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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 ) Increased release of matrix metalloproteinase-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. G Mautino. Unité INSERM 454 Montpellier Samedi 14 Février 1998 Présentateurs Modérateurs Experts 11h00-12h00 Réparation bronchique Bronchial remodelling C. Lafuma (Paris) G. Mautino (Montpellier) Discussion 15' 15' 30' J. Bousquet (Montpellier) D. Olivieri (Parme, I) J. Shute (Southampton, UK) L. Fabbri (Ferrara, I) Matrix metalloproteinases (MMPs) are major proteolytic enzymes which are involved in extracellular matrix (ECM) turnover, due to their ability to cleave all the proteins constituting ECM. During inflammation, tissue remodelling and repair, MMP gene expression is regulated by many factors including cytokines, growth factors, pro-inflammatory mediators and hormones. Dysregulation of MMP production has been implicated in chronic inflammatory diseases and several lung diseases. The possible implication of MMPs in asthma is suggested by morphologic studies that have observed some features of matrix remodelling, lung tissue damage, alveolar structure alterations or abnormal repair.

Macrophages are the most abundant defense cells present in both normal lung tissue and chronic inflammatory lung diseases with the capacity to degrade and remodel the ECM and the basement membrane through synthesis and secretion of proteinases including MMPs. The expression and regulation of MMPs in human macrophages has been studied using monocytes/macrophages, purified from peripheral blood mononuclear cells or alveolar macrophages (AM). AM expressed MMP-9, a 92 kD gelatinase with collagenolytic and elastolytic activities. Activation of AM by inflammatory agents, such as LPS, phorbol esters (PMA), stimulates MMP-9 production and an induction of other MMPs via protein kinase C (PKC) or PGE2-dependent protein kinase A (PKA) signalling pathways. In asthma, there is an increase of activated macrophages found in bronchial biopsies. Moreover, in this disease, AM recovered by bronchoalveolar lavage (BAL) were found to be hyperactive and less sensitive to in vitro modulation by cytokines such as IL-4.

The purpose of this study was, therefore, to explore whether MMPs were differently expressed and regulated in asthmatic patients and in control populations. Asthmatic patients, untreated or treated with inhaled corticosteroids, were compared to healthy non-smoking controls and to patients with chronic bronchitis (CB) enrolled as controls of another pulmonary inflammatory disease.

We studied first, the release of MMPs in BAL fluid and in the supernatants of AM after short term culture and second, their regulation by IL-4, IFNg, dexamethasone and the phorbol ester PMA, factors known to modulate MMP production in AM from control subjects. BAL was collected from 38 asthmatics (24 untreated and 14 treated with inhaled corticosteroids), 26 healthy non-smokers and 18 patients with CB. The profile of MMPs present in BAL fluid and AM supernatant, determined by zymographic analysis, was found similar in all populations. The main enzyme released was identified immunologically as MMP-9, a potent collagenolytic and elastolytic enzyme. Its release, measured using enzyme immuno-assay, was significantly enhanced in fluids and in AM supernatants from untreated asthmatics compared to those from the other populations. Enhanced MMP-9 levels, in asthma, could not be explained by a different sensitivity of AM to Interleukin-4, Interferon-g or dexamethasone, compounds that have been shown to inhibit MMP-9. The phorbol ester PMA, a PKC activator, significantly increased MMP-9 in AM from healthy controls but not in those from untreated asthmatics. Calphostin C and H7, PKC inhibitors, significantly reduced PMA-stimulated MMP-9 release in AM from healthy controls and spontaneous MMP-9 release in AM from untreated asthmatics. H8, a PKA inhibitor, was inactive in both populations. These data suggest that the stimulation of MMP-9 release in AM from untreated asthmatic patients occurs, at least partly, via signals activating PKC.

. Asmanet ENFUMOSA Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 5 Décembre 1997-Dernière mise à jour: 23/07/98
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