The airway smooth muscle is the key determinant of airway narrowing in asthma but its function in the absence of disease is unknown. Evidence for an intrinsic abnormality in the muscle in asthma is only just emerging. The airway smooth muscle is not merely a contractile cell, but also one which determines the composition of, and interacts with the extracellular matrix, and which may participate in inflammatory and allergic reactions and viral infections. The reason for the differences which have been observed in the in vitro properties of airway smooth muscle derived from asthmatic individuals may result from an inherent "supercontractility", an increased tendency to proliferate due to the absence of an inhibitory transcription factor C/EBP-α, the influence of an altered extracellular matrix and/or a decrease in release of factors such as PGE₂ which would under normal circumstances inhibit both proliferation and contraction. Although long acting beta agonists and corticosteroids are successful treatments for inflammation and bronchoconstriction, the structural changes which constitute airway remodelling may require additional therapeutic intervention, the nature of which will be determined by thorough investigation of the mechanisms underlying the asthmatic phenotype.

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In this review we discuss the potential of a new procedure, termed Bronchial Thermoplasty to prevent serious consequences resulting from excessive airway narrowing. The most important factor in minimizing an asthmatic attack is limiting the degree of smooth muscle shortening. The premise that airway smooth muscle can be either inactivated or obliterated without any long-term alteration of other lung tissues, and that airway function will remain normal, albeit with reduced bronchoconstriction, has now been demonstrated in dogs, a subset of normal subjects, and mild asthmatics. Bronchial Thermoplasty may thus develop into a useful clinical procedure to effectively impair the ability for airway smooth muscle to reach the levels of pathologic narrowing that characterizes an asthma attack. It may also enable more successful treatment of asthma patients who are unresponsive to more conventional therapies. Whether this will remain stable for the lifetime of the patient still remains to be determined, but at the present time, there are no indications that the smooth muscle contractility will return. This successful preliminary experience showing that Bronchial Thermoplasty could be safely performed in patients with asthma has led to an ongoing clinical trial at a number of sites in Europe and North America designed to examine the effectiveness of this procedure in subjects with moderately severe asthma.

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Airway remodeling in asthma has been recognized as structural changes of airways such as smooth muscle hypertrophy (an increase in size of airway smooth muscle cells) and hyperplasia (an increase in the number of airway smooth muscle cells), thickening and fibrosis of sub-epithelial basement membrane, hypertrophy of bronchial glands, goblet cell hyperplasia, and thickening of airway epithelium. In these pathological changes, airway smooth muscle remodeling has been recognized as one of the most important factors related to in vitro and in vitro airway responsiveness and the severity of asthma. Both hypertrophy and hyperplasia have been shown in asthmatic airways by morphometrical analyses, although there is a wide variation in the contribution of each mechanism in each patient. Such changes could also be recognized as a phenotypic modulation of airway smooth muscle. On the background of airway smooth muscle remodeling, the existence of several contributing factors, such as inflammatory mediators, growth factors, cytokines, extra-cellular matrix proteins, and genetic factors have been suggested. On the other hand, recent studies revealed that airway smooth muscle could also be a source of inflammatory mediators promoting airway inflammation. In this article, the recent understanding in the mechanisms of airway smooth muscle remodeling in asthma, its relations to airway inflammation and airway physiology, and possible usefulness of early intervention with inhaled glucocorticoids have been discussed.

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Protein kinase C (PKC) isoforms are being elucidated as an increasingly diverse family of enzymes involved in the downstream signal transduction and cell function in various types of cells. To date, 11 PKC isoforms have been identified; they are grouped according to their molecular structure and mode of activation: conventional PKCs (α, βI, βII, and γ), novel PKCs (δ, ε, μ, θ, and η), and atypical PKCs (ζ, and ι/λ). Eosinophils are involved in the pathogenesis of allergic diseases such as bronchial asthma, pollinosis, and atopic dermatitis as well as in the inflammatory response to parasitic infections. Recent studies using selective activators and inhibitors of individual PKC isoforms have revealed that this enzyme is involved in eosinophil dynamics such as cell motility and other functions. However, the role of PKCs in eosinophil functions has been not wholly understood. In this review, we have focused upon and summarized the current knowledge regarding the role of PKC isoforms in eosinophil functions.

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Background: Eosinophils are considered to be the major inflammatory cells in asthma. Since regulated on activation, normal T expressed and secreted (RANTES) is a potent chemoattractant for various important inflammatory cells such as eosinophils as well as memory T cells potentially recruiting these cells to an inflamed focus, RANTES has been considered to play a key role in various allergic disorders such as asthma.
Methods: To extend our understanding of the participation of eosinophils and T cells in relation to the production of RANTES in response to the specific allergen in asthma, we examined the production of RANTES from peripheral blood mononuclear cells cultured with specific allergen in atopic asthma patients by a sandwich enzyme-linked immunosorbent assay.
Results: It was revealed that mononuclear cells produced RANTES but not eotaxin in response to the specific allergen in asthma. RANTES production from mononuclear cells of asthma patients with eosinophilia was greater than that of asthma patients without eosinophilia. Moreover, in this study, no differences in RANTES production between CD4 negative cells and CD8 negative cells were observed.
Conclusions: Taken together, these findings may suggest that mononuclear cells play a crucial role in the pathogenesis, particular in eosinophil and T lymphocyte recruitment into the inflamed focus of asthma through RANTES production in response to the specific allergen.

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Background: Epinastine hydrochloride and fexofenadine hydrochloride, the second-generation antihistamines, are largely used in the indication of allergic rhinitis in Japan. The purpose of this study was to compare the protective efficacy of epinastine hydrochloride or fexofenadine hydrochloride using a nasal provocation test with Japanese cedar pollen allergen.
Methods: A single-dose, placebo-controlled, single-blind crossover clinical study was conducted in patients with Japanese cedar pollinosis. The pollen exposure was done by the antigen provocation by disc method and involved repeated provocation five times per day.
Results: Among the active agents studied—epinastine hydrochloride and fexofenadine hydrochloride—epinastine hydrochloride significantly decreased the number of sneezing attacks and the quantity of nasal discharge for 3 hours after drug administration compared with placebo, a finding supported by the quantity of nasal discharge in the nasal findings. In this study, fexofenadine hydrochloride showed no significant difference compared with placebo.
Conclusions: This study demonstrates better protection with epinastine hydrochloride than with fexofenadine hydrochloride or placebo in a nasal provocation test with Japanese cedar pollen allergen.

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Background: To investigate the functional role of protease activated receptor (PAR) -2 in T lymphocytes, we analyzed TCR-mediated inflammatory cytokine production using PAR-2 deficient (KO) and wild type (WT) mice.
Methods: Production of serum IgE and cytokines by spleen CD4⁺ T cells was determined in OVA-sensitized and OVA-challenged mice of PAR-2 KO in contrast to WT mice. Phosphorylation of JNK1 and 2 was determined by Western blotting.
Results: A reduction in serum levels of IgE and IL-4 production by splenic CD4⁺ T cells from OVA-sensitized and OVA-challenged KO mice compared to WT mice was observed. By contrast, IFN-γ production was upregulated after antigen stimulation in KO mice. Anti-CD3-mediated phosphorylation of JNK1 was upregulated in splenic CD4⁺ T cells from KO mice compared to WT mice.
Conclusions: PAR-2 participates in the regulation of T cell cytokine production that may be caused by modulation of JNK1 phosphorylation.

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Background: Histamine synthesized by histidine decarboxylase (HDC) from L-histidine is a major chemical mediator in the development of nasal allergy which is characterized by nasal hypersensitivity. However the regulatory mechanism of histamine synthesis by HDC remains to be elucidated. The objectives of the present study were to examine the changes of histamine content, HDC activity and HDC mRNA expression in the nasal mucosa of allergy model rats sensitized by the exposure to toluene diisocyanate (TDI) and to investigate the effect of dexamethasone on the above mentioned allergic parameters.
Methods: Rats were sensitized and provocated by TDI and the nasal allergy-like behaviors were scored during a 10 minute period after provocation. Histamine content and HDC activity in the nasal mucosa were determined using fluorometric high performance liquid chromatography. The expression of HDC mRNA in nasal mucosa was determined using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
Results: In TDI-sensitized rats, nasal allergy-like behaviors such as sneezing and watery rhinorrhea were induced. Histamine content, HDC activity and HDC mRNA expression in nasal mucosa were also significantly increased after TDI provocation. Pretreatment with dexamethasone significantly suppressed nasal allergy-like behaviors, up-regulation of histamine content, HDC activity and HDC mRNA induced by TDI in TDI-sensitized rats.
Conclusions: These findings indicate that increased synthesis of histamine through up-regulation of HDC gene expression and HDC activity in nasal mucosa plays an important role in the development of nasal hypersensitivity. Repression of HDC gene expression and HDC activity by dexamethasone may underlie its therapeutic effect in the treatment of allergy.

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Background: Inhaled corticosteroids (ICSs) are widely used in combination with other classes of drugs for treatment of childhood asthma. The efficacy and the safety of montelukast added to low-dose ICS therapy were compared with those of sustained-release theophylline added to low-dose ICS therapy in asthmatic children in the present study.
Methods: Following the 2-week run-in period, 6-to 14-year old patients receiving treatment with ICSs were randomized to treatment for 4 weeks with either montelukast 5 mg once daily or sustained release theophylline 5—8 mg/kg (dry syrup) or 100—200 mg (tablet) twice daily. Patients also received a fixed dose of ICS throughout the run-in and treatment periods. The primary efficacy endpoint was the change from baseline in peak expiratory flow (PEF) at Week 2.
Results: A significant increase in morning PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 2 (change from baseline of 22.8 L/minvs. 8.7 L/min; p = 0.041 for between-group difference) and at Week 4 (31.0 L/minvs. 9.8 L/min; p = 0.012). A significant increase in evening PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 4 (24.7 L/minvs. 8.7 L/min; p = 0.027). There were no significant differences between the treatment groups in incidences of clinical and laboratory adverse experiences.
Conclusions: The results indicate that montelukast added to low-dose ICS is an effective and safe option for the treatment of asthma in children.

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Background: Injectable methylxanthines are useful drugs in the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) that are followed in Japan recommend the use of sustained-release theophylline to control the disease and use of injectable methylxanthines to alleviate symptoms. In contrast, the guidelines followed in the west do not promote theophylline use due to safety concerns, and the use of injectable methylxanthines in particular are not recommended. We thus conducted a study on adult patients with bronchial asthma or chronic obstructive pulmonary disease treated with theophylline and injectable methylxanthines in Japan in order to assess the safety of these drugs.
Methods: 876 patients were surveyed at 55 medical institutions by the Committee on the Safety of Sustained-Release Theophylline and Injectable Methylxanthines (CST) of the Committee for Asthma Prevention and Management Guidelines of the Japanese Society of Allergology (JSA). 682 of the patients were evaluated for safety.
Results: Adverse reactions including facial flushing, palpitations, headache, tinnitus, diaphoresis, nausea, vomiting and tachycardia were reported by only 2 (0.29%) of the 682 patients, but none of these were serious.
Conclusions: The results confirm that injectable methylxanthines are safe, when used in accordance with the JGL.

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Background: We investigated the early efficacy of topical levocabastine, an H₁ histamine-receptor antagonist, in improving the clinical symptoms of allergic conjunctivitis.
Methods: Thirty-six patients with allergic conjunctivitis were enrolled. One drop of levocabastine was instilled in one eye and one drop of artificial tears in the contralateral eye. Clinical examinations were performed before, and 15 and 30 minutes after instillation. Symptoms of itching and signs of injection were assessed at each time point.
Results: Both levocabastine and artificial tears resulted in a statistically significant reduction in ocular itching. However, levocabastine was significantly more effective.
Conclusions: Although artificial tears had a positive effect in reducing symptoms of allergic conjunctivitis, by the washing out of allergens, levocabastine was more effective than artificial tears in controlling acute symptoms of allergic conjunctivitis, demonstrating that the selective H₁ histamine-receptor antagonist action of levocabastine is rapidly effective in a clinical setting.

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Background: Recent reports suggest that small airway as well as large airway involvement in asthma is important. We investigate the therapeutic effects of a meter-dose inhaler of chrolofluorocarbon-beclomethasone dipropionate (CFC-BDP) and dry-powder fluticasone (DP-FP).
Methods: Lung specimens obtained at operation due for small size lung cancer in 16 asthmatic patients and 16 controls were evaluated immunohistochemically using antibodies of EG2 (eosinophil), AA1 (mast cell), CD68 (macrophage), and CD34 (pluripotent hematopoietic stem cell). We calculated the number of each cell type in 5 fields in the inner and outer areas of large airways (luminal diameter; ≥2 mm) and small airways (<2 mm) using computer software.
Results: In asthmatic patients eosinophils were significantly increased in both inner and outer areas of small airways and the number of CD34+ cells was significantly elevated in inner areas as compared with controls. Although the density of eosinophils in the inner area of large airways was significantly suppressed (p < 0.02), there was no such suppression in the inner areas of small airways in asthmatic patients treated with CFC-BDP or DP-FP.
Conclusions: It was speculated that inhaled CFC-BDP and DP-FP might deposit mainly in large airways and fail to fully reach small airways, consequently allowing eosinophilic inflammation to continue in small airways.

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Background: Hypersensitivity reactions to fish are a common food allergy, but IgE-binding activity to fish species have not been fully elucidated. The aim of this study was to identify fish with high binding activity to IgE in sera from Japanese fish-hypersensitive individuals.
Methods: 38 children with a history of at least one episode of hypersensitivity after ingestion of fish were enrolled and 34 children with no history of reactions and negative IgE results for at least five kinds of fish antigen were included as controls. Using a radioallergosorbent test, we examined IgE-binding to each fish species using sera from fish-hypersensitive subjects. Fish were then graded according to IgE-binding activity.
Results: Many fish species, including red salmon, silver salmon, yellowfin tuna, big eyed tuna, Atlantic tuna, saurel, skipper, yellowtail, Japanese sardine, bonita and mackerel had high IgE-binding activity. All of these fish are abundantly consumed in Japan. The hypersensitivity reactions experienced by many subjects occurred after ingestion of species with high IgE-binding activity. Only halibut (Osteichthyes) and sharks (Chondrichthyes) had low IgE-binding activity.
Conclusions: A correlation was observed between IgE levels and expression of symptoms after fish ingestion. High consumption of salmon, tuna, scad (including saurel), skipper, yellowtail, sardine, bonita and mackerel in Japan might be the cause of the high IgE-binding activity of these species. The grades of fish species consumed widely in Japan are likely to be useful for nutritional instruction of fish-allergic patients.

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Background: Hydrofluoroalkane-134a (HFA) has been shown to be a safe replacement for chlorofluorocarbons (CFCs) as a pharmaceutical propellant, with the advantage that it has no ozone-depleting potential. This is the first report of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized solution formulation using an HFA propellant system (HFA-BDP) in Japanese children with bronchial asthma.
Methods: Plasma concentrations of beclomethasone 17-monopropionate (17-BMP),a major metabolite of BDP, following an inhaled dose of HFA-BDP (200μg as four inhalations from 50μg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters.
Results: The area under the concentration-time curve from time zero to the last quantifiable time (AUC_0-t) was 1659 ± 850pg·h/mL (arithmetic mean ± standard deviation (SD)), the maximum concentration observed (C_max) was 825 ± 453pg/mL and the apparent elimination half-life (t_1/2) was 2.1 ± 0.7 hours. The time to reach C_max (T_max) was 0.5 hours in all patients. No special relationship was observed between these parameters and age or body weight. These parameters were compared with the previously reported parameters of American children with bronchial asthma. The Japanese/American ratio of the geometric means of each parameter was 1.36 for AUC_0-t, 1.04 for C_max and 1.4 for t_1/2. The median of T_max was 0.5 hours in American patients as well as Japanese patients.
Conclusions: The pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma are reported for the first time and a similarity to those in American children is suggested.

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Background: While many cases of latex allergy have been reported in Japanese health care workers (HCWs) since 1992, there have been no follow-up studies after removing latex from the workplace. We had previously replaced all working environment latex gloves and latex products with low-allergen or non-latex products. The purpose of the investigation was to evaluate the benefits of the latex allergy countermeasures that were taken in our hospital, and the effects of life guidance education.
Methods: We investigated 16 latex-allergic HCWs in our hospital. We gave them a detailed questionnaire and tested them by a skin prick test (SPT) with latex extract and specific IgE antibodies against latex using the Pharmacia CAP RAST system, RAST FEIA. We compared these results with earlier results from the time of diagnosis.
Results: According to the questionnaire, none of the HCWs had changed their work habits, though all were avoiding the use of latex products as much as possible. Of the 16 patients, 81.2% were eating foods for which cross reactivity with latex has been reported. However, the foods had not induced severe allergic symptoms. In the SPT, 62.5% of scores decreased and 81.2% of patients had decreases in specific IgE antibody levels.
Conclusions: After avoiding latex products and following our educational suggestions, the patients' allergy symptoms had generally improved. This indicates that our countermeasures against latex allergy were largely successful.

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Background: Interleukin (IL)-13 induces goblet cell metaplasia and plays an important role in mucus hypersecretion in asthma. We previously reported that IL-13 induced goblet cell differentiation along with less ciliated cell differentiation in guinea pig tracheal epithelial cells in vitro. In this study, we asked whether elimination of IL-13 could reverse the established goblet cell metaplasia into ciliated epithelia.
Methods: Primary epithelial cells from guinea pig tracheas were cultured at an air-liquid interface with the medium containing human recombinant IL-13 for 14 days, and continuously cultured with IL-13-eliminated medium, or cultured under the condition of neutralization of IL-13 with anti IL-13 antibody.
Results: 2 days after elimination of IL-13, the periodic acid-Schiff-positive area as well as MUC5AC protein level rapidly decreased. After 4 days, the number of goblet cells dramatically decreased, while that of ciliated cells inversely increased. The total number of epithelial cells did not change, and 5-bromo-2'-deoxyuridine uptake decreased after IL-13 elimination. Transitional cells with cilia and secretory granules increased after IL-13 elimination. Similarly, the neutralization of IL-13 with anti-IL-13 antibody for 5 days reversed the goblet cell metaplasia into ciliated epithelia, and transitional cells also increased.
Conclusions: Elimination of IL-13 reverses goblet cell metaplasia into ciliated epithelia in vitro, and transition of goblet cells to other phenotypes, especially ciliated cells, may be involved in this phenomenon. IL-13 inhibition may be a therapeutic strategy of established goblet cell metaplasia in asthma.

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Background: We report two cases of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in patients in whom systemic juvenile idiopathic arthritis (JIA) had initially been diagnosed or suspected. One patient, given a diagnosis of systemic JIA, was a 10-year-old boy who had presented with recurrent episodes of spike-fever, skin rash, arthritis, and myalgia. The other patient was his 7-year-old sister, who presented with similar symptoms and was suspected of having systemic JIA.
Methods: Serum levels of soluble tumor necrosis factor receptor super family 1A (TNFRSF1A), TNF-alpha, Interleukin (IL) -6, and C-reactive protein (CRP) were measured in two siblings and JIA patients. In addition, DNA sequencing of the TNFRSF1A gene in two siblings was also performed.
Results: A detailed family history showed that their mother had an episode of recurrent fever, arthritis, and myalgia with an increased serum CRP after the delivery of a daughter. Both siblings had serum levels of soluble TNFRSF1A that were below the normal reference range, and that did not reach a level corresponding to that of systemic JIA. On TNFRSF1A gene analysis, a single missense mutation resulting in C30Y was found in both siblings.
Conclusions: Based on the clinical features and the TNFRSF1A mutation, both siblings were given a diagnosis of TRAPS. The serum levels of soluble TNFRSF1A, measured along with the CRP level, may be a useful screening marker for differentiating TRAPS from systemic JIA.

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Background: The mechanism of cutaneous allergic vasculitis still remains unclear, and to the best of our knowledge, no case has been reported in the literature in which the number of mast cells was examined.
Methods: A 33-year-old woman, with a past history of allergic rhinitis due to Japanese cedar and Phleum pratense (timothy), presented with a chief complaint of palpable papules on both lower legs in December 2002. On blood examination, peripheral blood eosinophilia was present, but all other examinations for immunologic diseases were negative, including specific IgE. We suspected cutaneous allergic vasculitis and performed skin biopsy.
Results: In December 2002, histological examination of biopsy specimens of the skin lesions showed leukocytoclastic vasculitis. The diagnosis of cutaneous allergic vasculitis was made based on the clinical symptoms and the pathological findings of biopsy specimens. Immunohistochemical staining for human mast cell tryptase using monoclonal antibody against human mast cell tryptase showed an accumulation of mast cells. Treatment with oral corticosteroid resulted in the disappearance of clinical symptoms, and the steroid tapered. A second skin biopsy was performed in June 2005 after informed consent was obtained. Histological examination showed no findings of leukocytoclastic vasculitis, and the number of mast cells had decreased. She has been well without treatment.
Conclusions: Mast cells may increase in the skin lesion of cutaneous allergic vasculitis.

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Background: Chronic airway inflammation is a basic pathology of bronchial asthma and it is important to control the inflammation by anti-inflammatory therapy mainly with steroids. However, in asthma in the elderly, there are cases where physicians hesitate to introduce the inhaled corticosteroid (ICS) therapy based on the diagnosis that the use of inhalants is difficult due to the existence of a functional lesion accompanying asthma.
Methods & Results: In cases where self-administrated inhalation therapy is difficult to execute due to the accompaniment of a functional lesion and in cases where sufficient curative effects of steroids are not produced in self-inhalation, administration of assisted inhalation resulted in improvement of clinical symptoms and pulmonary function and was proven effective.
Conclusions: Assisted inhalation therapy is expected to be useful in general and also in terms of expanding the application of ICS in the asthma in the elderly.

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