| ER stress |
LC3 and ubiquitinated protein immunoreactive staining and P62 protein levels are increased in IPF lung tissues. |
Autophagy induction by mTOR inhibitor Torin1 suppresses ER stress-induced cell senescence in HBEC. Lc3 and Atg5 silencing exacerbate ER stress-induced senescence. |
Araya et al. 2013 |
| ER stress (tunicamycin) increases LC3-II |
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| Tunicamycin intratracheal injection combined with infection with MHV68 (a murine gamaherpesvirus homologous to EBV) (an in vivo ER stress model) led to lung fibrosis. |
Silencing Pink1 in A549 cells enhanced tunicamycin and bafilomycin exposure-induced increase of mitochondrial mass. |
Bueno et al. 2015 |
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PINK1 is downregulated in AECIIs of IPF patient lung, and in mice exposed to ER stress. |
Pink1 overexpression ameliorated the tunicamycin and bafilomycin-induced mitochondrial accumulation. |
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Pink1 knockout mice exhibited enlarged swollen mitochondria in lung tissues, lower mitochondrial number per cell, decreased complex I and IV activities, but increased LC3-II accumulation. Enhanced p62 levels and increased fibrosis were evident in response to MHV68. |
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| TGFβ |
TGFβ decreased senescence and increased differentiation of fibroblasts from explanted human lungs. |
Lc3 and Atg5 silencing has no effect on HBEC senescence but increased α-SMA and type I collagen levels, and TGFβ further enhanced their expression. |
Araya et al. 2013 |
| TGFβ increased LC3-II and decreased p62 in lung fibroblasts |
mTOR inhibitor Torin1 suppressed α-SMA and type I collagen levels, without changing senescence. |
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| TGFβ induces fibronectin, collagen-1 and α-SMA in human lung fibroblast MRC-5 cells. mTOR is activated, LC3-II is decreased and p62 is increased. |
Silencing Becn1 and Lc3 enhanced, while rapamycin attenuated, TGFβ-induced fibronectin and α-SMA increase in MRC-5 cells. |
Patel et al. 2012 |
| Human IPF lung mitochondria exhibit higher PINK1 compared to controls. In Beas-2b cells, TGFβ increased PINK1, mitochondrial fragmentation, and colocalization of PINK1 with LC3. |
In Beas-2b cells, silencing Pink1 enhanced cell death in response to TGFβ. |
Patel et al. 2015 |
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In normal human lung fibroblasts, TGFβ suppresses autophagic flux as assessed by measurement of LC3-II levels with and without chloroquine. Furthermore, many autophagy genes are regulated by TGFβ. |
Induction of autophagy using Tat-beclin 1 reduced expression of fibrotic markers in fibroblasts, and inhibition of autophagy by knockdown of ATG5 and ATG7 had the opposite effect. |
Sosulski et al. 2015 |
| Bleomycin |
Bleomycin (a single intratracheal instillation of 2.5 U/kg of bleomycin)-treated rats (28th day) exhibited higher fibrotic markers including α-SMA, fibronectin, collagens I and III, together with higher p-mTOR, lower BECN1 and lower LC3-II. |
Berberine increased BECN1, LC3-II and autophagosomes, decreased bleomycin-induced p-mTOR, and reversed bleomycin-induced ultrastructural alteration of the lung, likely through inhibition of PI3K/Akt, and mTOR. |
Chitra et al. 2015 |
| Not assessed |
Inhibition of mTOR with rapamycin protected against bleomycin-induced fibrosis in mice. |
Patel et al. 2012 |
| In mice, bleomycin (3.0 U/kg, intratrachea instillation) on 28th day increases LC3-II, BECN1, p-mTOR, and p62; decreased VPS34 and p-Bcl-2. |
Inhibition of autophagy with 3-MA reversed the antifibrotic effect of IL17A blockage. |
Mi et al. 2011 |
| IL-17A neutralizing antibodies attenuate bleomycin-induced lung fibrosis, p-mTOR, and p62 in mice and further increase BECN1, VPS34, and p-Bcl-2. |
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| Bleomycin-induced fibrosis is exaggerated by Mmp19 knockout in mice. Mmp19−/− fibroblasts exhibited diminished ATG4C proteins. |
Not assessed |
Jara et al. 2015 |
| Not assessed |
Pink1 knockout mice exhibited increased fibrosis severity and elevated collagen deposition in response to bleomycin. |
Bueno et al. 2015 |
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Patel et al. 2015 |
| Aging |
There is an age effect in bleomycin induction of LC3 puncta, LC3-TOM20 colocalization, lipofuscin, and collagen deposition in mice. |
Not assessed |
Soulski et al. 2015 |
| There is an age effect on mitochondrial dynamics, ER stress, susceptibility to MHV68-induced mitochondrial dysfunction, Pink1 expression, and fibrosis in AECIIs. |
Pink1-deficient mice showed increased susceptibility to lung fibrosis after MHV68 infection. |
Bueno et al. 2015 |
| Familial |
Lung epithelia from patient with SFTPC I73T heterozygous mutation showed increased autophagic vacuoles. |
Not assessed |
Hawkins et al. 2015 |
| Exogenous expression of I73T in HEK cells increased autophagosomes, increased PARKIN and mitochondrial MTCO2, and increased LC3-II response to bafilomycin, while attenuating degradation of aggregate-prone protein substrates. |
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| HPS is an autosomal recessive disorder and some patients develop lung fibrosis, with surfactant accumulation, lysosomal stress, and AECII apoptosis. LC3B and p62 are increased in HPS1/2 mice and human patients' lungs. |
Lc3b overexpression decreased HPS1 knockdown-induced p62 accumulation in A549 cells. |
Ahuja et al. 2015 |
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Transgenic mice carrying misfolded variant α1-antitrypsin Z exhibited increased LC3-II in the lung, collagen deposition, and leukocyte infiltration. |
CBZ and Flu, or overexpression of transcription factor TFEB, decreased lung collagen deposition and leukocyte infiltration in α1-antitrypsin Z mice. |
Hidvegi et al. 2015 |
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