| Autophagy inhibition can induce EMT in ATII cells via the p62/SQSTM1-NFκB-Snail2 pathway. However this does not appear to drive fibrosis, instead secreted factors from autophagy-inhibited ATII cells promote fibrogenesis and this can be attenuated by depletion of Snail2. |
Hill et al.44
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| Reduced levels of autophagy may be responsible for increased senescence and myofibroblast differentiation. Autophagy inhibition induces myofibroblast differentiation. |
Araya et al (2013)37
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| IPF lung tissue shows reduced autophagy. In vitro, TGF-β inhibits autophagy in lung fibroblasts via mTORC1. Inducing autophagy in fibroblasts by rapamycin decreases α-SMA and fibronectin expression. |
Patel et al (2012)38
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| ANXA2 direct binding target of BLM, binding stops TFEB induced autophagic flux and this can induce pulmonary fibrosis. |
Wang et al (2018a)47
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Atg4b-deficient mice can exacerbate BLM induced fibrosis. It was associated with an increase in neutrophil infiltration and changes in pro-inflammatory cytokines. Increased epithelial apoptosis. By 28 days post-BLM, extensive fibrosis as observed in Atg4b-deficient mice. |
Cabrera et al (2015)48
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| STAT2 and JAK3 induced in IPF. Phosphorylation of both induces EMT in ATII cells and FMT in fibroblasts. Inhibition of STAT2 and JAK3 simultaneously resulted in an increase in autophagy, reduced fibroblast migration and senescence. |
Milara et al (2018)64
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| Inhibition of VimIFs reduces the invasiveness of fibroblasts and can protect against murine-BLM induced fibrosis. Treatment with VimIF inhibitor increased autophagy and invasiveness of fibroblasts was reduced in the murine model, 3D organoids and IPF-derived pulmospheres. |
Surolia et al (2019)72
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| Activation of autophagy in MRC5 cells, via PI3K/AKT/mTOR, protects from TGF-β induced fibrosis. |
He et al (2020a)51
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| Autophagy inhibited after LPS challenge in mouse lung fibroblasts together with PI3K-AktmTOR pathway activation. LPS promotes lung fibroblast proliferation by autophagy inhibition via the PI3K-Akt-mTOR pathway. |
Xie et al (2019)92
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| PQ induced PI3K/Akt/mTOR and Hh via miR-193a, together with an inhibition of autophagy; this increases fibrosis. |
Liu et al (2019)86
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| S1PL increased in IPF. TGF-β can increase its expression. Overexpression of S1PL reduces TGFβ- and S1PL-induced differentiation via expression of LC3 and Beclin1. |
Shuang Huang et al (2015)56
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| eEF2K increased in fibroblasts. eEF2K controls ECM deposition via p38 MAPK. Inhibition of eEF2K suppresses autophagy in fibroblasts treated with TGF-β. |
Wang et al (2018b).57
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| Impaired autophagy was observed in BLM-treated mice, IL-17A Ab-treated mice had increased autophagy, resolved fibrosis. |
Mi et al (2011)70
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In vitro, knockdown of ATG7 in endothelial cells (ECs) promotes endothelial−emesenchymal transition (EndMT). It also promotes TGF-β signaling and pro-fibrotic genes. ATG7 EC-specific knockout mice demonstrates increased susceptibility to BLM-induced fibrosis. |
Singh et al (2015)73
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| Overexpression of TFEB reduces lysosomal dysfunctional, increasing autophagy flux in alveolar macrophages, preventing fibrosis. |
He et al (2020b)51
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| Autophagy is inhibited by SiNPs in ATII cells. Rapamycin treatment in mice induces autophagy and protects AECs from apoptosis to reduce SiNP-induced fibrosis. |
Zhao et al (2019)53
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Lc3B KO mice are more susceptible to BLM-induced fibrosis, epithelial cell apoptosis and elevated ER stress. |
Kesireddy et al (2019)55
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| Leptin augments TGF-β1-induced EMT; this is mediated by inhibition of autophagy via the PI3K/Akt/mTOR pathway. |
Gui et al (2018)69
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| Fibrosis related to reduced miR-449a expression. Overexpression of miR-449a reduces lung fibrosis by upregulating autophagy. Bcl2 found to be a target of miR-449a. |
Han et al (2016)83
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| Reduced levels of miR-326 have also been reported in SiO2-murine models. Increased expression of miR-326 in SiO2-induced fibrosis, increases autophagy in fibroblasts and reduced fibrosis by downregulating both polypyrimidine tract-binding protein (PTBP1) and tumour necrosis factor superfamily 14 (TNFSF14). |
Xu et al (2019)84
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| Activated Akt can induce collagen production in the BLM-murine model. A transgenic mouse model that constitutively expresses the active form of Akt (myristoylated AKT), also demonstrated reduced autophagy. |
Dakhlallah et al (2019)89
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| FoxO3a, a direct target of Akt, has low expression in IPF fibroblasts. Reduced autophagy, via FoxO3a, contributes to fibrogenesis. |
Im et al (2015)79
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| Histone deacetylase 6 (HDAC6) expression is reduced in IPF lungs. Inhibition of HDAC6 (with Tubastatin), reduces TGF-β induced collagen expression; via reduced p-Akt, autophagy and regulation of HIF-1α-VEGF. HDAC6 inhibition by Tubastatin reduces fibrosis via TGF-β-PI3KAkt. |
Saito et al (2017)90
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| Reduced levels of autophagy induction in IPF fibroblasts compared to young- and age-matched-normal fibroblasts. Aged IPF fibroblasts exhibit reduced starvation-induced autophagy, regulated via mTOR. IPF fibroblasts display mTOR activation, which contributes to apoptosis resistance. Inhibition of mTOR stimulates starvation-induced autophagy in young and old, but not IPF fibroblasts. |
Romero et al (2016)77
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| BLM-treatment in mice displays activation of TGF-β and AKT/mTOR pathways. Younger-mice exposed to BLM exhibited more LC3 punctate. TGF-β1 inhibits autophagy and mitochondrial recycling in fibroblasts during FMT. |
Sosulski et al (2015)91
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| LPS-induced autophagy-inhibition in lung fibroblasts, concomitantly with PI3K-Akt-mTOR activation; by reducing thymocyte differentiation antigen-1 (Thy-1) expression and increase in integrin b3 (Itgb3) expression. |
Wan et al (2019)93
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| Elevated autophagy results in fibroblast senescence and inhibition of FMT via mTOR complex 2 (mTORC2). |
Bernard et al (2020)94
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| Ang-(1−7) reduces smoking-induced fibrosis by activating autophagy and reducing NOX4-dependent ROS. |
Pan et al (2018)54
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| In the BLM-induced murine model of fibrosis activated toll-like receptor 4 (TLR4) improved fibrosis and lung function, Inhibition of TLR4 abolished them. Increased autophagy, reversed the effect of TLR4 leading to reduced fibrosis; whereas autophagy inhibition reverses the anti-fibrotic roles of TLR4. |
Yang et al (2012b)52
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| IL17A was shown to inhibit the phosphorylation of B-cell CLL/lymphoma 2 (BCL2). IL17A regulates the phosphorylation of BCL2 via the IL17A-PI3K-GSK3B-BCL2 signaling pathway. |
Liu et al (2013a)71
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| In primary lung fibroblasts, TGF-β induced autophagy both ECM accumulation and UPR were attenuated with Baf-A1 (autophagy inhibitor). |
Ghavami et al (2018)102
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| IL-37 reduced in IPF patients. IL-37 shown to reduce fibrosis by attenuating TGF-β1 signaling and inducing autophagy. |
Kim et al (2019)98
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| In the BLM-mouse model, autophagy activation reduces Ang II-induced activation of NLPR3 by reducing ROS and mitochondrial dysfunction. Autophagy reduces fibrosis via NLRP activation, which is induced by Ang II-mediated ROS. |
Meng et al (2019)99
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| Rapamycin-treated IPF fibroblasts modified starvation-induced autophagy and apoptosis. mTORC may contribute to the resistance of cell death. |
Romero et al (2016)77
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| IPF-derived fibroblasts are resistant to type I collagen matrix-induced cell death. IPF fibroblasts have low levels of autophagic activity on polymerised collagen; aberrant PTEN-Akt signaling allows IPF fibroblasts to maintain their phenotype on collagen by suppressing autophagy. |
Nho et al (2014)78
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| FoxO3a was found to mediate Akt resulting in autophagy suppression. Autophagy inhibition enhanced IPF fibroblast viability. Inhibition of miR-96 resulted in an increase in FOXO3a mRNA and protein levels, attenuating IPF fibroblasts proliferation and promoting cell death. |
Nho et al (2014)78 Im et al (2015)79
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TOLLIP protects bronchial epithelial cells from BLM-induced apoptosis by reducing mtROS and upregulating autophagy. |
Li et al (2020)80
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