflammatory effect, but one of the lessons we have learnt from the past is that corticosteroids are not potent for all the steps of mechanisms in inflammatory diseases. The controversy over the use of corticosteroids to treat asthma, a disease characterized mainly by reversible airway constriction, has continued for years, reflecting frustration due to lack of convincing and satisfactory explanations, although it was empirically known that corticosteroids were amazingly effective against asthma. Resolution of this inconsistency eventually led to great advances in the treatment of asthma. The next antiasthma drug developed through the niche of treatment with inhaled corticosteroids might be a leukotriene receptor antagonist. This agent became available only shortly more than a decade ago. It is known that the leukotriene receptor antagonists induce bronchodilation and inhibit airway constriction induced by antigen inhalation or exercise [12], and also exert an anti-inflammatory effect [13]. Furthermore, leukotrienes are known to play an important role in airway remodelling [14–16]; in this regard, leukotrienes might be used as an inhibitor of airway remodelling. Long-term use of oral corticosteroids is still inevitable in a few patients. Systemic corticosteroids induce secondary diseases such as osteoporosis, peptic ulcer, and immunocompromised infections and so on. On the other hand, it is widely recognized that corticosteroids are not the panacea for all cases of allergic inflammation. As an anti-allergic inflammatory agent, drugs that are highly likely to follow corticosteroids are cromolynes. Sodium cromoglycate was first approved about 40 years ago. It was the first milestone drug to make the scientific community realize that bronchodilators were not the only useful drugs for asthma. The major targets of cromolynes Correspondence: Dr Yasuyuki Sano, Department of Allergy and Respiratory Medicine, Doai Memorial Hospital, 2-1-11 Yokoami, Sumida-ku, Tokyo 130-8587, Japan. E-mail: cky07460@moon.odn.ne.jp doi: 10.1111/j.1365-2222.2007.02755.x Clinical and Experimental Allergy, 37, 970–972

Comparison of salmeterol/fluticasone propionate (FP) combination with FP+sustained release theophylline in moderate asthma patients.

OBJECTIVES To compare the efficacy and safety of the salmeterol/fluticasone propionate combination product with concurrent sustained release theophylline plus fluticasone propionate in adult Japanese patients with persistent asthma. DESIGN Multicentre, randomised, double-blind, double-dummy, parallel-group study. PATIENTS AND INTERVENTIONS Three hundred and eighty-three asthmatic patients receiving sustained release theophylline 200-400mg/day entered the study and were randomised to receive either salmeterol/fluticasone propionate combination (SFC) 50microg/250microg+1 placebo tablet, fluticasone propionate 250microg+1 sustained release theophylline 200mg (SR-T+FP), twice daily for 8 weeks. RESULTS The adjusted mean change morning peak expiratory flow (PEF) over 8 weeks was 29.8L/min in the SFC group and 16.3L/min in the SR-T+FP group, with a treatment difference of 13.4L/min (p=0.0004). SFC improved evening PEF, FEV1, V50 and V25 at the completion of treatment to a greater extent than SR-T+FP (all p<0.05). A higher percentage of patients on SFC were symptom free (p=0.0286) and rescue free (ns) than those on SR-T+FP. There was not a statistically significant difference between treatments in symptom scores. Both treatments were well tolerated. CONCLUSIONS The finding that SFC was associated with greater improvements in lung function than SR-T+FP, a commonly employed treatment for asthmatic patients in Japan, suggests that SFC should be the preferred therapeutic option in these patients.