Maintenance use of short-acting adrenergic agents can cause tachyphylaxis, increased non-specific bronchial hyperreactivity, poorer clinical control, a worsened late allergic reaction and possibly an increased risk of death; therefore, 'as needed' use is preferable. The choice of a first line anti-inflammatory drug, between inhaled corticosteroids and non-steroidal drugs (cromolyn sodium or nedocromil sodium), has to be made considering their riskbenefit ratio. Although in severe patients the efficacy of inhaled corticosteroids is clearly superior to that of cromolyn, in mild-to-moderate patients the efficacy is comparable. In terms of safety, non-steroidal drugs have a better safety profile than inhaled corticosteroids, which can cause growth suppression even at regular doses, especially in mild- to-moderate patients. Although some investigators have raised the possibility of irreversible airway obstruction if treatment with inhaled corticosteroids is delayed, studies by my group and others, using non-steroidal drugs as first line, have not confirmed that suspicion. In conclusion, a step-wise approach in children is still justified, starting with non-steroidal drugs (cromolyn sodium or nedocromil sodium) in mild persistent asthma and using inhaled corticosteroids only in patients poorly controlled by the non-steroidal drugs.

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Asthma is a disease of chronic airway inflammation that is characterized clinically by bronchial hyperresponsiveness and airflow limitation. Chronic inflam- mation, coupled with ongoing repair of airways damaged by the persistent inflammatory process in asthma, results in permanent structural and functional airway changes (remodeling) that can lead to irreversible airflow obstruction. Current guidelines empha- size treatment of the underlying inflammatory process in asthma and recommend early, long-term anti-inflammatory treatment to diminish or prevent the irreversible component of airflow obstruction. Furthermore, they recognize that inhaled corticosteroids are the most effective anti-inflammatory agents available for the treatment of asthma. Patient adherence to prescribed inhaled corticosteroid medication is associated with decreased airway inflammation, improved pulmonary function and symptom control. Moreover, marked declines in morbidity and mortality due to asthma have been attributed to appropriate use of inhaled corticosteroids.
Strict patient adherence with prescribed anti-inflammatory medication is crucial for obtaining optimal therapeutic benefit for patients with asthma. Despite the proven effectiveness of inhaled corticosteroids, patient adherence to prescribed therapy is often low, resulting in increased patient morbidity. Complex dosing regimens contribute greatly to patient non-adherence. Thus, new once-daily regimens of inhaled corticosteroid treatment have been introduced as means to improve patient adherence and provide optimal therapeutic benefit. In the present review, the complex inflammatory and remodeling processes in asthma and their contributions to the clinical manifestations of the disease will be discussed. Currently available, once-daily inhaled corticosteroid treatment options and the advantages of these therapeutic options in the treatment of persistent asthma also will be discussed.

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Eosinophils and neuropeptides are thought to play effector roles in allergic diseases, such as rhinitis; however, little is known about the biological effects of neuromediators, especially vasoactive intestinal peptide (VIP), on eosinophil functional responses. In the present study, it is shown that VIP induces eosinophil chemotaxis and eosinophil-derived neurotoxin (EDN) release in potency comparable with that induced by platelet activator factor, and in a novel synergistic manner with recombinant human interleukin-5. Contrary to chemotaxis, EDN release was sensitive to staurosporine, the protein kinase C inhibitor, as well as intracellular calcium chelation. However, eosinophil treatment with inhibitors of tyrosine kinases (herbimycin A) and phosphatases (pervanadate) resulted in a dose-dependent potentiation and blockage of VIP-induced eosinophil chemotaxis, respectively. Treatment of eosinophils with VIP receptor antagonist did not modify VIP-induced chemotaxis or EDN release. Furthermore, exploration of vasoactive intestinal peptide receptor I expression was lacking in human eosinophils, but not lymphocytes. These results demonstrate two different mechanisms in triggering eosinophil activation of functional responses by VIP, a calcium-dependent degranulation and a calcium-independent chemotaxis, and elaborate on a novel cytokineneuropeptide interaction in eosinophilic inflammation.

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European studies have shown that approximately 20% of all pollen-allergic patients display IgE reactivity to various plant profilins. Profilins are ubiquitous intracellular proteins, with a role in cell signalling and morphology. Recently, functionally relevant human profilin tetramers were identified, but the characterization and allergenic roles of plant profilin multimers have not been reported. Because larger molecules are generally more antigenic, the present objectives were to: (i) determine if plant profilin forms multimers; (ii) use the allergenic property of profilin in the design of an immunoassay to detect type I allergies in the local population; and (iii) assess the allergenic potential of monomeric versus multimeric profilin. In agreement with other known profilin forms, silver-stained sodium dodecyl sulfatepolyacrylamide gel electrophoresis and immunoblot analyses revealed that a significant 14.8 kDa protein was purified from Escherichia coli transformed with the cDNA of a plant (Zea mays) profilin isoform (ZmPRO1). Higher molecular weight proteins (particularly 60 kDa and 30 kDa) were also observed, which became predominant and larger (> 90 kDa) in the absence of reducing agents. Human IgE reactivity to profilin was measured by enzyme-linked immunosorbent assay (ELISA) that was developed using patient serum samples classified as either negative (no type I allergies), positive (type I plant allergies) or miscellaneous (i.e. allergies other than classical type I plant allergies). The IgE-ZmPRO1 complexes were seen in three of nine patients with type I plant allergies, compared with one of eight negative controls and three of 14 from the miscellaneous category. Dot filtration immunoblots were subsequently developed to absorb profilin diluted in the presence or absence of reducing agent to yield mostly monomeric or multimeric profilin, respectively. Immunoglobulin E from positive patients displayed a greater intensity of binding to ZmPRO1 under conditions that favored profilin multimers. In summary, recombinant ZmPRO1 profilin forms multimers and is suitable for a developed ELISA. The data further suggest that profilin has pan-allergenic potential in the North American population and raise the possibility that profilin multimers have greater immunogenicity than monomers.

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The effects of chloroform extract of Tripterygium wilfordii Hook f (TWH extract) on eosinophilia and IgE hyperproduction induced by Mesocestoides cortii infection were examined in BALB/c mice. Mice were infected with M. cortii by intraperitoneal injection of 500 tetrathyridia. The number of peripheral blood eosinophils and IgE levels were examined 21 days after infection. Oral administration of TWH extract once per day for three weeks dose-dependently suppressed peripheral blood eosinophilia and serum IgE levels, which are enhanced by M. cortii infection. Significant suppression of both eosinophilia and serum IgE levels were first noted in mice treated with 300 µg/kg of the extract. The maximum inhibition was observed when mice were treated with 410 µg/kg TWH extract. The ability of spleen cells to produce interleukin (IL)-4 and IL-5 in response to M. cortii somatic antigen was also significantly suppressed when donor mice were treated with more than 400 µg/kg of the extract. Extraxct treatment at a daily dose of 400 µg/kg suppressed costimulatory molecule (CD40 and CD86) expression on spleen cells induced by M. cortii infection. These results may suggest that TWH extract will be a good candidate for immunotherapy in allergic diseases.

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Anti-IgE and anti-FcεRI α chain auto-antibodies have been detected in the sera of atopic and non-atopic subjects; however, the biological activity of these auto-antibodies is still unclear. These two kinds of auto-antibodies were examined in atopic dermatitis (AD) patients. In results, 12 of 92 AD patients have the anti-IgE, eight have the anti-FcεRI α auto-antibodies and two have both auto-antibodies. Furthermore, biological characterization of these auto-antibodies has been performed. In results, three of 12 samples with the anti-IgE auto-antibodies exhibited inhibitory activity for IgE-FcεRI α binding. Two of the eight samples with the anti-FcεRI α auto-antibodies and one of the two samples with both auto-antibodies had histamine releasing activity. It is documented here that both anti-IgE and anti-FcεRI α auto-antibodies were detected in some AD patients, some anti-IgE auto-antibodies had inhibitory activity for IgE-FcεRI binding and also histamine releasing activity was detected in the anti-FcεRI α chain auto-antibody.

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Bronchial asthma, characterized by chronic airway inflammation, involves many inflammatory cytokines. Interleukin (IL)-10 is a potent inhibitor of cytokine synthesis. Thus, the effects of IL-10 were examined on the production of granulocytemacrophage colony stimulating factor (GM-CSF), IL-5, IL-1β, IL-2 and interferon (IFN)-γ by antigen (Dermatophagoides farinae, Df)-stimulated mononuclear cells obtained from asthmatic patients who were sensitized with the antigen and from healthy subjects in vitro. Production of IL-5 and IL-2 was enhanced by Df antigen in the asthmatic subjects, but not in the healthy controls. In contrast, levels of GM-CSF, IFN-γ and IL-1β production were enhanced by the antigen in both groups. Exogenous IL-10 (10 ng/mL) inhibited the production of GM-CSF, IFN-γ and IL-1β induced by Df antigen in both groups and also inhibited the production of IL-5 and IL-2 induced by the antigen in the asthmatics subjects. The inhibition of GM-CSF production by IL-10 was stronger than that by IL-4. These results indicated that the responsiveness to the inhibitory effect of IL-10 on the production of inflammatory cytokines is not abrogated in asthmatic patients and that IL-10 may be useful in the treatment of bronchial asthma.

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Asthma is characterized by chronic airway inflammation and the recruitment of inflammatory cells, typically eosinophils and lymphocytes, into the airway. Although several chemical mediators are released during the inflammatory process of asthma, evidence strongly suggests that the cysteinyl leukotrienes (LT), LTC₄, LTD₄, and LTE₄, play key roles in asthma. The short-term clinical efficacy of an LT receptor antagonist, pranlukast hydrate, in symptomatic patients with asthma who had already been treated with moderate to high doses of inhaled corticosteroids was therefore investigated. Treatment with pranlukast hydrate for 4 weeks significantly improved respiratory function and decreased asthma symptoms, the rescue use of inhaled β2-agonists, the number of peripheral blood eosinophils and serum levels of eosinophil cationic protein. Furthermore, airway inflammation, as evaluated by the percentage of eosinophils in induced sputum and airway responsiveness to histamine, decreased significantly after treatment. There were no significant changes in these parameters in control patients with asthma whose treatment was not changed over 4 weeks. These preliminary results suggest that pranlukast hydrate, an LT receptor antagonist, is an effective agent in the management of asthma in combination with moderate to high doses of inhaled corticosteroids.

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The aim of the present study was to evaluate the anti-allergic effect of apple condensed tannins (ACT) in patients with atopic dermatitis (AD) as a pilot study. An ACT supplement given to the patients at oral doses of 10 mg/kg per day for 8 weeks reduced the inflammation, lichenification, cracking, itching, sleep dis- turbance and peripheral blood eosinophil counts. Itching and sleep disturbance scores after ACT supplement even for 2 weeks were significantly decreased compared with the control group. The results suggest that ACT has an anti-allergic effect and that its use improved the symptoms of AD.

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Some retinoids show an anti-inflammatory action through regulation of transcription of various genes. In the present study, the inhibitory effect of 4-((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbamoyl) benzoic acid (Am-80), a synthetic retinoid, on mouse contact hypersensitivity provoked by repeated applications of 2,4-dinitrofluorobenzene (DNFB) to the ear was investigated. Five-fold applications of DNFB on ears once per week elicited severe contact dermatitis with marked infiltration of inflammatory cells and elevation of anti-dinitrophenyl (DNP)-IgE antibody in the serum. The Am-80 significantly inhibited ear swelling in a dose-dependent manner. In the histopathologic study, infiltration of inflammatory cells was clearly decreased by Am-80. However, Am-80 did not affect the production of DNP-specific IgE antibody both at the transcriptional and post-transcriptional levels. The effects of Am-80 on the transcriptional level of cytokines, interferon (IFN)-γ, interleukin (IL)-1 and IL-4 in cervical lymph nodes were investigated. Marked elevation of mRNA for all cytokines was observed and Am-80 potently inhibited the expression of IFN-γ mRNA, but not IL-1 and IL-4 mRNA. These findings indicated that Am-80 may inhibit the contact dermatitis at the post-sensitization phase by inhibiting IFN-γ production at the transcriptional level in mice.

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A 52-year-old woman is reported with atopic cough, in whom bronchoprovocation with Streptomyces albus antigen induced cough and bronchoscopic biopsy revealed eosinophilic tracheobronchitis. She was admitted for the diagnosis and treatment of severe non-productive cough. Although her induced sputum contained 8% eosinophils of nucleated cells and bronchoscopic biopsy specimens revealed eosinophil infiltration in both tracheal and bronchial wall, she did not have bronchial hyperresponsiveness to methacholine or heightened bronchomotor tone. Bronchodilator therapy was not effective for her coughing. Her symptoms worsened on returning home, suggesting the existence of some etiologic agents in her house. Streptomyces albus was isolated from her house. A high titer of anti-S. albus antibody was detected in her serum and the bronchoprovocation test with S. albus antigen was positive: development of coughing 15 min later and decrease in cough threshold to inhaled capsaicin 24 h later (3.9 µmol/L from 31.3 µmol/L prechallenge). This is the first report on eosinophilic tracheobronchitis with cough hypersensitivity caused by allergic reaction to S. albus antigen.

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A 40-year-old female patient with chronic persistent cough was diagnosed with cough variant asthma (CVA). To investigate the effect of suplatast tosilate (suplatast, 300 mg/day, three times a day), cough scores, medication scores, pulmonary function, capsaicin cough threshold, bronchial hyperresponsiveness (BHR) to methacholine and eosinophilic cationic protein (ECP) concentration in hypertonic saline-induced sputum were evaluated before and after a 6-week treatment with suplatast. Treatment with suplatast resulted in a marked decrease in persistent cough and in the percentage of eosinophils and ECP concentration in induced sputum. It also resulted in a marked improvement in capsaicin cough threshold and a slight improvement in BHR. These results suggest that suplatast tosilate may be useful for treating patients with CVA.

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Recombinant pollen allergens rPhlp1, rPhlp2, rPhlp5, and rBetv2 may function as effective markers of atopy and account for a substantial proportion of grass pollen-specific IgE. The purpose of the present study was to determine the frequency of IgE antibodies to rPhlp1, rPhlp2, rPhlp5 and rBetv2 in patients allergic to grass pollen. Blood was taken from 436 patients, aged 4-70 years, with allergy to grass. The sample was stratified by 10-year age groups. Specific serum IgE were measured by the immunoenzymatic CAP Fluoroenzyme Immunoassay System. Specific IgE binding to rPhlp1, rPhlp5, rPhlp2, was, respectively, detected in 388 (88.9%), 353 (80.9%) and 265 (60.7%) of 436 patients. Sera from 252 patients (57.7%) showed IgE binding to rPhlp1, rPhlp2 and rPhlp5; sera from 102 patients (23.3%) reacted to rPhlp1 and rPhlp5, but not rPhlp2; 30 sera (6.8%) reacted to rPhlp1 but not rPhlp2 and rPhlp5; 22 sera (5.1%) reacted only to rPhlp5; one serum reacted to rPhlp2 (0.2%); and nine sera (2%) did not react to recombinant allergens. It was found that patients in the age group 0-20 years had higher IgE levels to timothy grass and rPhlp1, rPhlp2 and rPhlp5, than patients in the older age group (4160 years). We found, as expected, seasonal variation of IgE levels to recombinant allergens and natural allergen. Allergens rPhlp1, rPhlp2 and rPhlp5 were extremely positively correlated with timothy grass and rBetv2, but not rBetv1. These results encourage the use of recombinant pollen allergens for diagnosis and to improve specific immunotherapy in the near future.

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