We have undertaken detailed cellular and ultrastructural examination of bronchial biopsies and bronchial lavage fluid from allergic asthmatic patients in order to determine the nature and degree of the inflammatory processes in mild allergic asthma. Eight atopic asthmatic patients (mean PC20 histamine, 0.90 mg/ml) and four nonasthmatic control subjects underwent fiberoptic bronchoscopy. All asthmatic subjects were clinically stable for 2 wk prior to bronchoscopy and required either no treatment or inhaled albuterol alone. A single 50-ml bronchial wash was undertaken, followed by endobronchial biopsy of subcarinae. These procedures were repeated in the asthmatic subjects 18 h after bronchial provocation with allergen or methacholine. Subsequently, all subjects underwent bronchial reactivity testing with inhaled histamine. The clinical and physiologic data were not revealed to the pathologist interpreting the specimens. The asthmatic subjects shed a significantly greater number of epithelial cells into the lavage fluid than did the nonasthmatic subjects (7.23 versus 1.48 x 10(4)/ml, p = 0.048). There was a statistically significant inverse correlation between the lavage epithelial cell count and bronchial reactivity (rho = -0.64, p = 0.03). In the asthmatic subjects, but not in the control subjects, there was extensive deposition of collagen beneath the epithelial basement membrane, mast cell degranulation, and mucosal infiltration by eosinophils, which exhibited morphologic evidence of activation. Eosinophils, monocytes, and platelets were found in contact with the vascular endothelium, with emigration of eosinophils and monocytes in the asthmatic subjects. These changes were found irrespective of bronchial challenge with allergen. We conclude that allergic asthma is accompanied by extensive inflammatory changes in the airways, even in mild clinical and subclinical disease.

This review raises the issue of better consumer protection by recommending that older first-generation H(1)-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H(1)-antihistamines with superior risk/benefit ratios are widely available at competitive prices.

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle.Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving.Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

1 The airway response to the inhaled nucleosides, adenosine (6.7 x 10-4-6.7 mg/ml) and guanosine (7.3 x 10-4-1.4 mg/ml) was studied in normal and asthmatic subjects. Airway response, measured in the body plethysmograph, was expressed as percentage change in specific airway conductance (sGaw) from baseline.2 Inhaled adenosine caused no change in sGaw in normal subjects but produced a dose-dependent reduction in sGaw in both allergic and non-allergic asthmatic subjects (76 and 62% reduction respectively at 6.7 mg/ml).3 Kinetics of adenosine induced bronchoconstriction were studied in 12 asthmatic subjects who inhaled a single concentration of adenosine. Bronchoconstriction was maximal within 5 min (42% reduction in sGaw) with partial recovery by 30 min. 4 The related nucleoside guanosine caused no change in sGaw in normal or asthmatic subjects. 5 Adenosine, but not guanosine, is a potent bronchoconstrictor in asthma suggesting that it may have a specific pharmacological effect.

Epithelial damage is a characteristic feature of asthma. The epithelium is not merely a passive barrier but can generate a range of mediators that may play a role in the inflammatory and remodelling responses that occur in the lungs in asthma. For example, the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF), whose principal source is the epithelium, can prolong eosinophil survival while transforming growth factor is a potent profibrogenic cytokine. Deposition of collagen in the epithelial subbasement membrane is a characteristic feature of the remodelling response in asthma. This may be due to abnormal associations between myofibroblasts and epithelium, both of which are involved in early lung development (epithelial-mesenchymal trophic unit). In asthma, there may be a primary defect in the epithelium such that it responds abnormally to various stimuli and cannot undergo the normal repair response. Epidermal growth factor (EGF) appears to be a key factor in bronchial epithelial repair; it stimulates epithelial cell proliferation and migration. The 3v isoform of the adhesion molecule CD44 is overexpressed in damaged epithelium and seems to regulate the repair response by presenting EGF more efficiently to its receptor. Although EGF receptor expression is increased in asthma, it does not lead to an appropriate proliferative response and restitution of normal epithelium. Other factors such as transforming growth factor (TGF)beta which are generated by inflammatory cells and epithelium are also upregulated in asthma. An epithelial/fibroblast co-culture system has shown that following epithelial damage various growth factors are released from the underlying myofibroblasts and are responsible for the proliferative response. The TGFbeta family are most likely responsible for collagen production. In an in vitro study, an EGF receptor inhibitor slowed epithelial repair but enhanced TGFbeta production by the slowly repairing epithelial cells. In conclusion, the interaction between epithelial cells and myofibroblasts, i.e. reactivation of the epithelial-mesenchymal trophic unit appears to be central to the airway wall remodelling response.