Topical and systemic glucocorticoids have long been considered the most effective therapy for chronic asthma. Asthma patients who do not respond to systemic administration of high-dose glucocorticoids are termed 'steroid-resistant asthmatics'. Recent progress in the mechanisms of glucocorticoid action goes a long way to the understanding of steroid resistance. Several cellular responses to glucocorticoids have been characterized in steroid-resistant asthma. Based on molecular biological studies, excessive expression of glucocorticoid receptor β and c-fos, an inducible transcription factor, was suggested to result in steroid resistance. A thorough understanding of the pathophysiology of steroid-resistant asthma would facilitate the development of more powerful agents for the treatment of severe asthma.

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The application of molecular biology to the discovery of novel pathways to inhibit allergic tissue responses is becoming a reality. Particularly promising approaches are the use of vaccines and pharmacologic agents to downregulate the polarized T Helper (Th)-2 lymphocyte response through enhancement of interferon-γ production. Selective inhibition of specific mediators, such as interleukin (IL)-4, IL-5, IL-13 and eotaxin, should lead to a new class of anticytokine therapeutic agents. At the cellular level, more effective inhibition of mast cell activation and strategies to remove IgE as the triggering stimulus hold promise. With the discovery of susceptibility genes for allergic disease, the next decade is likely to witness substantial further developments in this field, with a strong focus targeted on induction mechanisms and disease prevention. If the current epidemic of allergic disease continues, then there is a strong incentive to identify those environmental factors that are responsible so that appropriate interventions can be introduced. These may include alterations to the maternal and infant diet to program the developing immune response or, in genetically susceptible individuals, the early introduction of a protective vaccine to reset the T lymphocyte balance more in favour of a Th-1 response. In this regard, the development of cytosine and guanosine nucleotide repeats and antigen-specific DNA vaccines look especially promising. In established allergic disease, the task of reversing sensitization is daunting. Safer and more efficacious allergen vaccines, whether using DNA or peptide approaches, offer the most promising approach for fundamentally changing the allergic immune response. Patients would also greatly benefit from more effective and orally active mast cell inhibitors and small molecules that could either remove IgE or effectively interrupt its capacity to signal through its cell surface receptors. In the meantime, the epidemic of allergic disease requires urgent attention, not only in the provision of specialist centers for providing accurate diagnosis and for administering treatment (including immunotherapy), but in a clear recognition that these disorders are caused by changing environmental factors and, as a consequence, deserve attention at the level of public health.

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Eosinophilic airway inflammation and increased cough sensitivity without bronchial hyperresponsiveness are the pathologic and physiologic features of bronchodilator-resistant non-productive cough-associated global atopic tendency, abbreviated herein as atopic cough. Histamine H₁ receptor antagonists are effective in relieving the cough in nearly 60% of patients with atopic cough. However, there is no direct evidence that histamine H₁ receptor antagonists can reduce cough hypersensitivity associated with eosinophilic airway inflammation. The purpose of the present study was to clarify this issue. The number of coughs caused by inhalation of increasing concentrations of capsaicin (10^-8, 10^-6 and 10^-4 mol/L) was counted 24 h after the administration of an aerosolized antigen in actively sensitized conscious guinea pigs and then bronchoalveolar lavage (BAL) was performed. Azelastine (0.1 or 1 mg/kg) or terfenadine (0.2 or 2 mg/kg) was given intraperitoneally 60 min before capsaicin provocation 24 h after the antigen challenge in sensitized guinea pigs. In addition, azelastine (0.1 or 1 mg/kg) was administered 90 min before the capsaicin challenge in naïve guinea pigs. The cough response to capsaicin and the number of eosinophils in BAL fluid (BALF) were significantly increased after antigen challenge. Azelastine and terfenadine significantly reduced the increased cough response after antigen challenge, while azelastine had no effect in naïve animals. In conclusion, histamine H₁ receptor antagonists reduce antigen-induced increases in cough sensitivity in sensitized guinea pigs without direct inhibition of a common cough reflex pathway.

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Platelet-activating factor (PAF) can activate various cellular functions, including degranulation in eosinophils. In the present study, we examined tyrosine phosphorylation of intracellular proteins induced by PAF in eosinophils derived from cord blood mononuclear cells. Platelet-activating factor induced tyrosine phosphorylation of many intracellular proteins, including 42,123 and 150 kDa proteins. Immunoprecipitation studies showed that the 123 kDa phosphorylated protein was proline-rich tyrosine kinase 2 (PYK-2; also known as related adhesion focal tyrosine kinase (RAFTK), cell adhesion kinase β (CAKβ) and calcium-dependent tyrosine kinase (CADTK)). Furthermore, blocking of cellular adhesion through β₂ integrin by anti-CD18 monoclonal antibody inhibited tyrosine phosphorylation of PYK-2 as well as the degranulation response. These findings suggest that tyrosine phosphorylation of PYK-2 is involved in a signaling pathway mediated by cellular adhesion through β₂ integrin in PAF-activated eosinophils.

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The role of interleukin (IL)-4 in the development of allergen-induced airway inflammation and bronchial hyperresponsiveness (BHR) is still controversial. To investigate the role of IL-4 in the development of antigen-induced airway inflammation and BHR, we used two different inbred IL-4 gene-knockout mice; one was BALB/c, which is known to be a high IgE responder, and the other was C57BL/6, known to be a low IgE responder and a lower responder to acetylcholine (ACh) in the airways. Mice were immunized with antigen at intervals of 12 days. Starting 10 days after the second immunization, mice were exposed to antigen three times every fourth day. Twenty-four hours after the last antigen challenge, bronchial responsiveness to ACh was measured and bronchoalveolar lavage was performed. In sensitized BALB/c mice, repeated aeroallergen challenge induced dramatic eosinophilia in the airways and severe increases in bronchial responsiveness to intravenous ACh, along with increases in serum antigen-specific IgE. In contrast, immunized C57BL/6 mice, after antigen provocation, developed a minor influx of eosinophils into the airways and only moderate increases in bronchial responsiveness without antigen-specific IgE in serum, indicating that the genetic background influenced not only IgE synthesis, but also the degree of airway inflammation and BHR. Moreover, disruption of the IL-4 gene in both strains of mice abolished allergen-induced BHR, airway eosinophilia and IgE response. Together, these findings suggest that the differences in genetic background can directly influence the pathophysiology of bronchial asthma, including the role of IgE, and that IL-4 has a crucial role in the development of allergen-induced BHR independent of genetic background.

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Pollinosis caused by Cryptomeria japonica is a very serious health problem in Japan. To clarify the relationship between C. japonica pollen emissions before the main pollen dispersal season and dormancy of the male flowers, pollen emissions from C. japonica trees were observed from November to February, using both flowering tests and an airborne pollen survey. Some C. japonica trees studied shed pollen in November and December, by one of two mechanisms. First, some male flowers turned brown and withered, resulting in the formation of small crevices between the scales and pollen leakage. Second, some pollen was released via elongation of the rachis, which is the normal mode of flowering in spring. These early pollen emissions from male flowers were considered to represent a process of self-thinning or unseasonable flowering. Cryptomeria japonica pollen counts between October and January were closely related to mean monthly temperatures and airborne pollen counts of the following pollen season. The present study clearly shows that some male flowers of the species can bloom and disperse abundant pollen via blooming or withering in November, if the temperature in October is high, in years of high pollen production.

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A 49-year-old Japanese man with bronchial asthma was admitted to hospital because of acute lobar pneumonia. A diagnosis of acute tuberculous pneumonia was made based on the pathologic findings of lung biopsy specimens and bacteriologic examination. For the 5 years before the onset of pneumonia, the patient had been treated with inhaled beclomethasone dipropionate (600 µg/day) and was well controlled. Laboratory findings revealed no immunosuppressive conditions, nor had the patient used oral corticosteroids for the treatment of his asthma. A tuberculin skin test had been negative approximately 30 years ago and annual chest X-ray examination had shown no evidence of tuberculosis over the past 5 years. Fiberoptic broncoscopic examination showed no evidence of bronchial tuberculosis or perforated lymph nodes. Because acute tuberculous lobar pneumonia in the lower lung field is rare, except in patients receiving oral corticosteroids or with immunodeficiency conditions, in this patient the inhalation of corticosteroids may have predisposed him to the onset of this condition.

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