Abstract
Autophagy is an intracellular catabolic process implicated in the recycling and degradation of intracellular components. Few studies have defined its role in corneal pathologies. Animal models are essential for understanding autophagy regulation and identifying new treatments to modulate its effects. A systematic review (SR) was conducted of studies employing animal models for investigations of autophagy in corneal diseases. Studies were identified using a structured search strategy (TS = autophagy AND cornea*) in Web of Science, Scopus, and PubMed from inception to September 2019. In this study, 230 articles were collected, of which 28 were analyzed. Mouse models were used in 82% of the studies, while rat, rabbit, and newt models were used in the other 18%. The most studied corneal layer was the epithelium, followed by the endothelium and stroma. In 13 articles, genetically modified animal models were used to study Fuch endothelial corneal dystrophy (FECD), granular corneal dystrophy type 2 (GCD2), dry eye disease (DED), and corneal infection. In other 13 articles, animal models were experimentally induced to mimic DED, keratitis, inflammation, and surgical scenarios. Furthermore, in 50% of studies, modulators that activated or inhibited autophagy were also investigated. Protective effects of autophagy activators were demonstrated, including rapamycin for DED and keratitis, lithium for FECD, LYN-1604 for DED, cysteamine and miR-34c antagomir for damaged corneal epithelium. Three autophagy suppressors were also found to have therapeutic effects, such as aminoimidazole-4-carboxamide-riboside (AICAR) for corneal allogeneic transplantation, celecoxib and chloroquine for DED.
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Abbreviations
- AICAR:
-
Aminoimidazole-4-carboxamide riboside
- AMD:
-
Age-related macular degeneration
- AMPK:
-
AMP-activated protein kinase
- ATGs:
-
Autophagy-related
- BBD:
-
Beclin-binding domain
- BECN1:
-
Beclin-1
- COX:
-
Cyclooxygenase
- CsA:
-
Cyclosporine A
- DC:
-
Dendritic cells
- DED:
-
Dry eye disease
- DDIT4:
-
DNA damage-inducible transcript 4
- ECM:
-
Extracellular matrix
- ELISA:
-
Enzyme-linked immunosorbent assay
- ER:
-
Endoplasmic reticulum
- ERK:
-
Extracellular signal regulated kinase
- FECD:
-
Fuch endothelial corneal dystrophy
- FoxO3:
-
Forkhead box O3
- FYCO1:
-
Coiled-coil domain containing 1
- GCD2:
-
Granular corneal dystrophy type 2
- GFAP:
-
Glial fibrillary acidic protein
- H&E:
-
Hematoxylin–eosin
- HCEC:
-
Human corneal epithelial cells
- HIF-1α:
-
Hypoxia-inducible factor
- HSK:
-
Herpetic stromal keratitis
- HSV-1:
-
Herpes simplex virus
- ICNs:
-
Intraepithelial corneal nerves
- IFNγ:
-
Gamma interferon
- IL:
-
Interleukin
- IMPase:
-
Inositol monophosphatase
- INT:
-
Intraepithelial nerve terminal
- IRF3:
-
IFN regulatory factor 3
- LAMP:
-
Lysosomal-associated membrane protein
- LYVE-1:
-
Lymphatic vascular endothelial gene
- MAP1LC3:
-
Microtubule-associated protein 1 light chain 3
- MHCII:
-
Histocompatibility complex class II
- MMC:
-
Mitomycin-C
- mTOR:
-
Mammalian target of rapamycin
- mTORC1:
-
Mammalian target of rapamycin complex
- NAC:
-
N-acetylcysteine
- NO:
-
Nitric oxide
- NOD:
-
Non-obese diabetic
- NOX4:
-
Nicotinamide adenine dinucleotide phosphate oxidase 4
- MMP:
-
Matrix metalloproteinase
- PAS:
-
Periodic acid Schiff
- PDGFR:
-
Platelet-derived growth factor receptors
- PECAM:
-
Platelet endothelial cell adhesion molecule
- PI3KC3, also known as VPS34:
-
Phosphatidylinositol 3-kinase, catalytic subunit type 3
- PI3P:
-
Phosphatidylinositol 3-phosphate
- PI3K:
-
Phosphatidylinositol-3-kinase
- PRISMA:
-
Preferred Reporting Items for Systematic reviews and Meta-Analysis
- PROSPERO:
-
Prospective Register of Systematic Reviews
- PrP:
-
Protein prion
- PUMA:
-
P53 upregulated modulator of apoptosis
- qPCR:
-
Quantitative polymerase chain reaction
- ROCK:
-
Rho-associated protein kinase
- ROS:
-
Reactive oxygen species
- RPE:
-
Retinal pigmented epithelium
- SiNPs:
-
Nonporous silica nanoparticles
- Sirt3:
-
Silent mating type information regulation 2 homolog 3
- SR:
-
Systematic review
- SYRCLE’s:
-
Systematic Review Center for Laboratory Animal Experimentation’s
- TFEB:
-
Transcription factor EB
- TGFB1:
-
Transforming growth factor beta 1
- TUNEL:
-
Terminal deoxynucleotidyl transferase dUTP nick end labeling
- TNF:
-
Tumor necrosis factor
- TSC:
-
Tuberous Sclerosis Complex
- ULK1:
-
UNC-51-like kinase
- UPR:
-
Unfolded protein response
- UPS:
-
Ubiquitin–proteasome system
- VEGF:
-
Vascular endothelial growth factor
- 3-MA:
-
3-Methyladenine
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Acknowledgements
The systematic review was performed at the Jesús Usón Minimally Invasive Surgery Center (CCMIJU) which is part of the ICTS “Nanbiosis.” G.MC was supported by ONCE Foundation. F.J. Vela, J.L. Campos, E. Abellán and A. Ballestín were supported by Jesús Usón Minimally Invasive Surgery Foundation. S.M.S. Y-D was supported by Isabel Gemio Foundation. Authors thank Raquel Lozano Delgado for the illustration of the Fig. 2. Autophagy modulators targeting different steps of the autophagic machinery in corneal diseases, and FUNDESALUD for helpful assistance.
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Martínez-Chacón, G., Vela, F.J., Campos, J.L. et al. Autophagy modulation in animal models of corneal diseases: a systematic review. Mol Cell Biochem 474, 41–55 (2020). https://doi.org/10.1007/s11010-020-03832-5
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DOI: https://doi.org/10.1007/s11010-020-03832-5