Session Type: Abstract Submissions (ACR)
Background/Purpose: Am80 is a synthetic retinoid serving as an agonist for retinoic acid receptor α/β with chemical and pharmacological advantages over all-trans retinoic acid, such as higher chemical stability, a lower affinity for cellular retinoic acid-binding protein, and a lack of affinity for retinoic acid receptor-γ. Am80 has been shown to modulate the pathological processes of various autoimmune and inflammatory diseases and their animal models. The aim of this study was to investigate the effect of Am80 on dermal fibrosis of a bleomycin (BLM)-induced animal model of systemic sclerosis (SSc), normal dermal fibroblasts treated with TGF-β1 and SSc dermal fibroblasts.
Methods: A BLM-induced murine model of SSc was generated with wild type C57BL/6 mice in the presence or absence of oral administration of Am80. The mRNA and protein levels of target molecules were determined by quantitative reverse transcription-PCR, immunostaining, and immunoblotting in the skin and cultured cells. Th1/Th2/Th17 polarization of immune response and macrophages polarization were evaluated by flow cytometry.
Results: Am80 significantly decreased tissue fibrosis and mRNA levels of the Tgfb and Ctgf genes in the lesional skin of BLM-treated mice. In response to Am80, the expression levels of cytokines and chemokines, including IL-4, IL-10, IL-13, IL-17A, TNF-α, IFN-γ, and MCP-1, in the lesional skin were decreased and the differentiation of naïve CD4+ T cells into cytokine producing effector T cells, such as Th1/Th2/Th17 cells, and regulatory T cells were suppressed in BLM-treated mice. In addition, the infiltration of macrophages, mast cells, and T cells was attenuated by Am80 in BLM-treated mice. Am80 also exerted on dermal microvascular endothelial cells through attenuating the induction of endothelial-to-mesenchymal transition and the expression of intercellular adhesion molecule-1, and shifted macrophages from M2 phenotype to M1 phenotype. Furthermore, Am80 directly reversed the pro-fibrotic phenotype of normal dermal fibroblasts treated with TGF-β1 and SSc dermal fibroblasts via suppressing the transcription and reducing the mRNA stability of COL1A2 gene, increasing mRNA levels of MMP-1 gene, and decreasing mRNA levels of CTGF gene.
Conclusion: These results suggest that Am80 inhibits the development of experimental dermal fibrosis via reversing the pro-fibrotic phenotype of fibroblasts, dermal microvascular endothelial cells, and immune cells and would be a candidate of new therapeutic drugs against dermal fibrosis of SSc.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/am80-ameliorates-bleomycin-induced-dermal-fibrosis-by-suppressing-the-pro-fibrotic-phenotype-of-fibroblasts-endothelial-cells-and-immune-cells/