Late asthmatic reaction (LAR) and dual asthmatic reaction (DAR) were developed in guinea pigs by repetitive treatment with toluene 2,4-diisocyanate (TDI). Development of LAR or DAR seemed to dependent on the TDI-treatment period. IgG was demonstrated in both the LAR and DAR models, whereas IgE was only in the DAR model. Increased numbers of eosinophils and goblet cells were observed in the epithelial mucosa of the bronchioles in addition to mast cells with decreased numbers of specific granules. Both LAR and DAR were inhibited in those model animals pretreated with dexamethasone. Serum corticosteroid and adrenal cytochrome P-450 levels in guinea pigs during TDI-treatment period were similar to those in untreated animals. Also, hepatic cytochrome P-450 levels and drug metabolizing activities were similar to those in untreated animals.

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Allergen-activated T cells secrete several kinds of bioactive lymphokines such as IL2, IL3, IL4, IL5 and IFN-γ. They function as helpers in IgE production involved in immediate type hypersensitivity and/or effect or cells in delayed type hypersensitivity in allergic patients. The acquisition of interleukin 2 (IL2) responsiveness by specific antigen-stimulated cells is generally an essential event for the induction of specific immunological phenomena. To investigate the immunological changes in asthmatic children in remission, the induction of IL2-responsiveness and production by Df (Dermatophagoides farinae)-stimulated patient lymphocytes, and Df-induced IFN-γ production by patient lymphocytes were evaluated. The patients were divided into 3 groups. The remission group (I) consisted of those patients who had had no or only a few asthmatic attacks for more than 2 years without medication. The group of active asthma were divided into 2 groups according to attack frequency and severity (II, partial remission; III, active asthma). IL2 responsiveness and production by Df-stimulated lymphocytes from group II and III were increased. As symptoms improved, the extent of the response subsided to a level comparable to that of normal individuals (group III). IFN-γ production by Df-stimulated lymphocytes from patients with active asthma was lower than that of normal lymphocytes. In contrast, lymphocytes from patients in complete remission group (I) induced far greater IFN-γ generation than those from normal and group II and III patients in a Df antigen-dependent manner, which might downregulate Df-induced hyperreactivity for Df-mediated allergic response. The combined data indicate that Df-induced response might be tolerated in the remission group of asthmatic children, which may reflect the clinical conditions of the disease.

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The prevalence of bronchial asthma in school children was examined both in 1982 (55,388 children) and in 1992 (45,674 children) in 11 western districts of Japan. Both studies were conducted with the same Japanese version of a modified ATS-DLD children's questionnaire in the same districts. Results: 1) The study in 1992 established a prevalence rate of 5.6% in males and 3.5% in females with an overall average of 4.6%, which was 1.4 times higher than that of 10 years ago. The higher prevalence was observed in every grade of school children and in all districts. 2) The study in 1992 showed no differences based on the grades the school children were in. The prevalence rate in males was 1.6 times higher than that in females with fewer regional differences than in the 1982 study. 3) Higher prevalence rates were found in those who had histories of respiratory diseases during their infancy, family histories of allergic disease or who lived in urban areas. The prevalence rate was 13.3% in children living in urban areas with family histories of bronchial asthma. 4) The prevalence rate of wheezing was 5.2%, which was 1.3 times higher than that of 10 years ago. The rate had increased in every district, but it decreased as the children moved into higher grades.

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The effect of the specific thromboxane (Tx) A_2 receptor antagonist, BAY u 3405 on the late asthmatic response (LAR) was investigated in quinea pigs which are sensitized actively with Ascaris suum antigen. Respiratory resistance (Rrs) of awaked guinea pigs was measured by 30 Hz oscillation method for 6 hours after antigen challenge. %Rrs was calculated as the increase rate of Rrs to baseline Rrs (pre-challenge value). Ten mg/kg of BAY u 3405 or vehicle (0.5% methyl cellulose) was administered orally after the end of immediate asthmatic response, i.e., 2 hours after antigen challenge. %Rrs of the control group at 4 and 5 hours after antigen challenge were 101.4±27.5% and 77.5±19.9%, respectively. Those of the BAY group were 32.5±6.2% and 23.5±5.0%, respectively. %Rrs of the BAY group were significantly lower than those of the control group at both timings (p<0.05). No significant difference was shown between the BAY group and the control group in the results of the bronchoalveolar lavage (BAL) 4 hours after challenge. Concerning the results of BAL at 6 hours after challenge, the total cell count and its segment, eosinophils count and lymphocytes count in the BAY group were 274.9±70.5, 62.5±13.1, 11.3±3.3 (×10^5 cells), respectively, resulting in significantly smaller numbers (each p<0.05) than those in the control group which were 491.9±55.1, 198.6±43.9, 32.1±7.3 (×10^5 cells), respectively. The concentrations of histamine (ng/ml), TxB_2 (pg/ml) and PGD_2 (pg/ml) in the BAL fluid at 4 hours after challenge were 2.06±0.83, 549.00±244.16, and 66.80±23.13, respectively, in the control group. They were not significantly different from those in the BAY group (2.98±1.22, 346.43±112.16 and 48.20±9.56, respectively). LTC_4 could not be detected (less than 20pg/ml) in the BAL fluid of both groups. These results suggest that BAY u 3405 inhibited the increase of Rrs and cellular infiltration to airways tissue at LAR, and therefore that TxA_2 may play an important role in the pathogenesis of LAR.

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As remarkable improvements have been made to the working environment and working methods of oyster shucking workers during the past 30 years, a study was made on the effects of these improvements on hoya (sea-squirt) asthma and the following results were obtained. 1) The prevalence of hoya (sea-squirt) asthma among oyster shucking workers was 36.0%, 30.1%, 21.7%, 22.0%, 18.0%, and 26.6% in 1963, 1968, 1976, 1984, 1988, and 1992, respectively. Accompanying the improvements made to the working environment and working methods, asthmatic symptoms failed to develop in some of the patients though engaged in oyster shucking work. Thus, those with symptoms actually accounted for 36.0%, 18.7%, 15/8%, 7.4%, 8.4%, and 8.0% of the workers, respectively. 2) The proportion of serious cases among the patients rapidly decreased from 29.2% in 1963 to 0% after 1984. On the other hand the proportion of slight cases was 35.4% in 1963, but after 1988 all the cases were slight cases. 3) During the period from 1984 to l992, the number of those newly engaged in oyster shucking work was 74. The number of those who developed hoya (sea-squirt) asthma during this period was 8 or 10.1%. All the cases were asthma of the rhinitis type. 4) The number of workers who did not develop asthmatic symptoms though engaged in oyster shucking work was 53 in 1984, 40 in 1988, and 49 in 1992. Of this number, 31% are now under hyposensitization therapy, 57.0% have received this therapy in the past, and 12.0% have not received any therapy.

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The clinical effects of spa therapy (swimming training in a hot spring pool + inhalation of iodine salt solution + fango therapy) were examined in 52 patients with steroid-dependent intractable asthma (SDIA). Clinical effects were found in 36 of the 52 (69.2%) patients with SDIA. The efficacy was higher in the patients between the ages of 41 and 50 (87.5%) and between 51 and 60 (84.2%) than in those in the other age groups. Regarding clinical asthma types, the efficacy of spa therapy was higher in patients with type Ia-2 (83.4%), type Ib (77.8%) and type II (80.0%) than in those with type Ia-1 (54.2%). Efficacy seemed to be related to airway inflammation: the proportion of neutrophils and eosinophils in bronchoalveolar lavage (BAL) fluid was higher in patients with marked and moderate improvement compared with those with slight and no improvement. Ventilatory function was improved by complex spa therapy. %MMF and %V_<25> values increased by more than 20% after therapy in patients with type Ia-2, Ib and II asthma. Bronchial hyperreactivity to methacholine was suppressed after therapy. Any decreased function of the adrenocortical glands expressed by low serum cortisollevels improved after therapy, accompanied by a reduction in the dose of glucocorticoids necessary to control asthma attacks.

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In order to examine fluticasone propionate's mechanism of inhibiting nasal allergic symptoms, topical dosing of FP to patients with Japanese cedar pollinosis was started before the pollen scattering season, and the kinetics of basophilic cells and eosinophils which infiltrated into the surface of nasal mucous membrane were observed. Patients with Japanese cedar pollinosis were divided into two groups. Before and in the early period of the pollen scattering season, one group received FP and the other group a placebo, topically into the nostrils. In the mid and late season, both groups were treated with FP topical dosing. The study was carried out in the double blind manner. In the pre-, early and late season, specimens were scraped from the nasal mucosal surface, basophilic cell and eosinophil counts in the specimens were measured, and histamine and ECP contents in the specimens were also determined. Topical use of FP starting pre-season significantly inhibited symptoms of Japanese cedar pollinosis, as well as accumulation of basophilic cells and eosinophils in the nasal mucosal surface. Histamine and ECP contents in the nasal specimens tended to decrease with the topical use of FP.

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Substance P (SP), a potent neuropeptide, which is localized in the sensory nerves and released by many physiological stimuli has been implicated in airway neurogenic inflammation. We have studied the effects of capsaicin (CAP), which releases tachykinins (TK) from the sensory nerves, on eosinophil (EOS) recruitment in the airway in guinea pigs in vivo. Male guinea pigs were used. The respiratory resistance (Rrs) of the guinea pigs were measured by an oscillation technique and histological studies of the right main bronchus were carried out. Exposure to inhaled CAP resulted in a significant increase in Rrs with PC_<200> CAP of 0.97±0.25 (×10^<-6> M) (n=5). This stimulation also provoked striking eosinophilia in the right bronchus in a dose-dependent manner. A neutral endopeptidase (NEP) inhibitor, phosphoramidon, potentiated CAP-induced EOS infiltration. By contrast, pretreatment with [D-Pro^2, D-Trp^<7,9>]-SP, an analogue of SP and its receptor antagnoist, diminished the response. We conclude that CAP-induced tachykinin release is capable of causing striking eosinophilia in the lung in vivo. This mechanism may contribute to airway inflammation in patients with asthma. This would provide further support for a link between tachykinin and bronchial eosinophilia in asthma.

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A relationship between rheumatoid arthritis (RA) and endocrinological abnormality has been suspected for many years. In the present study, we immunohistologically identified the presence of methionine-enkephaline (Met-enk) and leucine-enkephaline (Lek-enk), in synovial tissues collected from RA patients and determined the amount of these peptides and interleukin 1β (IL-1β) in the culture supernatant of tissue explants by RI and ELISA. Synovial membrane samples obtained by biopsy during artificial joint replacement and plasma samples simultaneously collected from 11 RA patients (11 joint) diagnosed as having classic or definite RA according to the diagnostic criteria of the American Rheumatism Association were used. All 11 patients were females and aged between 36 and 64 years (mean: 45.8 years). As a result of immunohistological standing (ABC method), Met-enk was detected in vascular endthelial cells and Leu-enk in superficial cells, vascular endthelial cells and interstitial cells. Leu-enk concentrations (42.3±15.8 pg/ml) were higher in the culture supernatant of the synovial membrane than in the plasma (20.7±13.3 pg/ml). Furthermore, in the culture supernatant the concentration of Leu-enk was positively correlated with that of IL-1P (r=0.789). These findings suggest that Met-enk and Leu-enk are locally produced by synovial tissues and may exert an immunological and/or inflammatory role in RA synovitis.

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We have examined the functional characteristics of mast cells grown in tissue culture from intra-hepatic lymphocytes of mice (IHL-MC) and compared them with mast cells grown from bone marrow (BMC-MC). Intra-hepatic lymphocyte derived mast cells had the functional characteristics of cultured mast cells. These cells were stained by alcian blue, had a lower histamine content than rat peritoneal mast cells (considered to be a model of connective tissue type mast cells) and responded to Ca^<2+> ionophore and IgE receptor mediated stimulation. However, there were some differences between IHL-MC and BMC-MC. IHL-MC had a higher histamine content and lower growth activity by T-cell derived factor than BMC-MC.

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