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The expression of the glucocorticoid receptor (GR) in untreated or in steroid-dependent asthmatic patients is poorly understood. We therefore studied GR mRNA and protein levels in bronchial biopsies obtained from seven untreated asthmatic patients, seven control volunteers, and seven patients with chronic bronchitis. We also studied in bronchial epithelial cells obtained by brushing from 13 untreated asthmatics, 18 steroid-dependent asthmatics, 11 control volunteers, and 12 patients with chronic bronchitis, GR and heat shock protein 90 kD (hsp90) mRNA as well as the immunoreactivity of GR, intercellular adhesion molecule (ICAM-1), and granulocyte macrophage-colony-stimulating factor (GM-CSF). GR mRNA and protein level was similar in all subject groups in both biopsies and bronchial epithelial cells. Hsp90 mRNA level was also similar in all subject groups. ICAM-1 expression was significantly increased in bronchial epithelial cells from untreated asthmatics, but ICAM-1 was not expressed in those from steroid-dependent asthmatic patients. GM-CSF expression was significantly increased in bronchial epithelial cells from untreated and steroid-dependent asthmatic patients. GR expression within the airways is unaltered by oral long-term steroid treatment in asthma, but the expression of some but not all specific markers for asthma is modified by oral steroid.

Bronchial epithelial cells are the first cells to come into contact with inhaled pneumoallergens. It has been suggested that these cells may play an important role in the allergic response, and indeed bronchial epithelial cells of some atopic asthmatic subjects have been shown to express the low-affinity receptor for IgE on their surface. In this report we demonstrate, using bronchial biopsies, that bronchial epithelial cells of some asthmatic subjects express both the alpha and gamma chains of the high-affinity receptor for IgE (Fcepsilon RI) on their surface and that they are capable of fixing IgE. Second, using reverse transcription-polymerase chain reaction, we show that both control and asthmatic subjects have messenger RNA for Fcepsilon RI. Finally, we demonstrate that this receptor may be functional since stimulation of the cells with the antibody to the alpha chain of Fcepsilon RI results in the liberation of 15-hydroxyeicosatetraenoic acid from epithelial cells of asthmatic, but not control, subjects or subjects suffering from chronic bronchitis. These data suggest that bronchial epithelial cells from at least some asthmatic subjects express a functional high-affinity receptor for IgE and it is therefore possible that these cells may be able to interact directly with inhaled allergens.

BRONCHIAL INFLAMMATION: Corticosteroids are currently the most important treatment for bronchial inflammation in asthma. SULFIDOPEPTIDE LEUKOTRIENES: These biologically active fatty acids play an important role in the inflammation process in asthma. A NEW THERAPEUTIC APPROACH: Some leukotriene receptor antagonists and synthesis inhibitors are effective and safe treatment for mild to moderate asthma. GLOBAL STRATEGY: The role of these new drugs in the management of asthma remains to be defined on the basis of comparative clinical trials with the standard reliever treatment: inhaled corticosteroids.

Not only unsaturated linear fatty acids, but also saturated monomethyl-branched fatty acids (MMBFAs), are provided by food. They are capable of penetrating into the membrane lipids and promoting lipid disorder. Both NADPH oxidase and protein kinase C (PKC) are bound to cell cytoplasmic membranes and are responsive to unesterified fatty acids (UEFAs). We found that the O2.- NADPH oxidase-mediated production of human adherent monocytes was modified by unsaturated linear and saturated branched UEFAs only in the presence of phorbol myristate acetate. This result together with our inhibition data indicated an action strictly linked to PKC activity. The type and intensity of action depended on the UEFA concentrations and chain structure. Nanomolar concentrations showed potentiating effects whereas micromolar (< CMC) concentrations displayed depressant influences MMBFAs were generally more active than the other FAs. With respect to the micromolar depressant effect, oleate and linoleate were as active and docosahexaenoate nearly as active as MMBFAs. As assessed by iso-15:0 or arachidonate action, such bimodal alteration did not occur in non-adherent monocytes and neutrophils. Certain UEFAs could be considered as 'cellular' anti-oxidants on the sites of adherent-monocyte recruitment.

Inflammatory processes in asthma are characterized by an infiltration of inflammatory cells including mononuclear phagocytes. It has been observed that mononuclear phagocytes, alveolar macrophages and blood monocytes, release higher quantities of reactive oxygen species in asthmatic patients than in healthy subjects. Chemiluminescence assays were developed to measure the superoxide anion and the other reactive oxygen species. The chemiluminescence response was first analysed with a luminometer, which made it possible to study cells in suspension before and after PMA-stimulation. Secondly a video-imaging camera was used in experiments on adherent cells before and after stimulation with PMA and/or specific stimulus IgE/anti-IgE. Both techniques showed that human alveolar macrophages, blood monocytes, PMN and lymphocytes were spontaneously primed in vivo and were more easily stimulated in asthma. Analysis of adherent cells in vitro may provide give information on the physiological condition of adherent cells in vivo.

Besides eosinophils, inflammatory processes in asthma are characterized by an infiltration of inflammatory cells, including mononuclear phagocytes, such as alveolar macrophages (AM) and blood monocytes, in the airways. Monocyte activation has been observed in the blood after exercise or allergen-induced asthma. Stimulated AM in chronic and stable asthmatic patients have been shown to release oxygen species. We thus investigated the intensity of the activation of monocytes from 18 asthmatic patients compared with 18 healthy subjects. Oxygen species release was analyzed for monocytes in suspension by chemiluminescence using a luminometer and for monocytes maintained in adherence using conventional assay and video imaging camera. Circulating blood monocytes in suspension from asthmatic patients and control subjects showed the same baseline free radical release. Monocytes in suspension from asthmatic patients were more stimulatable by PMA: specifically, monocytes release more H2O and peaks of O2-. are sooner; moreover, peaks of total free radical release are higher, and this plateau is sustained. Compared with monocytes from control subjects, those from asthmatic patients evaluated after adherence show a higher baseline for O2-. and higher total free radical release. Monocytes from asthmatic patients spontaneously release more O2-. over time in nonstimulated cells and release more O2-. with PMA stimulation; they show the same peak level total free radical release as those from control subjects after stimulation. SOD activity analysis on adherent monocytes was lower in asthmatic compared with control subjects. These data show that monocytes from asthmatic patients were activated compared with control monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

The study of cellular events in the bronchi of asthmatic patients shows significant epithelial destruction. The ciliated cells are more often destroyed than others in the respiratory epithelium. Using highly specific monoclonal antibodies, we detected that the epithelial cells were positive for HLA-DR antigen expression, whereas those from healthy subjects were negative. The aberrant expression could be explained by the presence of T lymphocytes in the asthmatic bronchial mucosa. The activated lymphocytes (CD4+) are known to release gamma interferon, which is a lymphokine that induces or enhances the expression of HLA-DR antigens. These cells, which are known to mediate cytotoxicity in an Ag-specific and Ia-restricted way, could take part in the shedding process of epithelial cells in asthma.