A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with SilicosisReport as inadecuate

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Myofibroblast differentiation, characterized by α-smooth muscle actin α-SMA expression, is a key process in organ fibrosis, and is induced by TGF-β. Here we examined whether an anti-fibrotic agent, N-acetyl-seryl-aspartyl-lysylproline Ac-SDKP, can regulate induction of TGF-β signaling and myofibroblast differentiation as a potential key component of its anti-fibrotic mechanism in vivo and in vitro.

Methodology-Principal Findings

Rat pulmonary fibroblasts were cultured in vitro and divided to 4 groups 1 control; 2 TGF-β1; 3 TGF-β1+ LY364947; 4 TGF-β1+Ac-SDKP. For in vivo studies, six groups of animals were utilized 1 control 4w; 2 silicotic 4w; 3 control 8w; 4 silicotic 8w; 5 Ac-SDKP post-treatment; 6Ac-SDKP pre-treatment. SiO2 powders were douched in the trachea of rat to make the silicotic model. Myofibroblast differentiation was measured by examining expression of α-SMA, as well as expression of serum response factor SRF, a key regulator of myofibroblast differentiation. The expressions of collagen, TGF-β1 and RAS signaling were also assessed. The results revealed that TGF-β1 strongly induced myofibroblast differentiation and collagen synthesis in vitro, and that pre-treatment with Ac-SDKP markedly attenuated myofibroblast activation, as well as induction of TGF-β1 and its receptor. Similar results were observed in vivo in the pathologically relevant rat model of silicosis. Ac-SDKP treatment in vivo strongly attenuated 1 silicosis-induced increased expressions of TGF-β1 and RAS signaling, 2 myofibroblast differentiation as indicated by a robust decrease of SRF and α-SMA-positive myofibroblast localization in siliconic nodules in the lung, 3 collagen deposition.


The results of the present study suggest a novel mechanism of action for Ac-SDKP’s beneficial effect in silicosis, which involves attenuation of TGF-β1 and its receptors, SRF and Ang II type 1 receptor AT1 expression, collagen deposition and myofibroblast differentiation. The results further suggest that therapies targeting myofibroblast differentiation may have therapeutic efficacy in treatment of silicosis of the lung.

Author: Hong Xu, Fang Yang , Ying Sun, Yuan Yuan, Hua Cheng, Zhongqiu Wei, Shuyu Li, Tan Cheng, Darrell Brann, Ruimin Wang

Source: http://plos.srce.hr/


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