Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Hill, Catherine M.; Li, Juanjuan; Liu, Dian; Conforti, Franco; Brereton, Christopher J.; Yao, Liudi; Zhou, Yilu; Alzetani, Aiman; Chee, Serena; Marshall, Ben G.; Fletcher, Sophie; Hancock, David C.; Ottensmeier, Christian; Steele, Andrew J.; Downward, Julian; Richeldi, Luca; Lü, Xin; Davies, Donna E.; Jones, Mark G.; Wang, Yihua

doi:10.1038/s41419-019-1820-x

Cited by 125 publications

(133 citation statements)

References 61 publications

(93 reference statements)

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“…(Macro) autophagy is where a double-membraned vesicle is formed, which captures material in the cytoplasm to be degraded, whereas selective autophagy specifically targets cargo to be degraded [12][13][14][15] . Autophagy has also been proposed to have roles in a number of diseases [16] , such as fibrosis [17][18][19] , neurodegeneration [20] and cancer [21,22] [ Figure 2].…”

Section: Autophagymentioning

confidence: 99%

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Hill¹,

Wang²

2019

CDR

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Epithelial-mesenchymal transition (EMT) and autophagy are both known to play important roles in the development of cancer. Subsequently, these processes are now being utilised as targets for therapy. Cancer is globally one of the leading causes of death, and, despite many advances in treatment options, patients still face many challenges. Drug resistance in cancer-therapy is a large problem, and both EMT and autophagy have been shown to contribute. However, given the context-dependent role of these processes and the complexity of the interactions between them, elucidating how they both act alone and interact is important. In this review, we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy, and how this ultimately may affect drug resistance in cancer therapy.

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Section: Autophagymentioning

confidence: 99%

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Hill¹,

Wang²

2019

CDR

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“…Finally, our results suggest that macrophagic autophagy can facilitate brosis. Although not in accordance with the initial acceptance that autophagy might be protective in lung brosis (11,13,28), our data are in line with more recent results from the literature showing an increased number of LC3-II puncta, an index of active autophagy, in broblast foci of patients with idiopathic pulmonary brosis (IPF), the most common form of pulmonary brosis (13,29). In vitro, these authors also showed that autophagy is induced by TGFß, and that it is necessary for TGFß-induced brosis in both non-IPF and IPF broblasts (7).…”

Section: Discussionmentioning

confidence: 78%

“…In vitro, these authors also showed that autophagy is induced by TGFß, and that it is necessary for TGFß-induced brosis in both non-IPF and IPF broblasts (7). Interestingly, such a cell-speci c role for autophagy has been recently described in chronic obstructive pulmonary disease (COPD) where autophagy is believed to be protective except in macrophages (10)(11)(12)28). In lung brosis, the majority of the studies has focused on lung epithelial cells and/or broblasts (28), as the two major cell type involved in brogenesis (15).…”

Section: Discussionmentioning

confidence: 92%

Deficient macrophage autophagy protects mice from Cerium Oxide nanoparticle-induced lung fibrosis

Annangi¹,

Lu²,

Bruniaux³

et al. 2020

Preprint

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BackgroundCerium (Ce) is a rare earth element, rapidly oxidizing to form CeO2, and currently used in numerous commercial applications, especially as nanoparticles (NP). The potential health effects of Ce remain uncertain, but literature indicates the development of rare earth pneumoconiosis accompanied with granuloma formation, interstitial fibrosis and inflammation. The exact underlying mechanisms are yet not completely understood, and we propose that autophagy could be an interesting target to study, particularly in macrophages. Therefore, the objective of our study was to investigate the role of macrophagic autophagy after pulmonary exposure to CeO2 NP in mice. Mice lacking the early autophagy gene Atg5 in their myeloid lineage and their wildtype counterparts were exposed to CeO2 NP by single oropharyngeal administration and sacrificed up to one month after. At that time, lung remodeling was thoroughly characterized (inflammatory cells infiltration, expression of fibrotic markers such as αSMA, TGFβ1, total and type I and III collagen deposition), as well as macrophage infiltration (quantification and M1/M2 phenotype). Results: Such pulmonary exposure to CeO2 NP induces a progressive and dose-dependent lung fibrosis in the bronchiolar and alveolar walls, together with the activation of autophagy. Blockade of macrophagic autophagy protects from alveolar but not bronchiolar fibrosis, via the modulation of macrophage polarization towards M2 phenotype. Conclusion: In conclusion, our findings bring novel insight on the role of macrophagic autophagy in lung fibrogenesis, and add to the current awareness of pulmonary macrophages as potential new therapeutic targets for future anti-fibrotic therapies.

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“…Autophagy plays a pivotal role in attenuating fibrosis. 21,22 To determine if ONG41008 could induce the induction of autophagosomes, DHLFs and ONGHEPA1 cells were treated with TGF plus ONG41008, resulting in the complete inhibition of fibrosis and of autophagosome production ( Figure 4A). Western blotting of ONGHEPA1 cell lysates with a cleavage-specific anti-LC3 antibody showed fragmentation of LC3 protein, generating A/B polypeptide fragments ( Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

A noble TGF beta biogenesis inhibitor exhibits both potent anti-fibrotic and anti-inflammatory capabilities

Kim

Meang²,

Kim³

et al. 2019

Preprint

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Fibrosis is caused by the proliferation of pathogenic myofibroblasts and the deposition of massive amounts of soluble collagen, altering the homeostasis of extracellular matrix (ECM) biogenesis and resulting in tissue scarring. Because a chromone scaffold (CS)-containing small molecule called eupatilin was shown to curb lung fibrosis, a new CS-containing analog, ONG41008, was generated. Plasma exposure was significantly increased. Orally-administered ONG41008 was more potent than pirfenidone at ameliorating fibrosis in a bleomycin-induced lung fibrosis model (BLM). ONG41008 also completely inhibited the trans-differentiation to myofibroblasts of ONGHEPA1, being a primary hepatic stellate cells (HSC) cell line, and of primary diseased human lung fibroblasts (DHLFs) derived from patients with idiopathic pulmonary fibrosis. ONG41008 inhibited the expression of LTBP1 and LAP, dismantling the latent TGF complex, likely limiting binding of TGF to TGF receptors I and II. ONG41008 also markedly inhibited the phosphorylation of SMAD2 and SMAD3, the induction of NADPH oxidase 4 (NOX4) in both cell types, and the production of reactive oxygen species.ONG41008 also completely inhibited the induction of chemokine ligands 2 (Ccl2) and 7 (Ccl7) and induced robust autophagy, suggesting that ONG41008 could curb liver inflammation and fibrosis. STAM mice model was orally administered with 50 mg/kg (mpk) ONG41008 exhibited high nonalcoholic fatty liver disease scores, suggesting that ONG41008, together with anti-diabetic drugs like GLP1 and peroxisome proliferator-activated receptor agonists, could reduce the development of nonalcoholic steatohepatitis (NASH).Treatment of macrophages with ONG41008 and lipopolysaccharide (LPS) markedly inhibited the expression of TNF, Interleukin 1, CHOP, CCL2, CCL7, and CXCL2.

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Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Cited by 125 publications

References 61 publications

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Deficient macrophage autophagy protects mice from Cerium Oxide nanoparticle-induced lung fibrosis

A noble TGF beta biogenesis inhibitor exhibits both potent anti-fibrotic and anti-inflammatory capabilities

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