Asmanet ENFUMOSA : Nelly Frossart Mast cell, fibroblast, and 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)

Mast cell, fibroblast, and asthma
Nelly FROSSARD, INSERM U425, STRASBOURG, France

Vendredi 13 Février 1998		Présentateurs		Modérateurs	Experts
16h30-18h00	Cytokines Molécules d'adhésion	Ph. Gosset, Ph. Lassalle (Lille) M. Humbert (Paris) N. Frossard (Illkirsh) Discussion	15' 15' 15' 45'	K.F. Chung (Londres)	M. Saetta (Padoue, I) J.C. Kips (Gand, B)

MAST CELL AND FIBROBLAST

The presence of an increased number of mast cells, often de granulated, is described in the bronchial mucosa from asthma patients compared with control subjects. The deleterious role of the mast cell in the early phase of asthma is well documented. However, a beneficial role for the mast cell has been raised from their location at various sites where repairing processes occur. This raised the possibility of a first beneficial effect of the mast cell in the airways, in the repairing processes following allergenic agression. They may be attracted there by some factor(s) inducing their differentiation. This step is followed (or associated) in the asthmatic airways with a deleterious effect, due to the presence of allergen specific IgEs at the mast cell surface, allowing their activation by the allergen and release of various bronchoactive, and pro-inflammatory mediators.

The presence of a subepithelial fibrosis, as a consequence of fibroblast proliferation and thickening of the basement membrane, is described in the asthmatic airways. Fibrosis occurs early in the disease, reported in mild atopic asthma, in symptomatic asthma, and in occupational asthma to isocyanates.

The interrelation between the mast cell and the fibroblast involves more specifically the expression by the fibroblast of mast cell growth factors like SCF (stem cell factor) and NGF(nerve growth factor). It involves in return the expression by the mast cell of profibrosing agents like transforming growth factor 8. These may play some role in asthma in the increased number of tissue mast cells on one hand, and on the presence of subepithelial fibrosis on the other hand.

THE MAST CELL GROWTH FACTORSAn increased expression of mast cell growth factors should occur in tissues where an increased number of mast cells is observed, like in the asthmatic airways. Three factors are described with a mast cell growth factor property, inducing differentiation of the CD34+ hematopoietic progenitor into the tissue mast cell: SCF, NGF and IL-3. In addition, these factors (SCF, NGF) also inhibit mast cell apoptosis, thus concourring to the increased mast cell number in the tissues through an increased survival.

SCF is the ligand of the c-Kit receptor, expressed as two forms, membrane-bound and soluble, from two mRNAs obtained after alternative splicing of the 6th exon encoding a proteolytic cleavage site. NGF, apart from its nerve growth induction, is also a growth factor for the mast cell, produced by the fibroblast, as well as by the mast cell itself.

THE TRANSFORMING GROWTH FACTOR: TGF-BMast cells possess the property of activating proliferation and migration of fibroblasts, and their collagen production, both in vitro and in vivo. This may be related with the expression by the mast cell, as well as by the fibroblast itself, of a pro- fibrosing cytokine, TGF-B. TGF-B regulates growth and differentiation of the fibroblast, and induces and increase in cell matrix formation, collagen and fibronectin. In addition, it decreases the matrix degradation through decrease of the proteolysis in the extracellular compartment. Thus, an altered expression of TGF-B by the submucosal fibroblasts in the asthmatic airways may contribute to the subepithelial fibrosis observed in asthma.

In aWition, TGF-B exerts a potent chemotactic effect on the mast cell and the fibroblast. This reinforces the hypothesis of existing important interactions between the mast cell and fibroblasts in asthma. TGF-B might thus be involved both in the subepithelial fibrosis and in the influx of mast cells in the bronchial mucosa of asthmatic patients.

EXPRESSION OF GROWTH FACTORS IN ASTHMAThe interaction between mast cells and fibroblasts in the asthmatic airways has been considered as dependent upon the growth factors TGF-,B1, and SCF. We have measured their local expression, and analyzed the regulation of their expression in cell cultures, leading to new hypotheses in asthma.