{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T20:15:01Z","timestamp":1790540101782,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,12]],"date-time":"2020-09-12T00:00:00Z","timestamp":1599868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lactoferrin is a naturally occurring iron-binding glycoprotein, produced and secreted by mucosal epithelial cells and neutrophils in various mammalian species, including humans. It is typically found in fluids like saliva, milk and tears, where it reaches the maximum concentration. Thanks to its unique anti-inflammatory, antioxidant and antimicrobial activities, topical application of lactoferrin plays a crucial role in the maintenance of a healthy ocular surface system. The present review aims to provide a comprehensive evaluation of the clinical applications of lactoferrin in ocular diseases. Besides the well-known antibacterial effect, novel interest has been rising towards its potential application in the field of dry eye and viral infections. A growing body of evidence supports the antimicrobial efficacy of lactoferrin, which is not limited to its iron-chelating properties but also depends on its capability to directly interact with pathogen particles while playing immunomodulatory effects. Nowadays, lactoferrin antiviral activity is of special interest, since lactoferrin-based eye drops could be adopted to treat\/prevent the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, which has conjunctivitis among its possible clinical manifestations. In the future, further data from randomized controlled studies are desirable to confirm the efficacy of lactoferrin in the wide range of ocular conditions where it can be used.<\/jats:p>","DOI":"10.3390\/ijms21186668","type":"journal-article","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T21:11:32Z","timestamp":1600031492000},"page":"6668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Therapeutic Effects of Lactoferrin in Ocular Diseases: From Dry Eye Disease to Infections"],"prefix":"10.3390","volume":"21","author":[{"given":"Aldo","family":"Vagge","sequence":"first","affiliation":[{"name":"University Eye Clinic of Genoa, DiNOGMI\u2014University of Genoa IRCCS Ospedale, Policlinico San Martino, Viale Benedetto XV, 5, 16132 Genova (GE), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Senni","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Bernabei","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6419-6941","authenticated-orcid":false,"given":"Marco","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6826-7957","authenticated-orcid":false,"given":"Vincenzo","family":"Scorcia","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Magna Gr\u00e6cia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo E","family":"Traverso","sequence":"additional","affiliation":[{"name":"University Eye Clinic of Genoa, DiNOGMI\u2014University of Genoa IRCCS Ospedale, Policlinico San Martino, Viale Benedetto XV, 5, 16132 Genova (GE), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-0289","authenticated-orcid":false,"given":"Giuseppe","family":"Giannaccare","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Magna Gr\u00e6cia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4391","DOI":"10.1167\/iovs.07-0770","article-title":"The ocular surface: The challenge to enable and protect vision: The Friedenwald lecture","volume":"48","author":"Gipson","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","first-page":"476","article-title":"Ultrastructural organization of human corneal nerves","volume":"37","author":"Muller","year":"1996","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4307","DOI":"10.4049\/jimmunol.164.8.4307","article-title":"Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells","volume":"164","author":"Tran","year":"2000","journal-title":"J. Immunol."},{"key":"ref_4","first-page":"3871","article-title":"Substance P differentially stimulates IL-8 synthesis in human cornea epithelial cells","volume":"41","author":"Tran","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1006\/clim.2001.5007","article-title":"The neutrophil: Function and regulation in innate and humoral immunity","volume":"99","author":"Burg","year":"2001","journal-title":"Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1146\/annurev.immunol.20.103001.114744","article-title":"Phagocytosis of microbes: Complexity in action","volume":"20","author":"Underhill","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.3389\/fimmu.2017.01438","article-title":"Lactoferrin in a Context of Inflammation-Induced Pathology","volume":"8","author":"Kruzel","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1159\/000315016","article-title":"Antimicrobial peptides as a major part of the innate immune defense at the ocular surface","volume":"45","author":"Garreis","year":"2010","journal-title":"Dev. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Giansanti, F., Panella, G., Leboffe, L., and Antonini, G. (2016). Lactoferrin from Milk: Nutraceutical and Pharmacological Properties. Pharmaceuticals, 9.","DOI":"10.3390\/ph9040061"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1210\/endo-124-2-992","article-title":"Lactotransferrin gene expression in the mouse uterus and mammary gland","volume":"124","author":"Teng","year":"1989","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1095\/biolreprod.101.002089","article-title":"Differential expression and estrogen response of lactoferrin gene in the female reproductive tract of mouse, rat, and hamster","volume":"67","author":"Teng","year":"2002","journal-title":"Biol. Reprod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1046\/j.1523-1755.2000.00050.x","article-title":"Expression of lactoferrin in the kidney: Implications for innate immunity and iron metabolism","volume":"57","author":"Abrink","year":"2000","journal-title":"Kidney Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0169-328X(99)00221-1","article-title":"Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment","volume":"72","author":"Fillebeen","year":"1999","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.crvi.2014.08.003","article-title":"Potential lactoferrin activity against pathogenic viruses","volume":"337","author":"Redwan","year":"2014","journal-title":"Comptes Rendus Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1159\/000489093","article-title":"Age-Related Dry Eye Lactoferrin and Lactobionic Acid","volume":"60","author":"Rusciano","year":"2018","journal-title":"Ophthalmic Res"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1097\/00003226-200003000-00015","article-title":"Lactoferrin protects against UV-B irradiation-induced corneal epithelial damage in rats","volume":"19","author":"Fujihara","year":"2000","journal-title":"Cornea"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.3109\/02713683.2013.811259","article-title":"Bovine lactoferrin promotes corneal wound healing and supresses IL-1 expression in alkali wounded mouse cornea","volume":"38","author":"Pattamatta","year":"2013","journal-title":"Curr. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1755-3768.1994.tb02791.x","article-title":"Ocular surface damage and tear lactoferrin in dry eye syndrome","volume":"72","author":"Danjo","year":"1994","journal-title":"Acta Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jtos.2018.11.001","article-title":"A novel and innovative paper-based analytical device for assessing tear lactoferrin of dry eye patients","volume":"17","author":"Sonobe","year":"2019","journal-title":"Ocul. Surf."},{"key":"ref_20","first-page":"11","article-title":"Tear lactoferrin levels in chronic meibomitis associated with acne rosacea","volume":"10","author":"Kiratli","year":"2000","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Roda, M., Corazza, I., Bacchi Reggiani, M.L., Pellegrini, M., Taroni, L., Giannaccare, G., and Versura, P. (2020). Dry Eye Disease and Tear Cytokine Levels-A Meta-Analysis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093111"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s00417-018-04225-7","article-title":"In vivo confocal microscopy morphometric analysis of corneal subbasal nerve plexus in dry eye disease using newly developed fully automated system","volume":"257","author":"Giannaccare","year":"2019","journal-title":"Graefes. Arch. Clin. Exp. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.biochi.2008.07.007","article-title":"Role of lactoferrin in the tear film","volume":"91","author":"Flanagan","year":"2009","journal-title":"Biochimie"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1016\/j.ophtha.2007.06.027","article-title":"Lactoferrin in Sj\u00f6gren\u2019s syndrome","volume":"114","author":"Dogru","year":"2007","journal-title":"Ophthalmology"},{"key":"ref_25","first-page":"NC06","article-title":"Effect of Oral Lactoferrin on Cataract Surgery Induced Dry Eye: A Randomised Controlled Trial","volume":"9","author":"Devendra","year":"2015","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1089\/jop.1998.14.99","article-title":"Lactoferrin suppresses loss of corneal epithelial integrity in a rabbit short-term dry eye model","volume":"14","author":"Fujihara","year":"1998","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1093\/clinids\/3.6.1127","article-title":"The significance of iron in infection","volume":"3","author":"Bullen","year":"1981","journal-title":"Rev. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/S1369-5274(02)00298-9","article-title":"Active transport of iron and siderophore antibiotics","volume":"5","author":"Braun","year":"2002","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.biochi.2008.05.015","article-title":"Antimicrobial properties of lactoferrin","volume":"91","author":"Jenssen","year":"2009","journal-title":"Biochimie"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1093\/infdis\/166.6.1375","article-title":"Interaction of lactoferrin and lipopolysacharide (LPS): Effects on the antioxidant property of lactoferrin and the ability of LPS to prime human neutrophils for enhanced superoxide formation","volume":"166","author":"Cohen","year":"1992","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0014-5793(00)01243-6","article-title":"Lactoferrin inhibits the binding of lipopolysaccharides to L-se- lectin and subsequent production of reactive oxygen species by neutrophils","volume":"469","author":"Baveye","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_32","first-page":"581","article-title":"The effect of iron compounds on the virulence of Escherichia coli for guinea-pigs","volume":"15","author":"Bullen","year":"1968","journal-title":"Immunology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"467e472","DOI":"10.1111\/j.1365-2958.1988.tb00052.x","article-title":"Characterization of the human transferrin and lactoferrin receptors in Haemophilus influenzae","volume":"2","author":"Schryvers","year":"1988","journal-title":"Mol. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0304-4165(68)90015-9","article-title":"Inhibition of bacteria by lactoferrin and other iron-chelating agents","volume":"170","author":"Oram","year":"1968","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1076\/ceyr.19.1.12.5342","article-title":"Lactoferrin increases the susceptibility of S. epidermidis biofilms to lysozyme and vancomycin","volume":"19","author":"Leitch","year":"1999","journal-title":"Curr. Eye Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1111\/j.1699-0463.1999.tb01499.x","article-title":"Lactoferrin: A multifunctional glycoprotein","volume":"107","author":"Vorland","year":"1999","journal-title":"APMIS"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/417552a","article-title":"A component of innate immunity prevents bacterial biofilm development","volume":"417","author":"Singh","year":"2002","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1076\/ceyr.27.4.227.16602","article-title":"The effect of protein-coated contact lenses on the adhesion and viability of gram negative bacteria","volume":"27","author":"Williams","year":"2003","journal-title":"Curr. Eye Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0166-3542(01)00195-4","article-title":"Antiviral activities of lactoferrin","volume":"52","author":"Beljaars","year":"2001","journal-title":"Antiviral. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.jiac.2014.08.003","article-title":"Lactoferrin for prevention of common viral infections","volume":"20","author":"Wakabayashi","year":"2014","journal-title":"J. Infect. Chemother."},{"key":"ref_41","first-page":"e090142","article-title":"Viral infections: Lactoferrin, a further arrow in the quiver of prevention","volume":"9","author":"Peroni","year":"2020","journal-title":"J. Pediatr. Neonat. Individual. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.2174\/138161209788453202","article-title":"Lactoferrin as a natural immune modulator","volume":"15","author":"Actor","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1271\/bbb.64.314","article-title":"Role of basic residues of human lactoferrin in the interaction with B lymphocytes","volume":"64","author":"Kawasaki","year":"2000","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"37","DOI":"10.2147\/EB.S117261","article-title":"Neurotrophic keratitis: Current challenges and future prospects","volume":"10","author":"Versura","year":"2018","journal-title":"Eye Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"537e44","DOI":"10.1271\/bbb.68.537","article-title":"Oral lactoferrin prevents body weight loss and increases cytokine responses during herpes simplex virus type 1 infection of mice","volume":"68","author":"Wakabayashi","year":"2004","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"73e85","DOI":"10.7883\/yoken1952.47.73","article-title":"Inhibition with lactoferrin of in vitro infection with human herpes virus","volume":"47","author":"Hasegawa","year":"1994","journal-title":"Jpn. J. Med. Sci. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"221e31","DOI":"10.1016\/0166-3542(95)00840-3","article-title":"Lactoferrin inhibits herpes simplex virus type 1 adsorption to vero cells","volume":"29","author":"Marchetti","year":"1996","journal-title":"Antivir. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"89e94","DOI":"10.1023\/A:1009217709851","article-title":"Metal complexes of bovine lactoferrin inhibit in vitro replication of herpes simplex virus type 1 and 2","volume":"11","author":"Marchetti","year":"1998","journal-title":"Biometals"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"19e23","DOI":"10.1006\/bbrc.1999.1318","article-title":"Bovine lactoferrin peptidic fragments involved in inhibition of herpes simplex virus type 1 infection","volume":"264","author":"Siciliano","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_50","first-page":"71e9","article-title":"Involvement of bovine lactoferrin moieties in the inhibition of herpes simplex virus type 1 infection","volume":"14","author":"Seganti","year":"2001","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.biochi.2008.05.016","article-title":"Bovine lactoferrin and lactoferricin interfere with intracellular trafficking of Herpes simplex virus-1","volume":"91","author":"Marr","year":"2009","journal-title":"Biochemistry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1007\/BF01322673","article-title":"Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea","volume":"140","author":"Fujihara","year":"1995","journal-title":"Arch. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.exer.2007.09.013","article-title":"Lactoferrin Glu561Asp polymorphism is associated with susceptibility to herpes simplex keratitis","volume":"86","author":"Keijser","year":"2008","journal-title":"Exp. Eye. Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Lang, J., Yang, N., Deng, J., Liu, K., Yang, P., Zhang, G., and Jiang, C. (2011). Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023710"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Marques de Carvalho, C.A., Matos, A.D.R., Caetano., B.C., Pedro de Sousa Junior, I., Pereira da Costa Campos, S., Geraldino, B.R., Barros, C.A., Patricio de Almeida, M.A., Rocha, V.P., and Vieira da Silva, A.M. (2020). In vitro inhibition of SARS-CoV-2 infection by bovine lactoferrin. BioRxiv.","DOI":"10.1101\/2020.05.13.093781"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6668\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:20Z","timestamp":1760177360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,12]]},"references-count":55,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21186668"],"URL":"https:\/\/doi.org\/10.3390\/ijms21186668","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,12]]}}}