title: Macitentan slows down the dermal fibrotic process in systemic sclerosis: in vitro findings.
abstract: Systemic sclerosis (or scleroderma) is an autoimmune disease characterized by skin and internal organ fibrosis, caused by microvascular dysfunction. The microvascular damage seems to be a consequence of an endothelial autoimmune response, followed by activation of the inflammatory cascade and massive deposition of collagen. Endothelin-1 (ET-1) contributes to the inflammatory and fibrotic processes by increasing the concentration of pro-inflammatory and pro-fibrotic cytokines, and it is considered one of the most relevant mediators of vascular damage in scleroderma. It is indeed found in very high concentration in serum of sclerodermic patients. Moreover, in these pathological conditions there is an increased expression of ET-1 receptors (ETA and ETB), which mediate the detrimental action of ET-1, and often a change of ETA/ETB ratio. The aim of the present study is to evaluate the in vitro effect of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist, and its major metabolite (ACT-132577) on alpha smooth muscle actin (alphaSMA) expression, evaluated on dermal fibroblasts from healthy subjects and on dermal fibroblasts from lesional and non-lesional skin from sclerodermic patients. The combination of macitentan and its major metabolite reduced the levels of &#945;SMA after 48 h in sclerodermic fibroblasts from lesional skin. No relevant changes in &#945;SMA levels were found in fibroblasts from non-lesional skin, whose behavior is similar to that of dermal fibroblasts from healthy patients.
authors.affiliation: Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Corallo
authors.forename: G
authors.initials: G
authors.lastname: Pecetti
authors.forename: M
authors.initials: M
authors.lastname: Iglarz
authors.forename: N
authors.initials: N
authors.lastname: Volpi
authors.forename: D
authors.initials: D
authors.lastname: Franci
authors.forename: A
authors.initials: A
authors.lastname: Montella
authors.forename: F
authors.initials: F
authors.lastname: D' Onofrio
authors.forename: R
authors.initials: R
authors.lastname: Nuti
authors.forename: N
authors.initials: N
authors.lastname: Giordano
mesh_terms: D000199:Actins / Q000032:analysis; D000368:Aged; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005260:Female; D005355:Fibrosis; D006801:Humans; D008875:Middle Aged; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000473:pathology; D012867:Skin / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan