A strong link between bronchiolitis and asthma has been indicated. Bronchiolitis that occurs in infants is manifested physiologically by a widespread narrowing of the air passages and, clinically, by asthma-like symptoms.The major cause of bronchiolitis is respiratory syncytial virus infection. While the precise pathophysiologic sequences of infection are incomplete, many observations have suggested that there is an infiltration of eosinophils in the airways. Current studies have shown that the respiratory syncytial virus penetrates the pulmonary defenses and initiates immunologic responses. The histamine and leukotriene mediators that are released produce an inflammatory reaction and the chemotactic factors bring eosinophils to the site of the reaction. Degranulation of eosinophils can release eosinophil cationic protein into the airways. Our finding that chemoattractants for eosinophils, interleukin-8 and RANTES (regulated upon activation, normal T cell expressed and presumably secreted) were detected in nasopharyngeal aspirates of infants with bronchiolitis suggests that such chemokines from epithelial cells may induce an eosinophil infiltration in the airway. Similar allergic inflammatory changes have been observed in asthma and in epithelial cells infected with respiratory viruses. Future investigation of the mechanism by which bronchiolitis can induce asthma will provide benefits in the treatment and prevention of asthma in sensitive individuals.

View full abstract

Prostaglandin E₂ (PGE₂) is produced by resident cells in the airway, such as airway epithelial cells, airway smooth muscle cells and alveolar macrophages, and is always present in the airway. Various exogenous and endogenous stimuli cause immediate increases in PGE₂ from several-fold to multiples of 10-fold. Prostaglandin E₂ controls the function of cells that contribute to immune and inflammatory responses, such as lymphocytes, eosinophils, mast cells, macrophages and polymorphonuclear cells, and exhibits suppressor activity in the initial and advanced stages of allergic airway inflammation (establishment of sensitization, induction of early asthmatic response, chemotaxis of inflammatory cells and continuation of the late asthmatic response). Therefore, if the endogenous protective effects of PGE₂ are weakened or absent, inflammation and hypersensitive responses readily occur in the airway. Although the effects of PGE₂ remain to be clarified, the possibility of the involvement of decreased PGE₂ activity in the pathogenesis of asthma exists. However, in aspirin-induced asthma the role of PGE₂ as a protective factor, through an as yet undetermined mechanism, is marked. It is thought that, in this type of asthma, symptoms may be induced by the elimination of the protective action of PGE₂ by non-steroidal anti-inflammatory drugs (NSAID). It is possible that PGE₂ agonists that produce little airway irritation and drugs that raise the endogenous PGE₂ level have potential as new types of anti-inflammatory or anti-asthma drugs.

View full abstract

Human IgE synthesis is largely dependent on the production of interleukin (IL)-4 or IL-13 and the expression of CD40 ligand. Such B cell help is not only provided by CD4⁺ T cells, but also by CD8⁺ T cells, γδ T cells, mast cells, basophils and eosinophils. The IL-4 receptor α chain (IL-4Rα) expressed on B cells is shared by the functional IL-4R and IL-13R and is a crucial component required for signal transduction leading to germline Cε transcription, which is a prerequisite for IgE isotype switching. Interleukin-4 activates Janus kinase (JAK)1, JAK3 and phosphatidylinositol 3-kinase (PI3-K) and, subsequently, induces nuclear translocation of signal transducers and activators of transcription (STAT)6 and nuclear factor (NF)-κB, which interact at the level of the Iε promoter. The two variants of the IL-4Rα, which have been identified in association with atopy, are associated with enhanced responsiveness to IL-4. Ligation of CD40 on B cells up-regulates IL-4- or IL-13-driven germline Cε transcription and further induces deletional switch recombination that results in IgE isotype switching, mature Cε transcription and IgE synthesis. Signaling pathways mediated by CD40 include activation of Lyn, PI3-K, JAK3 and members of the mitogen-activated protein kinase subfamily, multimerization of tumor necrosis factor-α receptor-associated factor (TRAF)2, TRAF3, TRAF5 and TRAF6 and translocation of NF-κB and STAT3. In addition, Ku70/86, DNA-dependent protein kinase and rad51/54 may be involved in switch recombination. Taken together, activation of kinases, induction of second messengers, nuclear expression of transcription factors and localization of DNA-binding proteins are integrated to produce the terminal differentiation of a B cell into an IgE-secreting plasma cell. Elucidation of the detailed mechanisms of IgE isotype switching will contribute to the development of potential new therapeutic procedures for the regulation of the IgE response in atopic patients.

View full abstract

Bee stings are a common health problem throughout the world and can sometimes result in fatal anaphylactic reactions. We have studied Asian bee (Apis cerana indica, Apis cerana nigrocincta and Apis dorsata) venoms and have discovered a novel protein with a molecular size of 50 kDa (p50), as shown by sodium dodecyl sulfatepolyacrylamide gel electrophoresis, which has not been reported in the venom of the Western honey-bee, Apis mellifera (AM). The p50 protein showed a unique affinity to human α1-microglobulin (α1-m). As a result, p50 was purified using an affinity column with α1-m. The p50 protein was further purified by an affinity column with a monoclonal antibody raised against p50 in mice. The p50 protein induced an inflammatory reaction following injection into mouse ear; that is, degranulation of mast cells, edema, hyperemia and hyperpermeation of the local capillaries were observed. The reaction was very similar to that seen when phospholipase A₂ of AM, a representative bee venom, was administered by injection. The inflammatory reaction induced by p50 was completely inhibited by mixing p50 with α1-m prior to injection. These results indicate that p50 is a unique venom component of the Asian bee that induces the inflammatory reaction and that human α1-m may be involved as a protective mechanism against bee stings of at least some Asian bee species.

View full abstract

In order to clarify the airway physiology of NC mice, the following experiments were carried out. To investigate inherent airway reactivity, we compared tracheal reactivity to various chemical mediators in NC, BALB/c, C57BL/6 and A/J mice in vitro. NC mice showed significantly greater reactivity to acetylcholine than BALB/c and C57BL/6 mice and a reactivity comparable to that of A/J mice, which are known as high responders. Then, airway reactivity to acetylcholine was investigated in those strains in vivo. NC mice again showed comparable airway reactivity to that seen in A/J mice and a significantly greater reactivity than that seen in BALB/c and C57BL/6 mice. To investigate the effects of airway inflammation on airway reactivity to acetylcholine in vivo, NC and BALB/c mice were sensitized to and challenged with antigen. Sensitization to and challenge with antigen induced accumulation of inflammatory cells, especially eosinophils, in lung and increased airway reactivity in NC and BALB/c mice. These results indicate that NC mice exhibit inherent and antigen-induced airway hyperreactivity. Therefore, NC mice are a suitable strain to use in investigating the mechanisms underlying airway hyperreactivity and such studies will provide beneficial information for understanding the pathophysiology of asthma.

View full abstract

Quantitatively cultured bacteria in sputum sampled from asthmatic children aged 0-14 years was examined to determine whether there is a relationship between asthmatic states and bacterial species present in the respiratory tract. We used cytological examination to improve the specificity of pathogens cultured in sputum. Asthmatic children were divided into three groups: (i) group 1, acute asthma attack (n = 191); (ii) group 2, prolonged asthma attack (n = 68); and (iii) group 3, pneumonia without asthma attack (n = 39). The number of specimens was 212, 75 and 44 for groups 1, 2 and 3, respectively. The number of specimens with pathogenic bacteria present in group 1 decreased with age, from 36.8% in infants under 1 year of age to 8.7% in children over the age of 9 years. The species of bacteria in group 1 were Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and these were distributed evenly in the samples. In group 2, pathogenic bacteria were present in 34.7% of patients (26/75), peaking at over 40% among children between 4 and 8 years of age. The presence of H. influenzae was dominant in group 2. The percentage of pathogenic bacteria present in group 3 specimens was 40.9%. The data suggest that there is a significant relationship between the presence of bacteria in sputum and clinical symptoms, such as fever and pneumonic episodes, during acute asthma attacks.

View full abstract

Recent guidelines for the management of asthma recommend that peak expiratory flow (PEF) should be measured to monitor the level of airflow limitation and to maintain PEF values within the green zone (80-100% of the patient's highest PEF value). Because no studies have evaluated the efficacy of PEF zone management on the basis of patients' physical activity, we studied the appearance of exercise-induced asthma (EIA) using treadmill exercise challenging in asthma patients whose PEF values had been maintained in the green zone for at least 3 months. Exercise-induced asthma was induced in nine of 44 (20.5%) asthma patients. The acetylcholine concentration required to cause a 20% fall in forced expiratory volume in 1 s (log PC₂₀) was significantly lower in patients with EIA (2.39 ± 0.21 µg/mL) compared with patients without EIA (3.22 ± 0.12 µg/mL; P < 0.03). These results suggest that PEF green zone management alone does not ensure the ability to perform vigorous physical activity, especially in patients whose airway reactivity remains enhanced. Therefore, airway reactivity should be considered for asthma management.

View full abstract