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Targeting the RAS axis alleviates silicotic fibrosis and Ang II-induced myofibroblast differentiation via inhibition of the hedgehog signaling pathway.
- Source :
-
Toxicology letters [Toxicol Lett] 2019 Oct 01; Vol. 313, pp. 30-41. Date of Electronic Publication: 2019 Jun 07. - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Adult
Aged
Animals
Anthracosis metabolism
Anthracosis pathology
Cell Line
Collagen metabolism
Disease Models, Animal
Female
Hedgehog Proteins metabolism
Humans
Lung metabolism
Lung pathology
Male
Middle Aged
Myofibroblasts metabolism
Myofibroblasts pathology
Pulmonary Fibrosis metabolism
Pulmonary Fibrosis pathology
Rats, Wistar
Signal Transduction drug effects
Silicosis metabolism
Silicosis pathology
Angiotensin I pharmacology
Angiotensin II pharmacology
Angiotensin-Converting Enzyme Inhibitors pharmacology
Captopril pharmacology
Cell Differentiation drug effects
Lung drug effects
Myofibroblasts drug effects
Oligopeptides pharmacology
Peptide Fragments pharmacology
Pulmonary Fibrosis prevention & control
Renin-Angiotensin System drug effects
Silicosis prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3169
- Volume :
- 313
- Database :
- MEDLINE
- Journal :
- Toxicology letters
- Publication Type :
- Academic Journal
- Accession number :
- 31181250
- Full Text :
- https://doi.org/10.1016/j.toxlet.2019.05.023