Influence of the interaction between Ac­SDKP and Ang II on the pathogenesis and development of silicotic fibrosis.

ABSTRACT

N­acetyl­seryl­aspartyl­lysyl­proline (Ac­SDKP) is a natural tetrapeptide that is released from thymosin ß4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin­angiotensin system, angiotensin­converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac­SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac­SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac­SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac­SDKP decreased. Ac­SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac­SDKP treatment had an anti­fibrotic effect in vivo. Compared with the silicosis group, the expression of α­smooth muscle actin (α­SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase­1 (MMP­1) expression and the MMP­1/tissue inhibitor of metalloproteinases­1 (TIMP­1) ratio was increased in the Ac­SDKP treatment group. In vitro, pre­treatment with Ac­SDKP or valsartan attenuated the expression of α­SMA, Col I, Fn and AT1 in Ang II­induced fibroblasts. In addition, MMP­1 expression and the MMP­1/TIMP­1 ratio were significantly higher in Ac­SDKP and valsartan pre­treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac­SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac­SDKP protects against silicotic fibrosis by inhibiting Ang II­induced myofibroblast differentiation and extracellular matrix production.