Asthma is a complex disease which is due to the interaction of an unknown number of genes with strong environmental factors. Segregation analysis suggests the presence of major genes underlying asthma and atopy. Different genetic effects have been recognized which predispose to generalized atopy, or modify the atopic response to particular allergens, or enhance bronchial inflammation, or modify bronchial tone. These known genes or genetic loci do not account for all of the familial clustering of asthma and atopy. Many studies are now under way to identify the remaining genes.

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The objective is to review β-adrenergic receptors and mechanisms in the immediate and late bronchial reaction in asthma and the new long-acting β-agonist. This will be discussed in light of the controversy of the potential adverse effect of regular use of long-acting β-agonists. We studied the effect of formoterol on the late asthmatic response (LAR) and airway inflammation in guinea-pigs. Formoterol suppressed the LAR, antigen-induced airway inflammation and hyperresponsiveness, although isoproterenol failed to inhibit these parameters. β-Adrenergic hyporesponsiveness, and cholinergic and α-adrenergic hyperresponsiveness have been implicated in the pathogenesis of asthma. A decrease in β-adrenoreceptor function can result either from exogenously administered β-agonist or from exposure to allergens resulting in a late bronchial reaction. There is increasing evidence that eosinophils, macrophages, and lymphocytes which are of primary importance in the late bronchial reaction are also modulated by β₂-adrenoreceptors. In functional studies of guinea-pig or human isolated trachea and lung parenchyma, PAF and certain cytokines significantly reduced the potency of isoproterenol to reverse methacholine- or histamine-induced contraction. The effect of glucocorticoids on pulmonary β-adrenergic receptors and responses suggests an important role for glucocorticoids to increase β-adrenergic receptors and responsiveness.

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Overwhelming evidence now points to asthma as a chronic inflammatory disease involving the airways. The T lymphocyte takes primacy in driving the inflammatory response through upregulation of cytokines, specifically those encoded in the IL-4 gene cluster: IL-4 and IL-13 (IgE isotype switching); IL-3, IL-5 and GM-CSF (eosinophil and basophil recruitment); and IL-9 (mast cell maturation). Additional cytokines of importance include TNFα and a range of related C-x-C and C-C cytokines. Although allergens are involved in initiating the Th-2 T-cell response, other factors are likely to operate that expand and maintain the inflammatory reaction. These include a potential role for superantigens and autoimmune mechanisms as well as the recruitment of accessory cytokine producing cells, especially mast cells and eosinophils. Leucocytes recruited from the microvasculature through interactions with specific adhesion molecules release an array of mediators, which in addition to causing bronchoconstriction also lead to damage to the epithelium and underlying structures. Neutral proteases from mast cells, metalloproteases from eosinophils and an array of mediators from the formed elements of the airway all contribute to the tissue destruction remodelling process. It was concluded that asthma is a dynamic disease process involving an interplay between inflammation and repair processes and that the differing proportions of these could account for the various disease phenotypes associated with severity and progression.

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For over 100 years, the association of eosinophils with bronchial asthma has been known. Over the past 20 years, the proteins comprising the eosinophil granule have been isolated and characterized. Four proteins are recognized and termed the major basic protein (MBP), the eosinophil peroxidase (EPO), the eosinophil-derived neurotoxin (EDN), and the eosinophil cationic protein (ECP). The activities of these proteins are reviewed with emphasis on their abilities to interact with structures in the bronchus and to reproduce features of the pathology of bronchial asthma. In addition, the relationship of these proteins to bronchial hyperreactivity, a major stigma of bronchial asthma, is discussed, and information highlighting the role of MBP is reviewed. Evidence also exists that eosinophil granule proteins may interact with the nervous system, and results showing increased vagal reactivity in an experimental animal model and the role of MBP as an allosteric muscarinic M₂ receptor are presented. Finally, the effects of eosinophil granule proteins as cytostimulants on other cells including basophils, mast cells, neutrophils, platelets and alveolar macrophages are reviewed. Overall, these results indicate that eosinophil granule proteins have many abilities to alter lung function in asthma and to reproduce many of the cardinal manifestations of this disease.

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Aspergillus restrictus, an osmophilic fungus, is abundant in house dust. We have shown previously that the incidence of immediate hypersensitivity to A. restrictus is comparable to that for Aspergillus fumigatus and Alternaria alternata in asthmatic children. Radioallergosorbent test (RAST) inhibition was used to determine whether A. restrictus shares similar allergenic components with A. fumigatus and A. alternata. Mycelial mats of the three species cultivated on completely synthetic media were used for extract preparation. IgE antibodies to each fungus were measured with RAST using a polyvinyl chloride microplate as a solid phase. Analysis of a serum pool obtained from nine asthmatic children with a positive RAST to A. restrictus showed that A. restrictus inhibited the RAST to A. restrictus, A. fumigatus and A. alternata by more than 80%. Similar results were observed with A. fumigatus and A. alternata. Additionally, when 13 serum samples with a positive RAST to A. restrictus were tested separately, A. restrictus substantially inhibited the A. restrictus RAST in all subjects tested. A. fumigatus and A. alternata inhibited the A. restrictus RAST in 10 and 8 of the samples studied, respectively. These findings indicate that A. restrictus shares allergenic components with A. fumigatus and A. alternata. The allergenic cross-reactivity between A. fumigatus and A. alternata was also demonstrated.

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Contact urticaria syndrome is a rare but potentially serious problem for hospital staff that handle antibiotics and other agents. While the cause is immunologic, little is known about the mediators involved. To investigate these mediators, three nurses with contact urticaria syndrome caused by exposure to cefotiam hydrochloride (CTM), and five normal controls were evaluated. IgE antibodies specific for CTM were detected by the radioallergosorbent technique (RAST). In response to CTM, cytokines were released from peripheral blood mononuclear cells (PBMC), and sulfidoleukotrienes were released from peripheral blood leukocytes. RAST counts in the three nurses with this syndrome exceeded those in the normal controls. The stimulation index of the leukotrienes released from the peripheral blood leukocytes in response to CTM also exceeded those in the normal controls. Higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were also detected in the supernatant of the patients' PBMC. The results suggest that contact urticaria syndrome caused by exposure to CTM was induced by an immunologic mechanism via IgE antibodies, and that GM-CSF and leukotrienes may be involved in this reaction.

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The role played by the interaction of nitric oxide (NO) and endothelins (ET) in the modulation of airway function, and the modulation of β-adrenergic-mediated bronchodilator responses by ascorbic acid in the presence or absence of endogenous NO induced by ET in anesthetized guinea-pigs was examined. Endothelins induced a concentration-dependent increase in respiratory resistance, and pretreatment with the NO synthase inhibitor, N_G-nitro-L-arginine methylester, (L-NAME), significantly increased ET-mediated bronchoconstriction. In addition, ET-3-mediated bronchoconstriction following pretreatment with L-NAME was reversed by L-arginine. These findings suggest that the response to the administration of ET-3 can be attributed to the release of NO from the guinea-pig airway. Neither inhaled isoproterenol nor salbutamol significantly affected ET-3-mediated bronchoconstriction, but pretreatment with L-NAME markedly enhanced isoproterenol-mediated bronchodilatation. These findings suggest that endogenous NO induced by ET-3 may attenuate isoproterenol-mediated bronchodilator responses. Ascorbic acid, an antioxidant, enhanced isoproterenol-mediated bronchodilator responses following precontraction with ET-3, but pretreatment with L-NAME reduced this effect of ascorbic acid. The findings suggest that ascorbic acid attenuates the effect of endogenous NO on β-adrenergic-mediated bronchodilator response via its antioxidant activity. Since 10^-7mol/L ET-1 does not induce the release of NO from the guinea-pig airway, ascorbic acid cannot enhance isoproterenol-mediated bronchodilator responses. It seems likely that endogenous NO plays an important regulatory role in modulating β-adrenergic-mediated bronchodilator responses in the airway.

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