Silica induced Expression of IL-1beta, IL-6, TNF-beta, TGF-alpha, in the Experimental Murine Lung Fibrosis

Background and Purpose Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms of tetrandrine against lung fibrosis has not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine in lung fibrosis. Experimental Approach The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP) and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Key Results Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy, accompanied by the up-regulation and enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that NRF2 bound to SQSTM1 promoter in tetrandrine-induced autophagy. Furthermore, TGF-β1-induced phosphorylated mTOR was inhibited by tetrandrine, with reduced activation levels of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Conclusion and Implications Our data suggest that tetrandrine might be recognized as a novel autophagy inducer, thus attenuating lung fibrosis. Tetrandrine should be investigated as a novel therapeutic strategy for IPF.

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Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches

Science ◽

10.1126/science.aau0964 ◽

2019 ◽

Vol 363 (6432) ◽

pp. eaau0964 ◽

Cited By ~ 162

Author(s):

Svetoslav Chakarov ◽

Hwee Ying Lim ◽

Leonard Tan ◽

Sheau Yng Lim ◽

Peter See ◽

...

Keyword(s):

Gene Expression ◽

Functional Programming ◽

Lung Fibrosis ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Tissue Homeostasis ◽

Murine Lung ◽

Macrophage Depletion ◽

Heterogeneous Cell Population ◽

Macrophage Populations

Macrophages are a heterogeneous cell population involved in tissue homeostasis, inflammation, and various pathologies. Although the major tissue-resident macrophage populations have been extensively studied, interstitial macrophages (IMs) residing within the tissue parenchyma remain poorly defined. Here we studied IMs from murine lung, fat, heart, and dermis. We identified two independent IM subpopulations that are conserved across tissues: Lyve1loMHCIIhiCX3CR1hi (Lyve1loMHCIIhi) and Lyve1hiMHCIIloCX3CR1lo (Lyve1hiMHCIIlo) monocyte-derived IMs, with distinct gene expression profiles, phenotypes, functions, and localizations. Using a new mouse model of inducible macrophage depletion (Slco2b1flox/DTR), we found that the absence of Lyve1hiMHCIIlo IMs exacerbated experimental lung fibrosis. Thus, we demonstrate that two independent populations of IMs coexist across tissues and exhibit conserved niche-dependent functional programming.

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Anti-fibrotic effect of meloxicam in a murine lung fibrosis model

European Journal of Pharmacology ◽

10.1016/j.ejphar.2007.02.065 ◽

2007 ◽

Vol 564 (1-3) ◽

pp. 181-189 ◽

Cited By ~ 36

Author(s):

Hossam M.M. Arafa ◽

Mohamed H. Abdel-Wahab ◽

Mohamed F. El-Shafeey ◽

Osama A. Badary ◽

Farid M.A. Hamada

Keyword(s):

Lung Fibrosis ◽

Murine Lung

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Interleukin (IL)-6 And IL-11 Depletion Attenuates Bleomycin-Induced Murine Lung Fibrosis

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5996 ◽

2011 ◽

Author(s):

Hui Ling Lau ◽

Robert J.J. O'Donoghue ◽

Gary P. Anderson ◽

Jessica Jones ◽

Cecilia M. Prele ◽

...

Keyword(s):

Lung Fibrosis ◽

Murine Lung

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Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.739220 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuanyuan Liu ◽

Wenshan Zhong ◽

Jinming Zhang ◽

Weimou Chen ◽

Ye lu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Smooth Muscle Actin ◽

Lung Fibroblasts ◽

Therapeutic Effects ◽

The Novel ◽

Induced Expression ◽

Tgf Β1

Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms have not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine against lung fibrosis. The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP), and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin, and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy flux, accompanied by enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that tetrandrine induced autophagy via increasing binding of NRF2 and SQSTM1 promoter. Furthermore, tetrandrine inhibited TGF-β1-induced phosphorylation of mTOR by reducing activation of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Our data suggest that protective effect of tetrandrine against lung fibrosis might be through promoting Rheb-mTOR and NRF2-SQSTM1 mediated autophagy. Tetrandrine may thus be potentially employed as a novel therapeutic medicine against IPF.

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