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TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Theophylline is a useful drug for the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) recommend use of sustained-release theophylline products as controllers and of injectable aminophylline products as relievers. The Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention, the NHLB/WHP Workshop Report 1995 (GINA, 1995) and guidelines in Western countries recommend sustained-release theophylline, but not as positively as in the JGL. The aim of this survey was to determine the occurrence of serious adverse reactions., Methods: The survey was conducted in 66 institutions staffed by physicians certified by the Japanese Society of Allergology (JSA). The target diseases were asthma and COPD including chronic bronchitis and pulmonary emphysema, which are indications for use of sustained-release theophylline products in Japan., Results: 3,921 patients were included in the safety evaluation. No serious adverse reactions were observed among the patients in this survey, although 54 patients (1.38%) exhibited non-serious adverse reactions. The incidence of adverse reactions was found to be high in patients who had begun use of sustained-release theophylline products at the time of registration in this survey, and in patients who were concomitantly taking macrolide antibiotics., Conclusions: The present survey demonstrates that sustained-release theophylline is safe, as long as used appropriately, although adverse reactions tend to develop early after initiation of administration.

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.

We examined the density of muscarinic acetylcholine receptor (mACh-R) subtypes (M1R, M2R and M3R) in guinea pig lung. The density of M3R in the lung tissue of ovalbumin (OA)-sensitized guinea pigs was higher than that in the control group. However, no difference was observed in the affinity of M3R between the sensitized and the control lungs. No difference was observed in the density and affinity of M1R and M2R in sensitized and control lungs. Pilocarpine, which is an M2R stimulant, increased the density of M3R in the lung tissue and the rate of the increase in sensitized guinea pigs was less than that in the control group. In contrast, methoctranine, which is an M2R antagonist, decreased the density of M3R and the rate ofthis decrease was the same in the sensitized and control groups. These results suggest that, in OA-sensitized guinea pigs, a dysfunction of M2R leads to the abnormal density of M3R.

Background: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma., Objective: To determine whether the addition of montelukast could lead to a reduction in inhaled corticosteroid dose without a significant decrease in peak expiratory flow rate (PEFR)., Methods: After a 4-week run-in period, 191 moderate-to-severe asthmatic patients whose asthma had been well controlled with daily inhaled corticosteroid therapy (beclometasone dipropionate 800 to 1600 micro g/day), were randomly assigned to one of two treatments - placebo (n = 98) or montelukast 10 mg once daily (n = 93) - for a 24-week, multicentre, double-blind, treatment period. At the beginning of the active treatment period, the daily dose of inhaled corticosteroid was halved in all of the patients. In addition, the inhaled corticosteroid dose was subsequently titrated every 8 weeks, based on PEFR, asthma symptoms and beta-agonist use., Results: After 8 weeks of a 50% reduction in inhaled corticosteroid use, morning PEFR increased by 5.3 +/- 32.3 L/min from baseline in patients receiving montelukast and significantly decreased by 6.9 +/- 29.0 L/min in those receiving placebo (P = 0.035). In addition, evening PEFR significantly decreased by 9.8 +/- 28.5 L/min (P = 0.003) in the placebo group, but was maintained in the montelukast group. In spite of a subsequent 50% reduction in the inhaled corticosteroid dose every 8 weeks, morning and evening PEFRs were maintained over the 24-week treatment period in the montelukast group; PEFR significantly decreased in the placebo group. There was a significant difference between the two groups with regard to morning PEFR, therapy score and asthmatic score at weeks 8, 16 and 24, as well as evening PEFR at week 8. However, the symptom scores were not significantly different between the two groups or within each group., Conclusion: These data suggest that montelukast reduces the need for inhaled corticosteroids while maintaining asthma control over a 24-week period. Therefore, montelukast may be useful for long-term treatment in patients with asthma who require high doses of inhaled corticosteroids.

Correlation between the level of reactive oxygen species (ROS) generated by airway inflammatory cells and superoxide dismutase (SOD) activity of pulmonary tissue during an asthma attach was investigated in a guinea pig model of allergic asthma. In addition, the influence of SOD inhibition by diethyldithiocarbamate (DDC, Cu-chelating agent) on the airway was investigated in terms of pulmonary function during an asthma attach. Relative to controls, the capacity of bronchoalveolar lavage fluid (BAL) cells to release ROS was significantly increased in guinea pigs sensitized with ovalbumin (OA) as the antigen, and significantly increased in guinea pigs with an asthma attack provoked by the inhalation of OA. SOD activity was increased significantly in the antigen-sensitized group. The asthma provocation group showed a tendency for increase in total SOD activity, compared with the sensitization group, whose increase was dependent on the increase in copper, zinc-SOD (Cu, Zn-SOD) activity. Pretreatment with DDC increased the severity and duration of the asthma attack. These results were indicated that Cu, Zn-SOD was closely involved in the asthma process, particularly in the scavenging of oxygen radicals secreted from BAL cells.

Objective: The aim of the study was to compare the efficacy and safety of budesonide Turbuhaler with that of beclomethasone dipropionate (BDP) pMDI., Methodology: Three hundred and fifty adult asthma patients (mean age 52.7 years, mean baseline morning peak expiratory flow (PEF) 294 L/min (< 80% predicted normal)), taking BDP via pressurized metered-dose inhaler (pMDI), 400 microg daily for at least 2 months, were randomized in an open 6 week study to receive daily doses of either budesonide 100 microg or 400 microg twice daily via Turbuhaler or continued treatment with BDP, 100 microg four times daily. The primary efficacy variable was the mean change in morning PEF from baseline to the end of treatment. Outcome was also assessed using symptom scores and investigators' assessments employed in Japanese clinical trials., Results: At the end of the 6 week treatment period, mean morning PEF improved significantly from baseline in both budesonide groups, 16 L/min and 33 L/min in the 200 microg and 800 microg groups, respectively, but not in the BDP group, 5 L/min. There was no significant difference between 200 microg budesonide and 400 microg BDP treatment in the effect on PEF (P = 0.29), but 800 microg budesonide was significantly superior to BDP (P < 0.001). Final assessment of improvement and usefulness ratings showed that both budesonide treatments were significantly superior to BDP (P < 0.001). All treatments were well tolerated., Conclusion: Budesonide Turbuhaler (200 microg) was as effective as 400 microg BDP pMDI. The efficacy of budesonide was improved significantly by increasing the dosage to 800 microg daily. The study design shows the importance of including a higher dose treatment group when comparing two formulations of inhaled corticosteroids in order to determine whether the treatments to be compared are on the steep part of the dose-response curve. Without that information, comparative studies are usually inconclusive.

Background: Lesions of trachea cuticles are a pathological histological characteristic of bronchial asthma. Furthermore, collected tracheal cuticles desquamated from the respiratory tract are found in patients' sputum when asthma attacks occur or after the induction of allergen inhalation. From these facts, it is assumed that desquamation of trachea cuticle cells is a pathological symptom of bronchial asthma. However, there has not been any chronological report of desquamation of trachea cuticles through the process of bronchial asthma attacks., Objective: For this report, we made an experimental bronchial asthma model using guinea pigs, and conducted chronological examinations of trachea cuticle lesions related to pathological symptoms of bronchial asthma using a transmission electron microscope and a scanning electron microscope., Methods: The experimental asthma models were made by injection of ovalbumin into the abdominal cavity of guinea pigs. Then the airway responses to inhaled aerosolized ovalbumin were induced. The trachea were enucleated and examined under an optical microscope, a transmission electron microscope (hereafter abbreviated as TEM), and a scanning electron microscope (hereafter abbreviated as SEM) after 1, 2, 4, 8, 12, 24 h and 7 days after the immediate airway responses., Results: Intercellular oedema of ciliated epithelium was observed in the sensitization groups immediately after the immediate airway response. SEM observation revealed increased mucus secretion and shortening of cilium. A slight case of desquamation or deciduation of ciliated epithelium was also beginning to appear. TEM observation revealed a dilation of ciliated epithelium intervals. Infiltration of eosinophilic leucocytes was already detectable beneath the ciliated epithelium. The degree of ciliated epithelium desquamation and infiltration of eosinophilic leucocytes progressed with time. When the late airway response occurred 4 hours later, eosinophilic leucocytes had increased drastically, and ciliate epithelium had desquamated to the extent that basal cells were exposed. Seven days after the immediate airway response, epithelium intercellular oedema had improved, and cilium had been reproduced., Conclusion: These results suggest that desquamation of epithelium caused by trachea cuticle lesions appears at an early stage of an asthma attack, owing to the contraction of the trachea, and that the damage is intensified by the infiltration of eosinophilic leucocytes.

Background: Airway hyperresponsiveness (AHR) is one of the characteristic features of human asthma. The presence of AHR and the precise mechanisms immediately after establishment of sensitization in guinea pigs are unclear, although there are many reports showing allergen exposure that causes an increase in bronchial responsiveness associated with eosinophil influx into the airway in sensitized guinea pigs., Objective: We investigated the inhibitory effects on AHR to histamine of ONO-1078, a leukotriene antagonist; indomethacin, a cyclooxygenase inhibitor; S-145, a thromboxane A(2) (TXA(2)) antagonist, and Y-24180, a platelet-activating factor (PAF) antagonist, to assess the involvement of chemical mediators in AHR employing ovalbumin (OA) sensitized guinea pig models., Methods: Male Hartley guinea pigs were used. Each group comprised 4-7 animals. The animals were sensitized to OA, injecting intraperitoneally 30 mg of cyclophosphamide and 2,000 microg of OA together with 100 mg of aluminum hydroxide as the adjuvant. The guinea pigs were artificially ventilated via a cannula using a small-animal respirator after intraperitoneal anesthesia with pentobarbital sodium for tracheotomy. The pressure at the airway opening (PAO) was measured using a differential pressure transducer, and a differential pressure of peak PAO (peak DeltaPAO) at inspiratory phase as an overall index of bronchial response to bronchoactive agents was used. While being artificially ventilated, the animals were exposed to physiological saline solution containing various concentrations of histamine (4.9, 9.8, 20, 39, 78, and 156 microg/ml) by inhalation for 30 s at 3-min intervals. Determinations were made at 1 min after each inhalation. The chemical mediators were each (30 mg/kg of ONO-1078, 3 mg/kg of S-1452, and 1 mg/kg of Y-24180) administered orally to sensitized guinea pigs, and the airway response to histamine was assessed. Each group comprised 4-7 animals., Results: The airway response to histamine was significantly greater in the sensitized group than in the nonsensitized group at histamine concentrations of 36 (p < 0.05), 78, and 156 mg/ml (p < 0.01). Leukotrienes C(4) and D(4): 30 mg/kg of ONO-178 did not show any inhibitory effect on airway response to inhaled histamine. Cyclooxygenase: 5 mg/kg of indomethacin did not show any inhibitory effect on the airway response to inhaled histamine. TXA(2): the AHR to inhaled histamine at doses of 9.8, 39, 78, and 156 microg/ml was significantly inhibited by prior administration of 3 mg/kg of S-1452. PAF: the AHR to inhaled histamine at doses of 9.8, 39, and 78 microg/ml was significantly inhibited by prior administration of 1 mg/kg of Y-24180., Conclusions: S-1452 (3 mg/kg) and Y-24180 (1 mg/kg) significantly inhibited AHR to histamine, while ONO-108 (30 mg/kg) and indomethacin (5 mg/kg) did not. The results suggest that TXA(2) and PAF are involved in AHR in OA-sensitized guinea pigs., (Copyright 2001 S. Karger AG, Basel)

Objective: The aim of this study was to evaluate the oral steroid-sparing capacity of budesonide Turbuhaler., Methodology: One hundred and thirteen oral steroid-dependent patients were treated for 6 months with placebo or budesonide 800 microg or 1600 microg daily. Every second week the oral steroid dose was reduced if asthma control permitted., Results: The reductions in oral steroid doses were 9, 35 and 60% in the placebo and budesonide 800 microg and 1600 microg groups, respectively. Oral steroid treatment could be discontinued in 4% (placebo), 15% (800 microg) and 23% (1600 microg). Mean peak expiratory flow values increased by 21 and 24 L/min in the budesonide groups but decreased by 6 L/min in the placebo group. Asthma attack, activity and sleep scores remained unchanged showing maintained efficacy. Plasma cortisol levels increased and an adrenocorticotropic hormone test showed improved adrenocortical response in both budesonide groups, indicating improved safety. Adverse drug reactions were infrequent and mild in all study groups., Conclusion: Budesonide Turbuhaler, 800 microg and 1600 microg daily, resulted in a significant reduction in oral steroid usage in steroid-dependent patients. The effect was achieved with maintained asthma control together with improvements in lung and adrenal functions.

Objective: The aim of this study was to investigate the dose-response for inhaled budesonide via Turbuhaler in Japanese patients with mild to moderate asthma., Methodology: Inhaled budesonide 100 microg, 200 microg, 400 microg or placebo was administered twice daily via Turbuhaler for 6 weeks, to 267 adult Japanese patients (mean age 51 years) with mild-to-moderate, non-steroid-dependent bronchial asthma, in a double-blind, placebo-controlled, randomized, parallel group study. The patients had to be symptomatic for more than 3 days/week and have an average morning peak expiratory flow (PEF) 50-80% of predicted normal value., Results: The response to budesonide was rapid, all treatments showing a significant improvement in morning PEF after 1 week (P<0.05). During week 6, mean improvements of 15, 45, 53 and 71 L/min were observed for the placebo, 200 microg, 400 microg and 800 microg budesonide groups, respectively. Compared with placebo all improvements in the budesonide groups were statistically significant and a significant dose-response was demonstrated (P<0.001). The difference between the 200 microg and 800 microg doses was significant. Also, for several secondary efficacy variables (e.g. evening PEF, symptom score, treatment score, daily activity score and sleep score) significant dose-responses were shown. Other variables included the investigators' assessments of improvement and usefulness. They also showed statistically significant dose-response relationships and confirmed the rapid onset of action. Budesonide was well tolerated at all tested doses, with a low incidence of adverse events, all of which were minor in severity., Conclusions: Budesonide Turbuhaler in the doses 100 microg to 400 microg twice daily was effective, well tolerated and showed a rapid onset of action in patients with mild-to-moderate asthma. Dose-response was demonstrated for several variables of clinical efficacy.

To clarify recent trends in adult asthma mortality, the Asthma Death Investigation Committee of Japan studied the clinical characteristics of 295 patients who died of asthma between 1995 and 1997. Males were slightly more than females among the death cases. Approximately half of the patients ranged in age from 60 to 79 years. Tendency to increase of death among young male adults continued. One third of the patient deaths involved the asphyxic type, while status asthmaticus was the cause death in 21.9%. Half of the asthmatics died in hospitals or emergency rooms, and places where the fatal attacks occurred were mainly patients' houses. The main cause fatal asthma attacks was respiratory infection, followed by fatigue, stress, and discontinuation of medication. Most of the patients were classified moderate or severe type of asthma 1 month before death. Histories of life-threatening attacks and hospitalization due to severe attacks, irregular visits to the hospital, low compliance, and insufficiency of corticosteroid treatment were suggested as the main risk factors in adult asthma deaths.

The authors have successfully developed an animal model of dual-phase bronchial responses and very high IgG titer by sensitizing Hartley-strain male guinea pigs. Specific airway resistance, which was determined in a two-chamber body plethysmograph, was elevated to sevenfold during immediate response, followed by a late phase response with a smaller but marked elevation in resistance. Furthermore, hematological and histological examinations revealed that the total cell count increased in BAL obtained during both immediate and late bronchial responses as compared to pre-OVA challenges. A significant increase in BAL eosinophils was present only for the late bronchial samples, and this finding was supported by histological examination.

The effects of an oral anti-allergic agent, TMK-688, which inhibits 5-lipoxygenase, at doses of 3.2 and 10 mg/kg were studied in guinea pigs with dual-phase asthmatic response. We previously observed that pretreatment with TMK-688 inhibited the late asthmatic response (LAR) induced by ovalbumin inhalation exposure. The present study focused on the effect of TMK-688 on infiltration by T-cells and eosinophils. TMK-688 inhibited both T-cell and eosinophilic infiltration. These findings suggest that TMK-688 is effective in inhibiting infiltration of T-cells and eosinophilic chemotaxis, and thereby suppresses LAR.

Background: In Japan in 1993, the Japanese Society of Allergology (JSA) developed guidelines for diagnosis and management of asthma (JGL), which were based on the concept that asthma is a chronic inflammatory disorder of the airway., Methods: This survey study was intended to investigate the recognition and utilization of JGL among physicians who had treated asthma. The survey comprised two methods: a quantitative mail survey and a qualitative door-to-door survey conducted by trained interviewers., Results: In the mail survey, a total of 1028 physicians responded; 552 members of the JSA and 476 nonmembers. Ninety-four percent of JSA members were aware of adult asthma management guidelines, while 53% of nonmembers were aware of them. Although approximately half of the physicians, both members and nonmembers, found differences between the asthma management policies in JGL and their previous policies, most of them utilized JGL once they read it. In the qualitative door-to-door survey, 80-90% of physicians evaluated JGL as good after they read it., Conclusions: JGL was recognized and utilized by most JSA members, but only half of nonmember physicians were aware of JGL, although they utilized JGL after they read it. Further action to implement JGL among nonspecialist physicians is needed to improve management of asthma.

We examined an effectiveness of a new asthma telemedicine system in reducing hospitalizations using a multi-site randomized control study. In this program, a nurse under physician supervision monitors the patient's airway status at home and provides instructions to individuals via the telephone, helping them manage exacerbations as well as reinforcing proper use of a zone-controlled management plan. Patients with a high risk for hospitalization were screened based on the numbers of emergency room visits and hospitalizations found in a previous study and randomly assigned to either the telemedicine or control group. After a six-month study period, an 83% reduction in hospitalization was demonstrated in the telemedicine group versus the control group, with a P value of 0.01. Improvement of peak expiratory flow and symptoms were also shown in the study group. We conclude that the key success factors in home asthma management for poorly controlled asthma patients are early detection of exacerbations through daily peak flow monitoring, compliance with prescribed daily prophylactic anti-inflammatory steroid medications, and immediate action as specified by a zone-controlled action plan upon the first signs of deterioration.

Background: ONO-1078 (pranlukast) is a leukotriene receptor antagonist developed in Japan. This drug has been shown to be useful in oral treatment of bronchial asthma. The present study was undertaken to assess the effects of this drug on the production of cytokines in the peripheral blood mononuclear cells of patients with asthma under stimulation with specific antigens., Methods: Peripheral blood mononuclear cells from mite antigen-positive asthmatic patients (immunoglobulin E RAST score > 3) were incubated for 72 h in the presence of mite antigen (10 microg/mL). The supernatant of the culture was subjected to enzyme-linked immunosorbent assay (ELISA) to quantify interleukin (IL) -4, IL-3, IL-5, and granulocyte macrophage-colony stimulating factor (GM-CSF). Other peripheral blood mononuclear cells from the same patients were incubated for 72 h in the presence of both mite antigen (10 microg/mL) and ONO-1078 (0.5, 1, or 10 microg/mL), followed by ELISA of the supernatant to quantify the cytokines., Results: Production of IL-4, IL-5, and GM-CSF by mononuclear cells under stimulation with mite antigen was markedly suppressed when they were exposed to ONO-1078 at a concentration of 10 microg/mL., Conclusion: The results suggest that ONO-1078 acts directly on peripheral blood mononuclear cells and that blockade of leukotriene receptors on blood mononuclear cells by the cysteinyl-leukotriene receptor antagonist (LTRA) pranlukast (ONO-1078) can dose-dependently inhibit release of immunoreactive TH2-type cytokines (IL-3, IL-4, GM-CSF, and possibly IL-5), but not of the TH1-type cytokine IL-2, when stimulated by mite allergen in vitro. The data may provide clues to the mechanism by which a number of LTRA including zafirulukast and montelukast can reduce airway, sputum and blood eosinophil counts in clinical asthma. It supports animal studies showing that anti-IL-5 antibodies partially block cys-LT-induced airway eosinophilia, suggesting that cys-LTs may cause secondary release of IL-5 from an unknown cell-type. These findings indicate that ONO-1078 suppresses the production of IL-4 (a cytokine that affects IgG antibody production), IL-5, and GM-CSF (cytokines that affect eosinophil activation) by peripheral blood mononuclear cells under stimulation with specific antigens in patients with bronchial asthma. Because of its anti-inflammatory effects, ONO-1078 should be useful in the treatment of bronchial asthma.

Eosinophils play an important role in the development of bronchial asthma, and the association between ICAM-1 and activation and migration of local eosinophils is attracting attention. Using an asthmatic model of dual phase bronchial response, the effects of anti-ICAM-1 antibody on the airway resistance, cell composition in the bronchoalveolar lavage fluid (BALF) and ultrastructure of bronchial ciliated epithelium were examined under the provoked response by inhalation of the antigen. By administration of anti-ICAM-1 antibody, the late asthmatic response (LAR) was suppressed. In the examination of bronchoalveolar lavage fluid, a significant decrease in eosinophils was found in LAR. In examining transmission and scanning electron microscopies, no difference was found in the immediate asthmatic response, but marked suppression of deciduation of bronchial ciliated epithelium was observed in LAR. These results indicated that anti-ICAM-1 antibody suppressed bronchial asthmatic attack, mainly in LAR, by controlling differentiation and migration of eosinophils.

In recent years, bronchial asthma has come to be regarded pathologically as a chronic inflammatory disease of the respiratory tract. Inhalational steroids and antiinflammatory drugs are recognized as being effective against bronchial asthma. In this study, the effects of Saiboku-to, a Chinese herbal (Kampo) formulation, were investigated on asthmatic guinea pigs sensitized to ovalbumin (OA). Following 7-day administration of Saiboku-to (500 micrograms/kg), the late asthmatic response (LAR) to an antigen challenge was found to be inhibited. The number of eosinophils in fluid obtained by bronchoalveolar lavage (BAL) 4 h after antigen challenge was decreased while the infiltration of eosinophils and T-lymphocytes into the lung parenchyma was inhibited. These findings suggest that Saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma.

Stress is one of the important factors influencing bronchial asthma, but many questions still remain unanswered. To clarify this point we examined airway hypersensitivity before and after electric shock stress and the role of substance P in an animal model of asthma. We determined airway hypersensitivity to histamine and the substance P levels in serum, bronchoalveolar lavage fluid, and bronchial tissue before and after electric shock stress in biphasic asthma-responsive guinea pigs which had been sensitized using ovalbumin. The cell components in bronchoalveolar lavage fluid were also examined. Airway hypersensitivity to histamine (4.9-156 micrograms/ml) was significantly increased (p < 0.01) by electric shock stress. The substance P level was also significantly increased in plasma and bronchoalveolar lavage fluid, but it was significantly decreased in bronchial tissue. The number of eosinophils in bronchoalveolar lavage fluid increased significantly after electric shock stress. These findings demonstrated that airway hypersensitivity to histamine was increased by stress and suggested that substance P, as well as eosinophils, contribute to the pathogenesis of hypersensitivity.

Histamine plays an important role in bronchoconstriction mediated by histamine receptors which provoke bronchial asthma attack. In this study, we measured H1 and H2 receptors in the guinea pig lung membrane fraction and obtained the following results. The maximum binding (Bmax) of H1 receptors in the guinea pig lung membrane fraction was significantly higher in the OA-sensitized group than that in the non-sensitized group, but affinity (Kd) did not differ between the groups. Otherwise, the maximum binding (Bmax) of H2 receptors in the guinea pig lung membrane fraction was significantly lower in the OA-sensitized group than that in the non-sensitized group. But affinity (Kd) did not differ between the groups. These findings suggest a close association of Histamine receptors both H1 and H2 in the pathology of asthma.

1. To clarify part of the bronchodilating effects of theophylline, lymphocyte cyclic AMP (cAMP) and phosphodiesterase (PDE) activity in asthmatic patients and healthy adults were measured. 2. No clear differences in lymphocyte PDE activity were found regarding sexes, ages or the types of asthma. 3. Lymphocyte PDE activity in the asthma group was significantly higher than that in the control group. 4. Lymphocyte cAMP significantly increased at 30 and 60 min after intravenous injection of aminophylline in the asthma group. 5. Lymphocyte PDE activity significantly decreased 60 min after intravenous injection of aminophylline in the asthma group.

It was recently reported that theophylline has an anti-inflammatory and bronchodilating effect on bronchial asthma. Accordingly, to examine the anti-inflammatory effect of theophylline on asthma, especially its effect on eosinophil activation, a sustained-release theophylline preparation (Theolong) was administered (daily dose: 400 mg) to 18 patients with mild to moderate bronchial asthma. This was done in order to study the preparation's effects on lung function, blood and sputum eosinophils and ECP four weeks pre- and post-administration. Lung function was determined by spirometry and sputum by induced sputum. Blood and sputum ECP levels were determined using an ECP RIA kit. In lung function, there were no differences in vital capacity (VC) or in forced expiratory volume 1 s (FEV 1.0) pre- and post-administration. There were also no differences in the number of blood and sputum eosinophils, but serum and sputum ECP levels decreased. Theophylline is thus expected to exert an inhibitory effect on eosinophil activation and it is suggested as an effective therapeutic drug for bronchial asthma.

To elucidate the mechanism of the anti-inflammatory effect of theophylline, peripheral blood mononuclear cells (PBMCs) collected from patients with bronchial asthma who had a RAST score for Dermatophagoides farinae (Df) > = 3 were stimulated with Df antigen, and the interleukin-4 (IL-4) production by the stimulated PBMCs was determined in the presence and absence of theophylline. The stimulated IL-4 production in the PBMCs was significantly suppressed by simultaneous treatment with theophylline (8 microg/ml). Furthermore, the intracellular 3',5'-adenosine monophosphate (cAMP) level following stimulation with Df was significantly higher in PBMCs simultaneously treated with theophylline (8 microg/ml) than in nontreated controls. These results suggest that theophylline suppresses the IL-4 production in inflammatory cells by increasing the intracellular cAMP level; this effect may thus provide an additional basis for the benefit of theophylline in antiasthmatic therapy.

Asthma patients have bronchial hyperreactivity compared with normal subjects. The pathophysiological characteristics of bronchial asthma show the reversible bronchial obstruction (air-flow limitation) caused by several physical and chemical stimuli. Thus, it is important to verify the bronchial responsiveness for diagnosis of bronchial asthma. Function testing of bronchial responsiveness is one of the bronchial reactivity tests which is important for the diagnosis of bronchial asthma as well as the judgment of severity, therapeutic effect and the differential diagnosis. Function testing of bronchial responsiveness consists of 2 major parts : 1) standard method of acetylcholine or histamine inhalation test 2) direct-writing recorder of the dose-response curves of the airway to methacholine test (Astograph).

The death rate among patients with asthma in Japan has been reported by Japan's Ministry of Health and Welfare to approximately 5/100,000 population. Over the past 15 years, this rate has remained relatively constant, but it is higher than that in western countries. To clarify recent trends in adult asthma mortality, the Japan Asthma Death Investigation Committee studied the clinical characteristics of 649 patients who died of asthma between 1986 and 1991. The annual number of deaths decreased slightly: from 145 in 1986 to 89 in 1991. There was a large difference between sexes: the male:female ratio was 3:2. Most patients ranged in age from 50 to 70 years old. It is noteworthy that in one third of the patients death was caused by asphyxic-type asthma, while status asthmaticus was the cause in only 23.7%. The number of patients with mild or moderate asthma was slightly increased, although patients with severe asthma accounted for at least 70% of all deaths. The main causes of fatal asthma attacks were airway infections, fatigue, and stress. Other responses on the questionnaires indicated the following areas of concern: deficiencies in patient education, delays in treatment with corticosteroids and other antiasthma drugs, and delays in provision of emergency treatment.

Fibronectin is an extracellular matrix (ECM) that binds to very late antigen-4 (a beta 1 integrin molecule) expressed by eosinophils. To investigate the effect of adherence to fibronectin on regulation of eosinophil cell death, survival of eosinophils was examined by trypan blue exclusion and Fas antigen expression on the cell surface using an eosinophilic cell line (EoL-1). Adhesion to fibronectin resulted in prolongation of eosinophil survival (fibronectin vs. bovine serum albumin (BSA), 62.9 +/- 5.10 vs. 53.9 +/- 4.30% viability at 72 h) and the decreasement of Fas antigen expression on EoL-1 (fibronectin vs. BSA, 24.3 +/- 2.15 vs. 74.5 +/- 8.25% positive). These findings suggest that eosinophil adhesion to ECM via adhesion molecules plays an important role in the pathogenesis of allergic inflammation, which involves eosinophil accumulation at the inflammatory site, through regulation of eosinophil cell death.

In this study, we tried to clarify the characteristics of peak expiratory flow (PEF) measurement maneuver as a tool of daily monitoring severity of asthma in accordance with peak expiratory flow rate (PEFR) of forced expiratory maneuver. PEF did not differ when measured either in the standing or sitting position. However, obese individuals may have higher PEF when measured in the standing position and subjects with emphysematous change may have higher PEF when measured in the sitting than in the standing position. PEF did not differ when measured either with or without nose clip. Expiration time and volume in PEF measurement requires only one fifth and a half of that of forced expiratory flow volume measurement, respectively. In 36% of asthmatic patients in whom PEF is measured daily, PEF measurements were thought to be measured after inspiring at about 90% of forced vital capacity. Although PEF is a well tolerated useful clinical parameter in the management of bronchial asthma, it has different characteristics from peak expiratory flow rate (PEFR) of forced expiratory volume measurement.

In long-term management of bronchial asthma, severity is classified according to the need for steroid treatment. In mild asthma, no chronic steroid treatment is needed; bronchodilators alone can relieve symptoms. In patients with moderate asthma, continuous inhaled steroids are necessary. In severe asthma, both oral and inhaled steroids are necessary. Patients resistant to steroids are included among those with severe asthma. Patients who need 10 mg or more of prednisolone per day to control their asthma are classified as steroid resistant. However, steroid resistance has also been defined in terms of the reversibility of the forced expiratory volume 1 second (FEV1) after 1 to 2 weeks of oral steroids. The mechanism of steroid resistance remains to be clarified; functional derangement and a reduction in the number of steroid receptors on lymphocytes have been postulated as mechanisms. Turner-Warwick classified asthmatics according to the way that peak flow is affected by therapy. In her classification, patients with "brittle" asthma are likely to be steroid resistant and those with "irreversible" asthma are likely to be steroid resistant and those with "irreversible" asthma are likely to be steroid dependent. This classification implies that response to steroid therapy may be predicted from measurements of peak expiratory flow. Therefore, although the response to steroid therapy may not be useful in classifying the pathogenesis of asthma, it is one of the most important ways to classify the severity of asthma.

A 42-year-old man was admitted to the hospital because of wheezing and dyspnea that began 20 minutes after accidental exposure to irritant gas containing chromate at a chrome pellet manufacturing plant. The patient had a positive skin reaction to chromite (Cr2O3). Reduction of FEV1.0 was observed 120 minutes after Cr2O3 inhalation challenge. By 150 minutes after Cr2O3 inhalation, FEV1.0 had decreased by 32%. Chest X-ray film revealed no abnormalities. Histological findings of the lung tissue obtained by open lung biopsy revealed bronchospasm and peri-bronchial inflammatory cell infiltration without bronchiolar obstruction, and thus bronchiolitis obliterans was ruled out. This patient fulfilled the criteria of reactive airway dysfunction syndrome (RADS) proposed by Brooks; onset of symptoms very soon after a single exposure to an irritant, persistence of asthmatic symptoms, obstructive pulmonary dysfunction, and the presence of airway hyperreactivity to methacholine. During the initial hospital stay, asthmatic symptoms were relieved by intensive anti-asthmatic treatment including oral and parenteral corticosteroids. However, the patient's asthmatic symptoms have lasted for eight years and necessitate the use of systemic steroids, and regular use of inhaled steroids and bronchodilators. We know of no previous reported case of RADS after chromate exposure.

Adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), recently have been considered to play a key role in inflammatory processes in asthma. Thus, from the point of view of cell interactions between mononuclear cells and eosinophils, we examined whether the supernatant of mononuclear cells (MNC) obtained from mite-allergic asthmatic patients cultured with specific allergen is involved in ICAM-1 expression using an eosinophilic cell line (EoL). ICAM-1 expression was induced by the supernatant of MNC from mite-allergic asthmatic patients stimulated with mite allergen as well as by a combination of IL-3, GM-CSF, and IL-5. Thus, we could conclude that some cytokines produced by specific allergen-stimulated MNC in asthmatics might be involved in allergic inflammation through the induction of adhesion molecule expression such as ICAM-1 on eosinophils in asthma or allergic disorders.

In order to clarify the effects of longterm inhaled steroid therapy on bone metabolism, we examined 72 patients with bronchial asthma treated mainly with BDP (beclomethasone dipropionate). Multiple scanning X-ray photodensitometry was used to evaluate the degree of bone mineral loss. Osteocalcin, alkaline phosphatase (total and type III) was measured as a marker of bone synthesis and urinary pyridinoline, and deoxy-pyridinoline was measured as a marker of bone resorption. There was age related bone mineral loss. Urinary pyridinoline increased with aging. Treatment related bone mineral loss was not observed either in cases treated with BDP or in cases treated with continual oral steroids. Urinary pyridinoline and deoxy-pyridinoline decreased in patients treated with larger doses of for longer periods with BDP. Serum osteocalcin levels were lower in patients on continual oral corticosteroids. We conclude that inhaled steroid do not deteriorate bone metabolism in patients with bronchial asthma, when used appropriately.

The effect of a new anti-asthmatic drug, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), was investigated in ovalbumin-sensitized guinea-pigs. When guinea-pigs were pretreated with TYB-2285 (300 mg kg-1, p.o., single dose or consecutively for 7 days), the immediate asthmatic response was inhibited as demonstrated by diminished cyanosis, but not the bronchoconstriction. TYB-2285, given singly or consecutively, inhibited the appearance of late asthmatic response and the infiltration of inflammatory cells, such as eosinophils, into the airway. Additionally, airway hyper-responsiveness was also reversed by the single administration of TYB-2285. Luminol-dependent chemiluminescence of airway-infiltrated cells stimulated with A23187 was inhibited by TYB-2285 in a dose-dependent manner. The present study suggests that TYB-2285 inhibits late asthmatic response and airway hyperresponsiveness by inhibiting the accumulation of eosinophils and other inflammatory cells into the airway, and also by inhibiting the production of oxygen radicals from airway-infiltrated cells.

Adhesion molecules recently have been considered to play an important role in inflammatory processes in bronchial asthma. Our previous study revealed high expression of beta 2-integrin family (CR3, LFA-1 alpha, CD18) on hypodense eosinophils. Thus, from the point of view of cell-to-cell interaction between mononuclear cells and eosinophils, we examined whether the supernatant of mononuclear cells obtained from mite-allergic asthmatic patients cultured with specific allergen mite-allergen is involved in adhesion molecule expression using an eosinophilic cell line (EoL-1). These characteristics of beta 2-integrin family expression (high expression of beta 2 integrin) were induced by the supernatant of mononuclear cells from mite-allergic asthmatic patients stimulated with mite-allergen as well as with a combination of the recombinant eosinophilopoietic growth cytokines (IL-3, GM-CSF and IL-5). Thus, we could conclude that some cytokines produced by specific allergen stimulated mononuclear cells in asthmatics might be involved in allergic inflammation through the induction of adhesion molecule expression on eosinophils in asthma or allergic disorders.

Recently, adhesion molecules have been considered to play an important role in inflammatory processes in bronchial asthma. To extend our understanding of the high-intensity expression of adhesion molecules (CR3, LFA-1 alpha, LFA-1 beta, ICAM-1) on hypodense eosinophils, which was observed in our previous study, we examined whether the supernatant of lymphocytes from mite-allergic asthmatic patients is involved in adhesion molecule expression using an eosinophilic cell line (EoL-1). These characteristics of adhesion molecule expression were induced by the supernatant of lymphocytes obtained from mite-allergic asthmatic patients cultured with specific allergen as well as a combination of recombinant cytokines (IL-3, GM-CSF, IL-5). Thus, we could conclude that some lymphokines produced by specific allergen in asthma might be involved in the high-intensity expression of adhesion molecules on hypodense eosinophils in asthma or allergic disorders.

Several characteristics of human eosinophil heterogeneity, as well as the existence of eosinophil subpopulations, "normodense" and "hypodense", have been reported in diseases associated with hypereosinophilia. Hypodense eosinophils can be distinguished by the increased expression of various membrane receptors including IL-5 receptor (J Exp Med 172: 1347) and various protein expression (J Immunol 142: 4416). On the other hand, recently, adhesion molecules are considered to play an important role in inflammatory processes in allergic and immune reactions such as bronchial asthma. Thus, in thin study, we examined the characteristics of expression of adhesion molecules on human eosinophils obtained from patients with hypereosinophila (hypodense eosinophils). As a result, high intensity expression of adhesion molecules (CR3, LFA-1 alpha, LFA-beta) on eosinophils were observed. Furthermore, ICAM-1, which is the ligand for LFA-1 molecules, was also expressed on eosinophils with hypereosinophilia. To extend our understanding of high intensity expression of adhesion molecules (CR3, LFA-1 alpha, LFA-1 beta, ICAM-1) on hypodense eosinophils, we examined whether chemotactic agents or eosinophilopoietic growth lymphokines (IL-3, GM-CSF, IL-5) are involved in adhesion molecule expression using an eosinophilic cell line, EoL-3. The expression of adhesion molecules on eosinophils was induced by some chemotactic agents and eosinophilopoietic growth lymphokines. Taken together, we conclude that eosinophilopoietic lymphokines as well as chemotactic agents may be involved in the high intensity expression of adhesion molecules on hypodense eosinophils.(ABSTRACT TRUNCATED AT 250 WORDS)

A remarkable "steroid sparing" effect of Saiboku-to was noted within 6 to 12 months of treatment in steroid-dependent asthmatic patients. Saiboku-to spared the downregulation of glucocorticoid receptor of human lymphocytes, plasma ACTH, and cortisol levels. It also spared downregulation of beta 2 receptor by beta 2 agonists and suppressed mACh receptor at the same time. Saiboku-to increased tyrosine aminotransferase (TAT) production, which was inhibited by actinomycin-D, thus having steroid-like activity. In mite-allergic asthma, Saiboku-to inhibited the induction of expression of IgE-Fc epsilon R/CD23 in the lymphocytes by mite allergen. It also inhibited IgE production by mite allergens. In experimental asthma in guinea pigs the use of Saiboku-to resulted in a decrease in the number of eosinophils in the bronchoalveolar lavage fluid during late asthmatic response. These findings suggest that Saiboku-to may be effective in inhibiting both the expression of IgE-Fc epsilon R2 and the induction of expression of IgE-Fc epsilon R1. Saiboku-to also has a steroid-like action and polyhedral anti-asthmatic activities.

The functions of eosinophils in immunological reactions and their heterogeneity have recently generated a matter of great interest. Several characteristics of human eosinophil heterogeneity, as well as the existence of eosinophil subpopulations, called "normodense" and "hypodense", in diseases associated with hypereosinophilia, have been reported. Hypodense eosinophils can be distinguished by the increased expression of various membrane receptors including IL-5 receptor (J Exp Med 172: 1347) and various protein expression (J Immunol 142:4416). On the other hand, recently, adhesion molecules are considered to play an important role in inflammatory processes in allergic and immune reactions such as bronchial asthma. It was recently described that symptoms of bronchial asthma in animal model were in particular improved by means of anti-ICAM-1 (Intercellular adhesion molecule-1) monoclonal antibody (mAb). Thus, in thin study, we examined the characteristics of expression of adhesion molecules on human eosinophils obtained from hypereosinophilia (hypodense eosinophils). As results, high intensity expression of adhesion molecules (CR3, LFA-1 alpha, LFA-1 beta) on eosinophils obtained from patients with hypereosinophilia were observed. Furthermore, ICAM-1, which is ligand for LFA-1 molecules, was also expressed on eosinophils with hypereosinophilia. To extend our understanding of high intensity expression of adhesion molecules (CR3, LFA-1 alpha, LFA-1 beta, ICAM-1) on hypodense eosinophils, we examined whether chemotactic agents or eosinophilopoietic growth lymphokines (IL-3, GM-CSF, IL-5) is involved in adhesion molecule expression using an eosinophilic cell line named EoL-3. These characteristics of adhesion molecules on eosinophils were induced by some chemotactic agents and eosinophilopoietic growth lymphokines.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to clarify whether Fc epsilon R2 can be induced on lymphocytes of patients with bronchial asthma by stimulation with specific antigen. Expression of Fc epsilon R2 on freshly isolated lymphocytes (at 0 hour) was significantly higher in both patients with mite-allergic asthma and those with nonmite-atopic asthma than in healthy individuals. In addition, expression of Fc epsilon R2 on lymphocytes was still higher in patients during acute asthma. Marked induction of Fc epsilon R2 on lymphocytes was observed 48 hours or more after addition of mite-allergen in patients with mite-allergic asthma while no Fc epsilon R2 expression was induced in patients with nonmite-atopic asthma or healthy individuals. Induction of Fc epsilon R2 expression was not observed at 30 minutes, two hours, and five hours, which are equivalent in kinetics to immediate asthmatic response and late asthmatic response in allergen inhalational challenges.