OP0297 Knockout of Endothelin Type B Receptor Signaling Attenuates Bleomycin-Induced Skin Sclerosis in Mice

Background Endothelin-1 (ET-1) is important in the pathogenesis of systemic sclerosis (SSc). It has been reported that plasma concentration of ET-1 are higher in SSc patients, and that endothelin receptor expression are also increased in lungs and skins in the patients. ET-1 binds two receptors, endothelin type A (ET A ) and endothelin type B (ET B ). Dual ET A /ET B receptor antagonists and a selective ET A receptor antagonist are used clinically to treat SSc, and the effect of these antagonists on fibroblast activation has been described. However, the role of ET B receptor signaling in fibrogenesis is less clear. Objectives This study was conducted to evaluate the profibrotic function of ET B receptor signaling in a murine model of bleomycin (BLM)-induced scleroderma. Methods We used ET B receptor–knockout (ET B KO) mice, which are genetically rescued from lethal intestinal aganglionosis by an ET B receptor transgene driven by the human dopamine β-hydroxylase (DβH)-gene promoter, and wild-type mice with DβH-ETB (WT). BLM or phosphate-buffered saline (PBS) was administered subcutaneously by osmotic minipump, and skin fibrosis was assessed by dermal thickness, subcutaneous fat atrophy, and alpha-smooth muscle actin (αSMA)-expressing myofibroblast count in the dermis. Dermal fibroblasts isolated from ET B KO and WT mice were cultured in vitro , stimulated with BLM or ET-1, and the expression of profibrotic genes was compared by quantitative PCR. Results Dermal thickness, subcutaneous fat atrophy, and myofibroblast counts in the dermis were significantly reduced in ET B KO mice compared to WT mice, after BLM treatment. Compared with wild-type, dermal fibroblasts isolated from ET B KO mice showed lower gene expressions of αSMA and collagen 1α1 in response to BLM or ET-1 stimulation in vitro. Conclusions ET-1–ET B receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts. Disclosure of Interest None declared