s-1743 and Fibrosis

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-β/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

Topics: Actins; Animals; Bleomycin; Cells, Cultured; Collagen Type I, alpha 1 Chain; Connective Tissue Growth Factor; Cytokines; Esomeprazole; Fibroblasts; Fibrosis; Humans; Lung; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, Aryl Hydrocarbon; Scleroderma, Systemic; Signal Transduction; Skin

Radiation therapy is a mainstream strategy in the treatment of several cancer types that are surgically unresectable. Unfortunately, cancer patients often suffer from unintended consequences of radiotherapy, including the development of skin inflammation (dermatitis), which may progress to fibrosis. These morbid complications often require interruption of radiotherapy and threaten the relapse of underlying cancer. Current treatment options for radiation dermatitis are suboptimal and compel the need to develop safer, more effective therapies. In this study, we assessed the biophysical properties of topically-formulated esomeprazole (here referred to as dermaprazole) and performed proof-of-concept studies to evaluate its efficacy

Topics: Active Transport, Cell Nucleus; Administration, Topical; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Esomeprazole; Fibrosis; Gene Expression Profiling; Heme Oxygenase-1; Humans; Inflammation; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Models, Anatomic; NF-E2-Related Factor 2; Radiodermatitis; Radiotherapy; Skin; Wound Healing