A new antifibrotic target of Ac-SDKP: inhibition of myofibroblast differentiation in rat lung with silicosis.
BACKGROUND
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.


RESULTS
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; 6)Ac-SDKP pre-treatment. SiO(2) 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.


CONCLUSIONS
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 (AT(1)) 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.
Department of Pathology, Hebei Medical University, Shi Jiazhuang, China.
Hong
H
Xu
Fang
F
Yang
Ying
Y
Sun
Yuan
Y
Yuan
Hua
H
Cheng
Zhongqiu
Z
Wei
Shuyu
S
Li
Tan
T
Cheng
Darrell
D
Brann
Ruimin
R
Wang
D000199:Actins / Q000096:biosynthesis; D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects*; D009842:Oligopeptides / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012829:Silicosis / Q000188:drug therapy* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D011804:Quinolines
D000199:Actins; D000804:Angiotensin II; D024042:Collagen Type I; D024061:Collagen Type III; D009842:Oligopeptides; D011720:Pyrazoles; D011758:Pyrroles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C506615:HTS 466284; D011804:Quinolines; C058504:goralatide