Blocage de l'endothéline dans la sclérodermie systémique : rationnel et bénéfice clinique

Abstract

Purpose. ‐ There has been an explosion of interest in the biology of endothelin in the context of connective tissue diseases, especially systemic sclerosis and in particular pulmonary arterial hypertension (PAH). This interest is based upon the proven efficacy of a broad spectrum of endothelin receptor blocking drugs as therapy for advanced pulmonary arterial hypertension. Key points. ‐ Endothelin 1 had a broad range of activities that include vasoconstriction, effects on cell differentiation, proliferation and apoptosis. Endothelin 1 is a particularly interesting molecule linking endothelial cell and mesenchymal fibroblast dysfunction in systemic sclerosis. Supportive evidence for the endothelin 1 role in disease's physiopathology arises from the observations of elevated serum levels of endothelin 1 and increase in endothelin 1 receptor expression in lesional tissue in systemic sclerosis and PAH. Moreover, the induction of profibrotic phenotype in fibroblast by endothelin 1 points to a central pathophysiological role in systemic sclerosis. Perspectives and projects. ‐ For both idiopathic PAH and systemic sclerosis-associated PAH, there is a growing body of evidence that treatment with endothelin receptor antagonists improves survival. This is unlikely to reflect only the vasodilatory effects of endothelin 1. More complex haemodynamic effects on right sided heart biomechanics or vascular remodelling or a modulation of the underlying pathogenic process leading to PAH are more plausible. Future studies will eventually define whether there are broader potentially beneficial effects of endothelin blockade in connective tissue diseases and if endothelin 1 is a key player or merely one of the team of factors underlying some of the most life-destroying connective tissue diseases.