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The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study?What are the effects of the antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) on the angiotensin‐converting enzyme 2 (ACE2)–angiotensin‐(1–7)–Mas axis during the occurrence and progression of silicosis?What is the main finding and its importance?Ac‐SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2–angiotensin‐(1–7)–Mas axis. Angiotensin‐(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 angiotesin‐(1–7) in silicosis could provide a new therapeutic strategy. The central role of angiotensin‐converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) can be degraded by ACE. The ACE2–angiotensin‐(1–7)–Mas axis is protective and acts to counterbalance the detrimental effects of ACE–angiotensin II (Ang II)–Ang II type 1 receptor and exerts antifibrotic 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 increased the level of ACE2–Ang‐(1–7)–Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α‐smooth muscle actin. Furthermore, exogenous Ang‐(1–7) had similar antifibrotic effects and increased the level of meprin α, a major Ac‐SDKP synthetase, both in vivo and in vitro. Compared with non‐silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang‐(1–7) were high in patients with silicosis phase II; 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 the renin–angiotensin system and exert antifibrotic effects. [ABSTRACT FROM AUTHOR]

• A total of 306 LncRNAs were altered in a chronic silicotic model. • Several LncRNAs had similar changes in TGF-β1-treated lung fibroblasts. • LOC103691771 promoted myofibroblast differentiation by TGF-β1/Smad signaling. The role and molecular mechanism of long non-coding RNA (lncRNA)-related pathways in silicosis have not been elucidated clearly. The aims of this study were to evaluate the expression of lncRNAs during silica-induced pulmonary fibrosis and verify the function and molecular mechanism of LOC103691771 in myofibroblast differentiation induced by transforming growth factor-β1 (TGF-β1). RNA-sequencing was performed to assess differential expression of lncRNAs in control and silicotic rat lungs. Differential expression of lncRNAs was analyzed by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes to identify their biological roles. LOC103691771, LOC102549714, LOC102550137, LOC103693125, and LOC103692016 were selected to verify their expression by real-time PCR of silicotic rat lung tissue and lung fibroblasts stimulated by TGF-β1. Specific small interfering RNA and an LOC103691771 overexpression plasmid were used to analyze the molecular mechanism in myofibroblast differentiation induced by TGF-β1. A total of 306 lncRNAs were expressed differentially in silicotic rat lungs, including 224 upregulated and 82 downregulated lncRNAs. The expression of LOC103691771, LOC102549714 and LOC102550137 was upregulated, while the expression of LOC103693125 and LOC103692016 was downregulated in silicotic rat lungs and TGF-β1-induced fibroblast, which was consistent with the results of RNA-sequencing. Furthermore, LOC103691771 gene silencing attenuated myofibroblast differentiation, whereas LOC103691771 overexpression promoted myofibroblast differentiation via regulation of the TGF-β1-Smad2/3 signaling pathway. Our findings revealed that differential expression of lncRNAs was related to the development of silicosis, and LOC103691771 played a major role in myofibroblast differentiation induced by TGF-β1, which may serve as a potential therapeutic target for silicosis. [ABSTRACT FROM AUTHOR]