OBJECTIVES: Tissue fibrosis is a major hallmark and a leading cause of death in systemic sclerosis (SSc). Here, we investigated the antifibrotic effects of pomalidomide, an analogue of thalidomide with potent immunomodulatory effects, in preclinical models of skin fibrosis. METHODS: We evaluated the antifibrotic effects of pomalidomide in preventive as well as therapeutic treatment regimes using bleomycin-induced dermal fibrosis as a model of early, inflammatory stages of fibrosis and the tight-skin mouse model as a model of later stages of fibrosis with endogenous activation of fibroblasts. RESULTS: Treatment with pomalidomide in doses from 0.3 to 30 mg/kd/day prevented skin fibrosis in Tsk-1 mice and in bleomycin-induced dermal fibrosis in a dose-dependent manner and reduced the expression of transforming growth factor (TGF) β-target genes such as PAI-1, CTGF and col 1a1. Pomalidomide was also effective in the setting of pre-established fibrosis and reduced dermal thickness, myofibroblast counts and hydroxyproline content below pretreatment levels. CONCLUSIONS: We demonstrate for the first time that pomalidomide exerts potent antifibrotic effects in different preclinical models of skin fibrosis. These findings lend preclinical support for the clinical studies of pomalidomide in SSc.
OBJECTIVES: Tissue fibrosis is a major hallmark and a leading cause of death in systemic sclerosis (SSc). Here, we investigated the antifibrotic effects of pomalidomide, an analogue of thalidomide with potent immunomodulatory effects, in preclinical models of skin fibrosis. METHODS: We evaluated the antifibrotic effects of pomalidomide in preventive as well as therapeutic treatment regimes using bleomycin-induced dermal fibrosis as a model of early, inflammatory stages of fibrosis and the tight-skin mouse model as a model of later stages of fibrosis with endogenous activation of fibroblasts. RESULTS: Treatment with pomalidomide in doses from 0.3 to 30 mg/kd/day prevented skin fibrosis in Tsk-1mice and in bleomycin-induced dermal fibrosis in a dose-dependent manner and reduced the expression of transforming growth factor (TGF) β-target genes such as PAI-1, CTGF and col 1a1. Pomalidomide was also effective in the setting of pre-established fibrosis and reduced dermal thickness, myofibroblast counts and hydroxyproline content below pretreatment levels. CONCLUSIONS: We demonstrate for the first time that pomalidomide exerts potent antifibrotic effects in different preclinical models of skin fibrosis. These findings lend preclinical support for the clinical studies of pomalidomide in SSc.
Authors: I Pusic; M P Rettig; J F DiPersio; S Bauer; K McFarland; R P Gale; S Z Pavletic Journal: Bone Marrow Transplant Date: 2015-12-14 Impact factor: 5.483
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Authors: Swati Bhattacharyya; Wenxia Wang; Wenyi Qin; Kui Cheng; Sara Coulup; Sherry Chavez; Shuangshang Jiang; Kirtee Raparia; Lucia Maria V De Almeida; Christian Stehlik; Zenshiro Tamaki; Hang Yin; John Varga Journal: JCI Insight Date: 2018-07-12
Authors: Lauren M Curtis; Alen Ostojic; David J Venzon; Noa G Holtzman; Filip Pirsl; Zoya J Kuzmina; Kristin Baird; Jeremy J Rose; Edward W Cowen; Jacqueline W Mays; Sandra A Mitchell; Laura Parsons-Wandell; Galen O Joe; Leora E Comis; Ann Berger; Iskra Pusic; Cody J Peer; William D Figg; Liang Cao; Robert Peter Gale; Frances T Hakim; Steven Z Pavletic Journal: Blood Date: 2021-02-18 Impact factor: 22.113