Asmanet ENFUMOSA : Alison Campbell Bronchial epithelial cells in asthma

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màj 23/07/98

ENFUMOSA
(courriel: Chanez (at) montp.inserm.fr )
The European Network For Understanding
Mechanisms of Severe Asthma
BIOMED 2 Program - European Commission

4th quaterly meeting, with the support of INSERM and
Merck Sharp & Dhome Laboratory
February 13-14th 1998 in Montpellier- France
(see programm, abstracts and experts comments )

Bronchial epithelial cells in asthma
Alison M. Campbell

Vendredi 13 Février 1998		Présentateurs		Modérateurs	Experts
15h00-16h00	Epithelium	A. Campbell (Montpellier) D. Dusser (Paris) Discussion	15' 15' 30'	M. Murris (Toulouse) N. Roche (Paris)	A.M. Vignola (Palerme) W. Coers (Groningen, NL)

The important role played by bronchial epithelial cells in the protection of the airways is clear. Not only do these cells form the primary defence in preventing the entry of noxious substances into the airways and removing particulate matter by means of the mucociliary stairway, but they are also capable of playing an active role in the immune response. Epithelium shedding is a histological feature observed in bronchial biopsies obtained from asthmatic subjects. It is characterized by a loss of the normal bronchial pseudostratified epithelium and the maintenance of few basal cells on a thickened basement membrane. Moreover, a significant correlation has been observed between epithelium shedding and bronchial hyperactivity . The bronchial epithelial cells of asthmatic patients are less viable and more "fragile" than those of their non-asthmatic counterparts . In addition, the bronchial epithelial cells of asthmatic subjects appear to be in a more activated state both in terms of cell surface markers and in the liberation of inflammatory mediators.

Various investigative strategies are available to researchers who wish to study the bronchial epithelium in man. Cells can be obtained at autopsy, during surgery or during fibreoptic bronchoscopy by bronchial brushing or biopsy. All these methods have different strengths and weaknesses. At autopsy large numbers of cells can be obtained but post-mortem changes may have occurred compromising their representiveness and the clinical history of the patient is often incomplete. Tissue obtained during surgery although macroscopically normal may differ in the state of activation of cells and finally, the number of cells or the size of the biopsy obtained during fibreoptic bronchoscopy is often small. In view of these limitations, many studies have been performed on either cell lines or on epithelial cells cultured from explants. It should be borne in mind, however, that different techniques used for studying the epithelium as well as different techniques for fixation of bronchial biopsies may give rise to different results.

It has been demonstrated that bronchial epithelial cells can synthesize and release a wide range of mediators both spontaneously and following stimulation. These mediators include arachidonic acid metabolites such as 15-HETE, prostaglandin E2 and sulphidopeptide leukotrienes. The generation and release of these eicosanoids is upregulated in asthma and it has been shown that there is a clear correlation between the release of 15-HETE and the clinical status of the patient.

Bronchial epithelial cells are also capable of synthesizing and releasing a wide range of cytokines. These include GM-CSF , TNFalpha, IL-6, IL-8 and RANTES. There appears to be good cell-cell co-operation between bronchial epithelial cells and other cell types present in the lung since macrophage-derived cytokines such as TNFalpha and IL-1alpha induce cytokine expression in bronchial epithelial cells and cytokines released by the epithelium help to ensure the continued survival of other cell types.

Epithelial cells lining the airways are at high risk for damage by pollutants. Epidemiologic studies have demonstrated that following periods of increased exposure to environmental pollutants such as NO₂ or SO₂ hospital admissions for respiratory problems including asthma increase . It is possible that at least some of the increase in severity of the disease is due to the effects of pollutants on the respiratory epithelium. In order to investigate the effect of nitrogen dioxide on the airways, Devalia and colleagues performed a study in which they investigated the effect of exposure of bronchial epithelial cells in vitro to this agent . They demonstrated that nitrogen dioxide significantly increases the release of IL-8, GM-CSF and TNFa by bronchial epithelial cells and that these responses occur at levels of nitrogen dioxide which are commonly found at the curbside in heavy traffic conditions. These findings were confirmed by Kienast and colleagues who showed that exposure of a human bronchial epithelial cell line to 1.5 ppm NO₂ for 1h increased both the mRNA for and protein levels of IL-6 and IL-8 . A further study by Devalia and colleagues demonstrated that exposure of epithelial cells to the nitrogen dioxide also leads to a decrease in ciliary beat frequency and affects bronchial epithelial cell membrane integrity . Taken together these studies suggest that exposure of the bronchial epithelium to everyday concentrations of pollutants may lead to functional and morphologic changes in the airways, particularly in susceptible individuals.

The airway epithelium is also the first cell type to come into contact with inhaled allergens. In our laboratory we investigated the expression of CD23, the low affinity receptor for IgE, on bronchial epithelial cells. CD23 expression was studied using two different immunocytochemical methods. The alkaline phosphatase anti-alkaline phosphatase (APAAP) technique was used to determine the percentage of cells expressing CD23 and the second technique used immunofluorescence detected by a Zeiss laser confocal scanning laser microscope system . In addition, we have investigated the expression of the high afinity receptor for IgE (FceR1) on bronchial epithelial cells. We have shown that a sub-population of allergic asthmatic subjects express CD23 and also that a sub-population of allergic asthmatics express the high affinity receptor for IgE.

Bronchial epithelial cells from 3/4 asthmatics who expressed CD23 were capable of responding to IgE-mediated activation with the release of endothelin and cells which expressed the high affinity receptor for IgE could be activated with the antibody to FceR1 to release 15-HETE. These data suggest that bronchial epithelial cells may be able to play a direct role in the allerigc response.