TABLE 2.
Summary of the scientific evidence of the anti-fibrotic role of autophagy in IBD. HIF, human intestinal fibroblasts; UC; Ulcerative Colitis; CD, Crohn Disease; IBD, inflammatory bowel disease; TNBS, 2,4,6-Trinitrobenzene-1-sulfonic acid; DSS, Dextran sulfate sodium; TGFβ1, transforming growth factor beta 1; LC3, Microtubule-associated protein 1A/1B-light chain 3; mTOR, mammalian target of rapamycin; ATG, autophagy-related gen; ULK1, Unc-51-like kinase-1; ECM, extracellular matrix; FGF, Fibroblast Growth Factor; PARP, poly-ADP ribose polymerase; COL, collagen; TIMP, tissue inhibitors of metalloproteinases; MMP, metalloproteinases; ITGB6, integrin subunit beta 6; α-SMA, Alpha Smooth Muscle Actin; IL, interleukin; CTGF, Connective Tissue Growth Factor; EMT, epithelial mesenchymal transition; ERK, Ras-dependent extracellular signal-regulated kinase, SNAIL, zinc-finger transcription factor.
| Intestinal fibrotic samples | Treatment | Autophagy | Fibrosis | |||
|---|---|---|---|---|---|---|
| (Luna, Masamunt, Rickmann, et al., 2011a) | Primary HIFs from UC, CD and controls | Tocotrienols | (+) | ↑LC3II ↑autophagic vacuoles | ↓ | ↓ECM proteins (↓procollagen type I and laminin) ↓fibroblast proliferation (↓FGF, ↑apoptosis (CASPASES-3, -8, and -9, PARP)) |
| (Ortiz-Masiá et al., 2014) | IBD samples | - | (−) | ↑ P62, p-mTOR ↓LC3II | - | |
| (Cosin-Roger et al., 2019) | Murine heterotopic transplant model | - | (−) | ↑ P62 ↓Lc3II/I, Beclin-1 | ↑ | ↑Col1a1, Col3a1, Vimentin, Tgfβ1, Timp1, Mmp2, Snail1, Snail2, Itgb6 |
| Murine heterotopic transplant model | 3-Methyladenine | (−) | ↑ P62 ↓Lc3II/I, Beclin-1 | ↑ | ↑Col1a1, Col3a1, Vimentin, Tgfβ1, Timp1, Mmp2, Snail1, Snail2, Itgb6 | |
| Murine heterotopic transplant model | Rapamycin | (+) | ↓ P62 ↑Lc3II/I, Beclin-1 | ↓ | ↓Col1a1, Col31, Vimentin, Tgfβ1, Timp1, Mmp2, Snail1, Snail2, Itgb6 | |
| Primary HIFs | TGFβ1 | No significant changes (P62) | ↑ | ↑Col1A1 | ||
| Primary HIFs | Rapamycin/TGFβ1 | (+) | ↓ P62 | ↓ | ↓Col1A1 | |
| Primary HIFs | Bafilomycin/TGFβ1 | (−) | ↑ P62 ↑LC3II/I | ↑ | ↑Col1A1 | |
| (Holvoet et al., 2017) | Murine DSS model/Myofibroblasts | - | No significant changes (Lc3II/I) | ↑ | ↑Il6, Tgfβ1, Mmp2, Mmp3, Mmp8, Mmp9, Mmp12, α-Sma | |
| Murine DSS model/Myofibroblasts | AMA0825 | (+) | ↑Lc3II/I | ↓ | ↓IL6, TGFβ1, MMP2, MMP8, MMP9, MMP12, α-SMA | |
| Human biopsies | AMA0825 | (+) | - | ↓ | ↓MMP2-3-9-12¸TGFβ1, IL6 | |
| Primary HIFs | TGFβ1 | (+) | ↑ Autophagosomes ↓ P62 | ↑ | ↑MMP2, IL6, COL1A1, CTGF, TGFβ1 (+) Myofibroblast transition (↓F-ACTIN, VIMENTIN) | |
| Primary HIFs | AMA0825/TGFβ1 | (+) | ↑↑ Autophagosomes ↓↓ P62 | ↓ | ↓ MMP2-12, TGFβ1, CTGF, COL1A1 (−) Myofibroblast transition (↓F-ACTIN, VIMENTIN) | |
| (Butera et al., 2022, 147) | Murine TNBS model | - | ↑Lc3II/I | ↑ | ↑ α-Sma, TGFβ1, CD147, Ctgf, Col1a2, Col3a1, p-Erk1/2, Il-6, and Il-23, Il-17, Il-13, Il-36, Il-34 | |
| Murine TNBS model | AC-73 | (+) | ↑Lc3II/I | ↓ | ↓ α-Sma, Ctgf, Col1a2, Col3a1, P-Erk1/2, Il-6, and Il-23, Il-17, Il-13, Il-36, Il-34 | |
| (Zeng et al., 2022) | Murine DSS model/Intestinal epithelial cells (IEC) | - | (−) | ↑ P62, Lc3ii/Lc3i ↓Atg7, Atg9b, Atg14, Ulk1 | ↑ | ↑ α-Sma, Col1a2, Col3a1 ↑EMT (↓E-cadherin, ↑N-cadherin, Vimentin) |
| Resolvin D1 | (+) | ↓ P62, Lc3II/I ↑Atg7, Atg9b, Atg14, Ulk1 | ↓ | ↓ α-Sma, Col1a2, Col3a1 ↓EMT (↑E-cadherin, ↓N-cadherin, Vimentin) | ||
| HT-29 | Chloroquine | (−) | ↑ P62, LC3II/LC3I | ↓ | ↑EMT (↓E-CADHERIN, ↑N-CADHERIN, VIMENTIN) | |
| HT-29 | Chloroquine/Resolvin D1 | (+) | - | ↓EMT (↑E-CADHERIN, ↓N-CADHERIN, VIMENTIN, SNAIL2) | ||
| (Arab, Al-Shorbagy, y Saad, 2021) | Murine TNBS model | Dapagliflozin | (+) | ↑Beclin1 ↑AMPK/mTOR ↓ P62 | ↓ colonic apoptosis (↓capase.3, ↓Bax/Bcl2-2) ↓ Inflammation (↓ HMGB1/RAGE/NF-kβ) ↓ROS (↑Nrf2/HO-1) | |