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Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy.

ABSTRACT: Dysregulation of autophagy plays a pivotal role in fibrosis in multiple organs. However, the role of autophagy in peritendinous fibrosis is not well understood. Here, we hypothesize that autophagy plays a protective role in preventing adhesion formation. In a rat model of tendon injury, we observed dysregulated autophagy during excessive extracellular matrix deposition. Pharmacological induction of autophagy by rapamycin markedly alleviated the severity of peritendinous fibrosis in vivo. In NIH/3T3 fibroblasts and tenocytes, transforming growth factor ?1 (TGF-?1) markedly activated myofibroblasts and increased collagen synthesis. Addition of rapamycin activated autophagy, reduced collagen synthesis, and suppressed myofibroblast activation. In vitro experiments also showed that rapamycin decreased cell proliferation and increased the number of cells arrested in G0/G1 phase. However, following pretreatment with the autophagy inhibitor 3-methyladenine (3-MA), rapamycin was unable to repress the fibrotic changes induced by TGF-?1. Autophagy related protein 5 (Atg5) RNA interference in fibroblasts also abolished the protective effects of rapamycin in vitro. In conclusion, our results point to rapamycin as a potential treatment strategy in the prevention of peritendinous fibrosis after tendon injury.

SUBMITTER: Zheng W

PROVIDER: S-EPMC5921906 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy.

Zheng Wei W Qian Yun Y Chen Shuai S Ruan Hongjiang H Fan Cunyi C

Frontiers in pharmacology 20180420

Dysregulation of autophagy plays a pivotal role in fibrosis in multiple organs. However, the role of autophagy in peritendinous fibrosis is not well understood. Here, we hypothesize that autophagy plays a protective role in preventing adhesion formation. In a rat model of tendon injury, we observed dysregulated autophagy during excessive extracellular matrix deposition. Pharmacological induction of autophagy by rapamycin markedly alleviated the severity of peritendinous fibrosis <i>in vivo</i>. ...[more]

PMID: 29731718

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Project description:Background: Liver injury is one of the serious complications of sepsis. Previous studies suggested that dexmedetomidine (DEX) could alleviate cecal ligation and puncture (CLP)-induced liver injury. However, it is unclear whether the protective effect of DEX on sepsis-induced liver injury is related to autophagy. Methods: Mice (n = 105) were randomly divided into the following groups: (i) CON group (Sham); (ii) CLP group (CLP-induced liver injury + saline); (iii) CLP + DEX group (CLP-induced liver injury + DEX). Mouse models of sepsis-induced liver injury were established using CLP. DEX or normal saline was administered by intraperitoneal injection at 0, 2, and 4 h after CLP surgery. The mortality rate within 120 h was calculated. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and inflammatory cytokines were measured at 6, 12, and 24 h in each group. Hematoxylin and eosin staining assay was carried out to detect the morphological changes of mouse liver cells in each group. The levels of autophagy-associated proteins LC3II, Beclin-1, p62, and LAMP-2 were detected in three groups of mice using western blotting. The expression of LC3II was detected using immunofluorescence. Transmission electron microscopy (TEM) of liver tissue was used to observe autophagosomes and autophagosome-lysosomes. Lastly, the effect of DEX on the AMPK/SIRT1 pathway-associated protein levels were detected using western blotting. Meanwhile, we used L0-2 cells infected with mRFP-GFP-LC3 adenovirus to further analyze the role of SIRT1 in DEX-induced autophagy in liver injury model in vitro. Results: DEX significantly improved the survival rate of septic mice at the early stage and ameliorated the pathology of sepsis-induced liver injury. The level of autophagy-associated proteins, phosphorylated (p)-AMPK/AMPK, and SIRT1 in the liver of CLP-induced sepsis mice peaked at 12 h post-CLP and decreased significantly at 24 h. In the CLP + DEX group, the levels of autophagy-associated proteins, p-AMPK/AMPK, and SIRT1 increased, whereas inflammatory cytokines decreased at 24 h. The autophagosome structure was clearly observed at different time points in the CLP + DEX group. In the in vitro hepatocyte injury model, the SIRT1 inhibitor significantly increased intracellular ROS levels and reversed the effect of DEX on autophagy flux. Conclusion: We demonstrated a novel mechanism in which DEX protects against CLP-induced liver injury. DEX enhances autophagy, which alleviates the inflammatory responses in CLP-induced liver injury by regulating the SIRT1/AMPK pathway.

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Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy.

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Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy.

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