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NEW FINDINGS What is the central question of this study? To explore the effects of Ac-SDKP on ACE2/Ang (1-7)/Mas axis in occurrence and progress of silicosis. What is the main finding and its importance? Ac-SDKP inhibited lung fibrosis in rats exposed to silica by activation of ACE2/Ang (1-7)/Mas. Ang (1-7) potentially promotes Ac-SDKP by increasing the level of meprin α, the major synthetase of Ac-SDKP. Thus, the interaction Ac-SDKP and Ang (1-7) in silicosis could be a new therapeutic strategy. ABSTRACT The central role of angiotensin-converting enzyme (ACE) has been established in the occurrence and progression of silicosis. The anti-fibrotic peptide Ac-SDKP can be degraded by ACE. ACE2/Ang (1-7)/Mas is protective and acts to counterbalance the detrimental effects of ACE/Ang II/AT1 and also exerts anti-fibrotic effects. Here we demonstrate an interaction between Ac-SDKP and Ang (1-7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac-SDKP could increase the level of ACE2/Ang (1-7)/Mas in rats or in fibroblasts, and decrease the level of Col I and alpha-smooth muscle actin (α-SMA). Furthermore, exogenous Ang (1-7) has the similar anti-fibrotic effects and promotes the level of merpin α, a major Ac-SDKP synthetase, in vivo and in vitro. Compared with non-silicotic patients exposed to silica, the level of serum ACE was increased in silicosis phase III; the levels of Ang II and Ang (1-7) were high in silicosis phase II patients; and, the level of Ac-SDKP was high in the silicosis phase III group. These data imply that Ac-SDKP and Ang (1-7) have an interactive effect as regulatory peptides of RAS and exert antifibrotic effects. This article is protected by copyright. All rights reserved.