Skip to main content

Autophagy modulation in animal models of corneal diseases: a systematic review


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2



Aminoimidazole-4-carboxamide riboside


Age-related macular degeneration


AMP-activated protein kinase




Beclin-binding domain






Cyclosporine A


Dendritic cells


Dry eye disease


DNA damage-inducible transcript 4


Extracellular matrix


Enzyme-linked immunosorbent assay


Endoplasmic reticulum


Extracellular signal regulated kinase


Fuch endothelial corneal dystrophy


Forkhead box O3


Coiled-coil domain containing 1


Granular corneal dystrophy type 2


Glial fibrillary acidic protein




Human corneal epithelial cells


Hypoxia-inducible factor


Herpetic stromal keratitis


Herpes simplex virus


Intraepithelial corneal nerves


Gamma interferon




Inositol monophosphatase


Intraepithelial nerve terminal


IFN regulatory factor 3


Lysosomal-associated membrane protein


Lymphatic vascular endothelial gene


Microtubule-associated protein 1 light chain 3


Histocompatibility complex class II




Mammalian target of rapamycin


Mammalian target of rapamycin complex




Nitric oxide


Non-obese diabetic


Nicotinamide adenine dinucleotide phosphate oxidase 4


Matrix metalloproteinase


Periodic acid Schiff


Platelet-derived growth factor receptors


Platelet endothelial cell adhesion molecule

PI3KC3, also known as VPS34:

Phosphatidylinositol 3-kinase, catalytic subunit type 3


Phosphatidylinositol 3-phosphate




Preferred Reporting Items for Systematic reviews and Meta-Analysis


Prospective Register of Systematic Reviews


Protein prion


P53 upregulated modulator of apoptosis


Quantitative polymerase chain reaction


Rho-associated protein kinase


Reactive oxygen species


Retinal pigmented epithelium


Nonporous silica nanoparticles


Silent mating type information regulation 2 homolog 3


Systematic review


Systematic Review Center for Laboratory Animal Experimentation’s


Transcription factor EB


Transforming growth factor beta 1


Terminal deoxynucleotidyl transferase dUTP nick end labeling


Tumor necrosis factor


Tuberous Sclerosis Complex


UNC-51-like kinase


Unfolded protein response


Ubiquitin–proteasome system


Vascular endothelial growth factor




  1. González-Polo RA, Pizarro-Estrella E, Yakhine-Diop SMS et al (2015) Is the modulation of autophagy the future in the treatment of neurodegenerative diseases? Curr Top Med Chem 15:2152–2174

    Article  Google Scholar 

  2. Tanida I (2011) Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal 14:2201–2214.

    CAS  Article  PubMed  Google Scholar 

  3. Yakhine-Diop SMS, Martínez-Chacón G, González-Polo RA et al (2017) Fluorescent FYVE chimeras to quantify PtdIns3P synthesis during autophagy. Methods Enzymol 587:257–269.

    CAS  Article  PubMed  Google Scholar 

  4. Rubinsztein DC, Shpilka T, Elazar Z (2012) Mechanisms of autophagosome biogenesis. Curr Biol 22:R29–R34.

    CAS  Article  PubMed  Google Scholar 

  5. Bjørkøy G, Lamark T, Pankiv S et al (2009) Chapter 12 monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol 451:181–197.

    CAS  Article  Google Scholar 

  6. Kim YC, Guan K, Kim YC, Guan K (2015) mTOR: a pharmacologic target for autophagy regulation. 125:25–32.

  7. Bukowiecki A, Hos D, Cursiefen C, Eming SA (2017) Wound-healing studies in cornea and skin: parallels, differences and opportunities. Int J Mol Sci 18:1–24.

    Article  Google Scholar 

  8. Bron AJ (2001) The architecture of the corneal stroma. Br J Ophthalmol 85:379–381.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Dua HS, Faraj LA, Said DG et al (2013) Human corneal anatomy redefined: a novel pre-descemet’s layer (Dua’s layer). Ophthalmology 120:1778–1785.

    Article  PubMed  Google Scholar 

  10. Moshirfar M, Murri MS, Shah TJ et al (2019) A review of corneal endotheliitis and endotheliopathy: differential diagnosis, evaluation, and treatment. Ophthalmol Ther 8:195–213.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yee RW, Matsuda M, Schultz RO, Edelhauser HF (1985) Changes in the normal corneal endothelial cellular pattern as a function of age. Curr Eye Res 4:671–678.

    CAS  Article  PubMed  Google Scholar 

  12. Boya P, Esteban-Martínez L, Serrano-Puebla A et al (2016) Autophagy in the eye: development, degeneration, and aging. Prog Retin Eye Res 55:206–245.

    Article  PubMed  Google Scholar 

  13. Robaei D, Watson S (2014) Corneal blindness: a global problem. Clin Exp Ophthalmol 42:213–214.

    Article  PubMed  Google Scholar 

  14. Martin LM, Jeyabalan N, Tripathi R et al (2019) Autophagy in corneal health and disease: a concise review. Ocul Surf 17:186–197.

    Article  PubMed  Google Scholar 

  15. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Chai P, Ni H, Zhang H, Fan X (2016) The evolving functions of autophagy in ocular health: a double-edged sword. Int J Biol Sci 12:1332–1340.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9:1102–1109.

    CAS  Article  PubMed  Google Scholar 

  18. Smith JA, Al-beitz J, Begley C, Caffery B, Nichols K, Schaumberg D, Schein O (2007) The epidemiology of dry eye disease: report of the epidemiology subcommitee of The International Dry Eye WorkShop. Ocul Surf 5:93–107.

    Article  Google Scholar 

  19. Ogawa Y, Tsubota K (2013) Dry eye disease and inflammation. Inflamm Regen 33:238–248.

    CAS  Article  Google Scholar 

  20. Kim EC, Meng H, Jun AS (2013) Lithium treatment increases endothelial cell survival and autophagy in a mouse model of Fuchs endothelial corneal dystrophy. Br J Ophthalmol 97:1068–1073.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Meng H, Matthaei M, Ramanan N et al (2013) L450W and Q455K Col8a2 knock-in mouse models of fuchs endothelial corneal dystrophy show distinct phenotypes and evidence for altered autophagy. Investig Ophthalmol Vis Sci 54:1887–1897.

    CAS  Article  Google Scholar 

  22. Petrovski G, Pásztor K, Orosz L et al (2014) Herpes simplex virus types 1 and 2 modulate autophagy in SIRC corneal cells. J Biosci 39:683–692.

    Article  PubMed  Google Scholar 

  23. Reme CE, Young RW (1977) The effects of hibernation on cone visual cells in the ground squirrel. Investig Ophthalmol Vis Sci 16:815–840

    CAS  Google Scholar 

  24. Shetty R, Sharma A, Pahuja N et al (2017) Oxidative stress induces dysregulated autophagy in corneal epithelium of keratoconus patients. PLoS ONE 12:e0184628.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Choi S-I, Kim B-Y, Dadakhujaev S et al (2012) Impaired autophagy and delayed autophagic clearance of transforming growth factor β-induced protein (TGFBI) in granular corneal dystrophy type 2. Autophagy 8:1782–1797.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Szabó DJ, Nagymihály R, Veréb Z, et al (2018) Ex vivo 3D human corneal stroma model for {Schnyder} corneal dystrophy—role of autophagy in its pathogenesis and resolution. Histol Histopathol 33:455–462.

  27. Il CS, Kim KS, Oh JY et al (2013) Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp. J Pineal Res 54:361–372.

    CAS  Article  Google Scholar 

  28. Nie D, Peng Y, Li M et al (2018) Lithium chloride (LiCl) induced autophagy and downregulated expression of transforming growth factor β-induced protein (TGFBI) in granular corneal dystrophy. Exp Eye Res 173:44–50.

    CAS  Article  PubMed  Google Scholar 

  29. Vakifahmetoglu-norberg H, Xia H, Vakifahmetoglu-norberg H et al (2015) Pharmacologic agents targeting autophagy Find the latest version: pharmacologic agents targeting autophagy. J Clin Invest 125:5–13.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Klionsky DJ, Abdelmohsen K, Abe A et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1–222.

    Article  PubMed  PubMed Central  Google Scholar 

  31. McWilliams TG, Prescott AR, Villarejo-Zori B et al (2019) A comparative map of macroautophagy and mitophagy in the vertebrate eye. Autophagy 15:1296–1308.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Neumann S, Romonath R (2009) Faculty of human sciences pedagogics & therapy of speech and language disorders effectiveness of nasopharyngoscopic biofeedback in clients with cleft palate speech—a systematic review. PLoS Med 6:50931.

    Article  Google Scholar 

  33. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hooijmans CR, Rovers MM, De Vries RBM et al (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14:1–9.

    Article  Google Scholar 

  35. Wang B, Peng L, Ouyang H et al (2019) Induction of DDIT4 impairs autophagy through oxidative stress in dry eye. Invest Ophthalmol Vis Sci 60(8):2836–2847

    CAS  Article  Google Scholar 

  36. Wang G, Xue Y, Wang Y et al (2019) The role of autophagy in the pathogenesis of exposure keratitis. J Cell Mol Med 23:4217–4228.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. He J, Pham TL, Kakazu AH, Bazan HEP (2019) Remodeling of substance P sensory nerves and transient receptor potential melastatin 8 (TRPM8) cold receptors after corneal experimental surgery. Investig Ophthalmol Vis Sci 60:2449–2460.

    CAS  Article  Google Scholar 

  38. Hu J, Hu X, Kan T (2019) MiR-34c participates in diabetic corneal neuropathy via regulation of autophagy. Investig Ophthalmol Vis Sci 60:16–25.

    CAS  Article  Google Scholar 

  39. Hu J, Kan T, Hu X (2019) Sirt3 regulates mitophagy level to promote diabetic corneal epithelial wound healing. Exp Eye Res 181:223–231.

    CAS  Article  PubMed  Google Scholar 

  40. Korom M, Wylie KM, Wang H et al (2013) A proautophagic antiviral role for the cellular prion protein identified by infection with a herpes simplex virus 1 ICP34.5 mutant. J Virol 87:5882–5894.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Lee HJ, Shin S, Yoon S-G et al (2019) The effect of chloroquine on the development of dry eye in Sjögren Syndrome animal model. Investig Opthalmology Vis Sci 60:3708.

    CAS  Article  Google Scholar 

  42. Leib DA, Alexander DE, Cox D et al (2009) Interaction of ICP34.5 with beclin 1 modulates herpes simplex virus type 1 pathogenesis through control of CD4+ T-cell responses. J Virol 83:12164–12171.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Jiang L, Liu T, Xie L et al (2019) AICAR prolongs corneal allograft survival via the AMPK-mTOR signaling pathway in mice. Biomed Pharmacother 113:108558.

    CAS  Article  PubMed  Google Scholar 

  44. Ma S, Yu Z, Feng S et al (2019) Corneal autophagy and ocular surface inflammation: a new perspective in dry eye. Exp Eye Res 184:126–134.

    CAS  Article  PubMed  Google Scholar 

  45. Miao Q, Xu Y, Zhang H et al (2019) Cigarette smoke induces ROS mediated autophagy impairment in human corneal epithelial cells. Environ Pollut (Barking, Essex, 1987) 245:389–397.

    CAS  Article  Google Scholar 

  46. Parker ZM, Murphy AA, Leib DA (2015) Role of the DNA Sensor STING in protection from lethal infection following corneal and intracerebral challenge with herpes simplex virus 1. J Virol 89:11080–11091.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Seo Y, Ji YW, Lee SM et al (2014) Activation of HIF-1α (hypoxia inducible factor-1α) prevents dry eye-induced acinar cell death in the lacrimal gland. Cell Death Dis 5:e1309.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Shah M, Edman MC, Reddy Janga S et al (2017) Rapamycin eye drops suppress lacrimal gland inflammation in a murine model of Sjögren’s Syndrome. Invest Ophthalmol Vis Sci 58:372–385.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Stepp MA, Pal-Ghosh S, Tadvalkar G et al (2018) Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice. Exp Eye Res 169:91–98.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Stepp MA, Pal-Ghosh S, Tadvalkar G et al (2018) Reduced corneal innervation in the CD25 null model of Sjögren syndrome. Int J Mol Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Yamazoe K, Yoshida S, Yasuda M et al (2015) Development of a transgenic mouse with R124H human TGFBI mutation associated with granular corneal dystrophy type 2. PLoS ONE 10:e0133397.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Jiang Y, Yin X, Stuart PM, Leib DA (2015) Dendritic cell autophagy contributes to herpes simplex virus-driven stromal keratitis and immunopathology. MBio.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Zhang F, Li Y, Tang Z et al (2012) Proliferative and survival effects of PUMA promote angiogenesis. Cell Rep 2:1272–1285.

    CAS  Article  PubMed  Google Scholar 

  54. Li C, Li C, Li H, et al (2019) Disparate expression of autophagy in corneas of C57BL/6 mice and BALB/c mice after Aspergillus fumigatus infection. Int J Ophthalmol 12:705–710.

  55. Uchida K, Unuma K, Funakoshi T et al (2014) Activation of master autophagy regulator TFEB during systemic LPS administration in the cornea. J Toxicol Pathol 27:153–158.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Yin Y, Zong R, Bao X et al (2018) Oxidative stress suppresses cellular autophagy in corneal epithelium. Invest Ophthalmol Vis Sci 59:3286–3293.

    CAS  Article  PubMed  Google Scholar 

  57. Di Tommaso C, Torriglia A, Furrer P et al (2011) Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers. Int J Pharm 416:515–524.

    CAS  Article  PubMed  Google Scholar 

  58. Kim J-Y, Park J-H, Kim M et al (2017) Safety of nonporous silica nanoparticles in human corneal endothelial cells. Sci Rep 7:14566.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Kanao T, Miyachi Y (2006) Lymphangiogenesis promotes lens destruction and subsequent lens regeneration in the newt eyeball, and both processes can be accelerated by transplantation of dendritic cells. Dev Biol 290:118–124.

    CAS  Article  PubMed  Google Scholar 

  60. Kim HS, Il CS, Jeung EB, Yoo YM (2014) Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells. PLoS ONE 9:1–9.

    CAS  Article  Google Scholar 

  61. Y. Zernii E, E. Baksheeva V, N. Iomdina E, et al (2016) Rabbit models of ocular diseases: new relevance for classical approaches. CNS Neurol Disord Drug Targets 15:267–291.

    CAS  Article  PubMed  Google Scholar 

  62. Koizumi N, Okumura N, Kinoshita S (2012) Development of new therapeutic modalities for corneal endothelial disease focused on the proliferation of corneal endothelial cells using animal models. Exp Eye Res 95:60–67.

    CAS  Article  PubMed  Google Scholar 

  63. Kimura T, Jain A, Choi SW et al (2017) TRIM-directed selective autophagy regulates immune activation. Autophagy 13:989–990.

    CAS  Article  PubMed  Google Scholar 

  64. Yang J, Chen D, He Y et al (2013) MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9. Age (Omaha) 35:11–22.

    CAS  Article  Google Scholar 

  65. Yakhine-Diop SMS, Rodríguez-Arribas M, Martínez-Chacón G et al (2018) Acetylome in human fibroblasts from Parkinson’s disease patients. Front Cell Neurosci 12:1–8.

    CAS  Article  Google Scholar 

  66. Aldrich BT, Schlötzer-Schrehardt U, Skeie JM et al (2017) Mitochondrial and morphologic alterations in native human corneal endothelial cells associated with diabetes mellitus. Investig Ophthalmol Vis Sci 58:2130–2138.

    Article  Google Scholar 

  67. Chen J, Ma Z, Jiao X et al (2011) Mutations in FYCO1 cause autosomal-recessive congenital cataracts. Am J Hum Genet 88:827–838.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Morishita H, Eguchi S, Kimura H et al (2013) Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J Biol Chem 288:11436–11447.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Rezaie T, Child A, Hitchings R et al (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295:1077–1079.

    CAS  Article  PubMed  Google Scholar 

  70. Mitter SK, Song C, Qi X et al (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10:1989–2005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Park HYL, Kim JH, Park CK (2012) Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model. Cell Death Dis 3:e290–e299.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Zhao C, Yasumura D, Li X et al (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369–383.

    CAS  Article  PubMed  Google Scholar 

  73. Yao J, Tao ZF, Li CP et al (2014) Regulation of autophagy by high glucose in human retinal pigment epithelium. Cell Physiol Biochem 33:107–116.

    CAS  Article  PubMed  Google Scholar 

  74. Pal-Ghosh S, Pajoohesh-Ganji A, Tadvalkar G et al (2016) Topical Mitomycin-C enhances subbasal nerve regeneration and reduces erosion frequency in the debridement wounded mouse cornea. Exp Eye Res 146:361–369.

    CAS  Article  PubMed  Google Scholar 

  75. Schmidl D, Werkmeister R, Kaya S et al (2017) A controlled, randomized double-blind study to evaluate the safety and efficacy of chitosan-N-acetylcysteine for the treatment of dry eye syndrome. J Ocul Pharmacol Ther 33:375–382.

    CAS  Article  PubMed  Google Scholar 

  76. Matsuo T, Tsuchida Y, Morimoto N (2002) Trehalose eye drops in the treatment of dry eye syndrome. Ophthalmology 109:2024–2029.

    Article  PubMed  Google Scholar 

  77. Lu Y, Liu LL, Liu SS et al (2016) Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells. J Transl Med 14:1–13.

    CAS  Article  Google Scholar 

  78. Zhang L, Fu L, Zhang S et al (2017) Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo. Chem Sci 8:2687–2701.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Moscovici BK, Holzchuh R, Sakassegawa-Naves FE et al (2015) Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: prospective double-blind randomized study. Contact Lens Anterior Eye 38:373–378.

    Article  PubMed  Google Scholar 

  80. Koch JC, Tatenhorst L, Roser AE et al (2018) ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacol Ther 189:1–21.

    CAS  Article  PubMed  Google Scholar 

  81. Park JH, Kim JY, Kim DJ et al (2017) Effect of nitric oxide on human corneal epithelial cell viability and corneal wound healing. Sci Rep 7:1–10.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Sarkar S, Korolchuk VI, Renna M et al (2011) Complex inhibitory effects of nitric oxide on autophagy. Mol Cell 43:19–32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. De Stefano D, Villella VR, Esposito S et al (2014) Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy 10:2053–2074.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Sarkar S, Floto RA, Berger Z et al (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170:1101–1111.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Hall DT, Griss T, Ma JF, et al (2018) Inflammation-associated cachectic muscle wasting. EMBO Mol Med.

  86. Shivakumar S, Panigrahi T, Shetty R et al (2018) Chloroquine protects human corneal epithelial cells from desiccation stress induced inflammation without altering the autophagy flux. Biomed Res Int.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ciechomska IA, Gabrusiewicz K, Szczepankiewicz AA, Kaminska B (2013) Endoplasmic reticulum stress triggers autophagy in malignant glioma cells undergoing cyclosporine A-induced cell death. Oncogene 32:1518–1529.

    CAS  Article  PubMed  Google Scholar 

  88. Okumura N, Kinoshita S, Koizumi N (2017) Application of Rho kinase inhibitors for the treatment of corneal endothelial diseases. J Ophthalmol.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Linares-Alba MA, Gómez-Guajardo MB, Fonzar JF et al (2016) Preformulation studies of a liposomal formulation containing sirolimus for the treatment of dry eye disease. J Ocul Pharmacol Ther 32:11–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. El Sanharawi M, Kowalczuk L, Touchard E et al (2010) Protein delivery for retinal diseases: from basic considerations to clinical applications. Prog Retin Eye Res 29:443–465.

    CAS  Article  PubMed  Google Scholar 

  91. Okumura N, Koizumi N, Ueno M et al (2012) ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. Am J Pathol 181:268–277.

    CAS  Article  PubMed  Google Scholar 

Download references


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.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Guadalupe Martínez-Chacón.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 85 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Autophagy
  • Animal model
  • Corneal disease
  • Systematic review