{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T23:18:56Z","timestamp":1793488736478,"version":"4.5.0"},"reference-count":111,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"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>The shape and transparency of the cornea are essential for clear vision. However, its location at the ocular surface renders the cornea vulnerable to pathogenic microorganisms in the external environment. Pseudomonas aeruginosa and Staphylococcus aureus are two such microorganisms and are responsible for most cases of bacterial keratitis. The development of antimicrobial agents has allowed the successful treatment of bacterial keratitis if the infection is diagnosed promptly. However, no effective medical treatment is available after progression to corneal ulcer, which is characterized by excessive degradation of collagen in the corneal stroma and can lead to corneal perforation and corneal blindness. This collagen degradation is mediated by both infecting bacteria and corneal fibroblasts themselves, with a urokinase-type plasminogen activator (uPA)-plasmin-matrix metalloproteinase (MMP) cascade playing a central role in collagen destruction by the host cells. Bacterial factors stimulate the production by corneal fibroblasts of both uPA and pro-MMPs, released uPA mediates the conversion of plasminogen in the extracellular environment to plasmin, and plasmin mediates the conversion of secreted pro-MMPs to the active form of these enzymes, which then degrade stromal collagen. Bacterial factors also stimulate expression by corneal fibroblasts of the chemokine interleukin-8 and the adhesion molecule ICAM-1, both of which contribute to recruitment and activation of polymorphonuclear neutrophils, and these cells then further stimulate corneal fibroblasts via the secretion of interleukin-1. At this stage of the disease, bacteria are no longer necessary for collagen degradation. In this review, we discuss the pivotal role of corneal fibroblasts in corneal ulcer associated with infection by P. aeruginosa or S. aureus as well as the development of potential new modes of treatment for this condition.<\/jats:p>","DOI":"10.3390\/ijms22168979","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T08:44:45Z","timestamp":1629449085000},"page":"8979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pivotal Role of Corneal Fibroblasts in Progression to Corneal Ulcer in Bacterial Keratitis"],"prefix":"10.3390","volume":"22","author":[{"given":"Teruo","family":"Nishida","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan"},{"name":"Division of Cornea and Ocular Surface, Ohshima Eye Hospital, Fukuoka 812-0036, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Sugioka","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kindai University Nara Hospital, Ikoma, Nara 630-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4990-6308","authenticated-orcid":false,"given":"Ken","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Murakami","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Sakibana Hospital, Izumi, Osaka 594-1105, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.preteyeres.2012.02.003","article-title":"Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease","volume":"31","author":"Barabino","year":"2012","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cca.2005.12.035","article-title":"Laboratory findings in tear fluid analysis","volume":"369","author":"Ohashi","year":"2006","journal-title":"Clin. Chim. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1136\/bjo.70.2.122","article-title":"Bacteriology and tear protein profiles of the dry eye","volume":"70","author":"Seal","year":"1986","journal-title":"Br. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Asbell, P., and Lemp, M. (2006). Future trends in the treatment of dry eye disease. Dry Eye Disease: The Clinician\u2019s Guide to Diagnosis and Treatment, Thieme Medical Publishers.","DOI":"10.1055\/b-002-51025"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1128\/IAI.00854-10","article-title":"Role of defensins in corneal epithelial barrier function against Pseudomonas aeruginosa traversal","volume":"79","author":"Augustin","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.exer.2013.07.014","article-title":"Antimicrobial compounds in tears","volume":"117","author":"McDermott","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1167\/iovs.18-25822","article-title":"InflammAging at ocular surface: Clinical and biomolecular analyses in healthy volunteers","volume":"60","author":"Micera","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.it.2017.11.007","article-title":"When Clarity Is Crucial: Regulating Ocular Surface Immunity","volume":"39","author":"Foulsham","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2017.03.004","article-title":"Human antimicrobial peptides in ocular surface defense","volume":"61","author":"Mohammed","year":"2017","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108094","DOI":"10.1016\/j.exer.2020.108094","article-title":"Corneal epithelial biology: Lessons stemming from old to new","volume":"198","author":"Lavker","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1136\/bjo.2006.097188","article-title":"The suprabasal layer of corneal epithelial cells represents the major barrier site to the passive movement of small molecules and trafficking leukocytes","volume":"91","author":"Kuchynka","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.biocel.2003.08.007","article-title":"Regulation of tight junctions and loss of barrier function in pathophysiology","volume":"36","author":"Harhaj","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S1350-9462(02)00042-3","article-title":"Cell-matrix and cell-cell interactions during corneal epithelial wound healing","volume":"22","author":"Suzuki","year":"2003","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1002\/bies.10144","article-title":"Epithelial barrier function: Assembly and structural features of the cornified cell envelope","volume":"24","author":"Kalinin","year":"2002","journal-title":"Bioessays"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S1350-9462(01)00007-6","article-title":"Characteristics of the human ocular surface epithelium","volume":"20","author":"Kinoshita","year":"2001","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1099\/jmm.0.001110","article-title":"Pseudomonas aeruginosa and microbial keratitis","volume":"69","author":"Hilliam","year":"2020","journal-title":"J. Med. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"O\u2019Callaghan, R., Caballero, A., Tang, A., and Bierdeman, M. (2019). Pseudomonas aeruginosa Keratitis: Protease IV and PASP as Corneal Virulence Mediators. Microorganisms, 7.","DOI":"10.3390\/microorganisms7090281"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lee, J.W., Somerville, T., Kaye, S.B., and Romano, V. (2021). Staphylococcus aureus Keratitis: Incidence, Pathophysiology, Risk Factors and Novel Strategies for Treatment. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040758"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/s41433-020-01339-3","article-title":"Infectious keratitis: An update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance","volume":"35","author":"Ting","year":"2021","journal-title":"Eye"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1001\/archophthalmol.2010.144","article-title":"Epidemiology of ulcerative keratitis in Northern California","volume":"128","author":"Jeng","year":"2010","journal-title":"Arch. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1128\/CMR.00134-14","article-title":"Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management","volume":"28","author":"Tong","year":"2015","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ong, S.J., Huang, Y.C., Tan, H.Y., Ma, D.H., Lin, H.C., Yeh, L.K., Chen, P.Y., Chen, H.C., Chuang, C.C., and Chang, C.J. (2013). Staphylococcus aureus keratitis: A review of hospital cases. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080119"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1159\/000099269","article-title":"Bacterial infections of the cornea (Pseudomonas aeruginosa)","volume":"92","author":"Hazlett","year":"2007","journal-title":"Chem. Immunol. Allergy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1136\/bjo.87.7.834","article-title":"Bacterial keratitis: Predisposing factors, clinical and microbiological review of 300 cases","volume":"87","author":"Bourcier","year":"2003","journal-title":"Br. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1097\/01.icl.0000234002.88643.d0","article-title":"Microbial keratitis pathogens and antibiotic susceptibilities: A 5-year review of cases at an urban county hospital in north Texas","volume":"33","author":"Pachigolla","year":"2007","journal-title":"Eye Contact Lens"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/ICO.0b013e318156caf2","article-title":"Risk factors and causative organisms in microbial keratitis","volume":"27","author":"Green","year":"2008","journal-title":"Cornea"},{"key":"ref_28","first-page":"802","article-title":"Bacterial keratitis","volume":"Volume 1","author":"Mannis","year":"2018","journal-title":"Cornea: Fundamentals, Diagnosis and Management"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108647","DOI":"10.1016\/j.exer.2021.108647","article-title":"Foundational concepts in the biology of bacterial keratitis","volume":"209","author":"Ung","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.clae.2020.11.014","article-title":"Understanding clinical and immunological features associated with Pseudomonas and Staphylococcus keratitis","volume":"44","author":"Shrestha","year":"2021","journal-title":"Cont. Lens Anterior Eye"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100804","DOI":"10.1016\/j.preteyeres.2019.100804","article-title":"Contact lens-related corneal infection: Intrinsic resistance and its compromise","volume":"76","author":"Fleiszig","year":"2020","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"O\u2019Callaghan, R.J. (2018). The Pathogenesis of Staphylococcus aureus Eye Infections. Pathogens, 7.","DOI":"10.3390\/pathogens7010009"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2003.10.002","article-title":"Corneal response to Pseudomonas aeruginosa infection","volume":"23","author":"Hazlett","year":"2004","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1097\/ICO.0b013e3181f2d578","article-title":"Commanding roles of keratocytes in health and disease","volume":"29","author":"Nishida","year":"2010","journal-title":"Cornea"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fukuda, K., Ishida, W., Fukushima, A., and Nishida, T. (2017). Corneal Fibroblasts as Sentinel Cells and Local Immune Modulators in Infectious Keratitis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091831"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108229","DOI":"10.1016\/j.exer.2020.108229","article-title":"Corneal fibroblasts: Function and markers","volume":"200","author":"Fukuda","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_37","unstructured":"Dartt, D.A. (2010). Inflammation of the conjunctiva. Encyclopedia of the Eye, Academic Press."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s10384-017-0528-7","article-title":"Cytokine expression and barrier disruption in human corneal epithelial cells induced by alarmin released from necrotic cells","volume":"61","author":"Fukuda","year":"2017","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1167\/iovs.08-2606","article-title":"Interleukin-1beta-induced disruption of barrier function in cultured human corneal epithelial cells","volume":"50","author":"Kimura","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1167\/iovs.07-0419","article-title":"Delayed Disruption of Barrier Function in Cultured Human Corneal Epithelial Cells Induced by Tumor Necrosis Factor-\u03b1 in a Manner Dependent on NF-\u03baB","volume":"49","author":"Kimura","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2174\/156652406776894572","article-title":"Toll-like receptors and corneal innate immunity","volume":"6","author":"Kumar","year":"2006","journal-title":"Curr. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.bbrc.2009.08.062","article-title":"Toll-like receptors and innate immunity","volume":"388","author":"Kumar","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1042\/CS20100425","article-title":"Toll-like receptors in ocular surface diseases: Overview and new findings","volume":"120","author":"Lambiase","year":"2011","journal-title":"Clin. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s10384-009-0787-z","article-title":"Levels of soluble CD14 and lipopolysaccharide-binding protein in human basal tears","volume":"54","author":"Fukuda","year":"2010","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3095","DOI":"10.1167\/iovs.04-1365","article-title":"Potentiation of lipopolysaccharide-induced chemokine and adhesion molecule expression in corneal fibroblasts by soluble CD14 or LPS-binding protein","volume":"46","author":"Fukuda","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1167\/iovs.04-0922","article-title":"Lipopolysaccharide-induced expression of intercellular adhesion molecule-1 and chemokines in cultured human corneal fibroblasts","volume":"46","author":"Kumagai","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1167\/iovs.06-0319","article-title":"Inhibition by triptolide of chemokine, proinflammatory cytokine, and adhesion molecule expression induced by lipopolysaccharide in corneal fibroblasts","volume":"47","author":"Lu","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Livingston, E.T., Mursalin, M.H., and Callegan, M.C. (2019). A Pyrrhic Victory: The PMN Response to Ocular Bacterial Infections. Microorganisms, 7.","DOI":"10.3390\/microorganisms7110537"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1097\/00003226-199309000-00009","article-title":"Regulation of corneal fibroblast MMP-1 collagenase secretion by plasmin","volume":"12","author":"Berman","year":"1993","journal-title":"Cornea"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1007\/PL00007449","article-title":"Proteolytic mechanisms in corneal ulceration and repair","volume":"290","author":"Fini","year":"1998","journal-title":"Arch. Dermatol. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1097\/ICO.0000000000000995","article-title":"Regulatory Mechanism of Collagen Degradation by Keratocytes and Corneal Inflammation: The Role of Urokinase-Type Plasminogen Activator","volume":"35","author":"Sugioka","year":"2016","journal-title":"Cornea"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1189\/jlb.0801757","article-title":"Enhancement by neutrophils of collagen degradation by corneal fibroblasts","volume":"74","author":"Li","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"ref_53","first-page":"1887","article-title":"The network structure of corneal fibroblasts in the rat as revealed by scanning electron microscopy","volume":"29","author":"Nishida","year":"1988","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/BF00215533","article-title":"Electron-microscopic studies on the presence of gap junctions between corneal fibroblasts in rabbits","volume":"249","author":"Ueda","year":"1987","journal-title":"Cell Tissue Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1007\/BF02620874","article-title":"Interactions of extracellular collagen and corneal fibroblasts: Morphologic and biochemical changes of rabbit corneal cells cultured in a collagen matrix","volume":"24","author":"Nishida","year":"1988","journal-title":"In Vitro Cell. Dev. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1167\/iovs.16-20685","article-title":"Extracellular Collagen Promotes Interleukin-1beta-Induced Urokinase-Type Plasminogen Activator Production by Human Corneal Fibroblasts","volume":"58","author":"Sugioka","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1189\/jlb.0209098","article-title":"Integrin-mediated inhibition of interleukin-8 secretion from human neutrophils by collagen type I","volume":"87","author":"Quan","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0021-5155(97)00115-9","article-title":"Collagenolytic activity of keratocytes cultured in a collagen matrix","volume":"42","author":"Mishima","year":"1998","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1006\/exer.1999.0755","article-title":"Effect of galardin on collagen degradation by Pseudomonas aeruginosa","volume":"69","author":"Hao","year":"1999","journal-title":"Exp. Eye Res."},{"key":"ref_60","first-page":"84","article-title":"Increased lysosomal enzyme activity of keratocytes after endocytosis of foreign particles","volume":"36","author":"Mishima","year":"1992","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1016\/j.celrep.2017.12.011","article-title":"Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake","volume":"21","author":"Madsen","year":"2017","journal-title":"Cell Rep."},{"key":"ref_62","unstructured":"Kaufman, H.E., Barron, B.A., McDonald, M.B., and Waltman, S.R. (1988). Bacterial and fungal keratitis. The Cornea, Churchill Livingstone."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6098","DOI":"10.1128\/AEM.00883-15","article-title":"Diversity, Structures, and Collagen-Degrading Mechanisms of Bacterial Collagenolytic Proteases","volume":"81","author":"Zhang","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3109\/1040841X.2014.904270","article-title":"Bacterial collagenases\u2014A review","volume":"42","author":"Duarte","year":"2016","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S94","DOI":"10.1093\/infdis\/130.Supplement.S94","article-title":"Extracellular toxins of Pseudomonas aeruginosa","volume":"130","author":"Liu","year":"1974","journal-title":"J. Infect. Dis."},{"key":"ref_66","first-page":"507","article-title":"The immune system in experimental Pseudomonas keratitis. Model and early effects","volume":"27","author":"Twining","year":"1986","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1099\/mic.0.044503-0","article-title":"Degradation of fibrinogen and collagen by staphopains, cysteine proteases released from Staphylococcus aureus","volume":"157","author":"Ohbayashi","year":"2011","journal-title":"Microbiology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5098","DOI":"10.1167\/iovs.18-24925","article-title":"Plasminogen-Dependent Collagenolytic Properties of Staphylococcus aureus in Collagen Gel Cultures of Human Corneal Fibroblasts","volume":"59","author":"Sugioka","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1183\/09031936.00146510","article-title":"Series \u201cmatrix metalloproteinases in lung health and disease\u201d: Biological role of matrix metalloproteinases: A critical balance","volume":"38","author":"Loffek","year":"2011","journal-title":"Eur. Respir. J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3109\/14756366.2016.1161620","article-title":"Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs","volume":"31","author":"Matejczyk","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s40139-018-0162-1","article-title":"Alerting the body to tissue injury: The role of alarmins and DAMPs in cutaneous wound healing","volume":"6","author":"Wilgus","year":"2018","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s10384-017-0541-x","article-title":"The expression of matrix metalloproteinases and their inhibitors in corneal fibroblasts by alarmins from necrotic corneal epithelial cells","volume":"62","author":"Iwatake","year":"2018","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.job.2020.07.003","article-title":"Role of interleukin-1 and inflammasomes in oral disease","volume":"62","author":"Murakami","year":"2020","journal-title":"J. Oral Biosci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Kitanaka, N., Nakano, R., Sakai, M., Kitanaka, T., Namba, S., Konno, T., Nakayama, T., and Sugiya, H. (2019). ERK1\/ATF-2 signaling axis contributes to interleukin-1beta-induced MMP-3 expression in dermal fibroblasts. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0222869"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"39513","DOI":"10.1074\/jbc.M405844200","article-title":"Differential regulation of matrix metalloproteinase-2 and -9 expression and activity in adult rat cardiac fibroblasts in response to interleukin-1beta","volume":"279","author":"Xie","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_76","first-page":"583","article-title":"Effects and relationship of ERK1 and ERK2 in interleukin-1beta-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes","volume":"27","author":"Wang","year":"2011","journal-title":"Int. J. Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3524759","DOI":"10.1155\/2018\/3524759","article-title":"IL-1beta-Induced Matrix Metalloprotease-1 Promotes Mesenchymal Stem Cell Migration via PAR1 and G-Protein-Coupled Signaling Pathway","volume":"2018","author":"Chen","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11291","DOI":"10.1016\/S0021-9258(19)78124-1","article-title":"Interleukin 1 alpha mediates collagenase synthesis stimulated by phorbol 12-myristate 13-acetate","volume":"269","author":"Fini","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1006\/exer.1998.0637","article-title":"Galardin inhibits collagen degradation by rabbit keratocytes by inhibiting the activation of pro-matrix metalloproteinases","volume":"68","author":"Hao","year":"1999","journal-title":"Exp. Eye Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"C867","DOI":"10.1152\/ajpcell.00161.2006","article-title":"Interleukin-1beta increases expression and activity of matrix metalloproteinase-2 in cardiac microvascular endothelial cells: Role of PKCalpha\/beta1 and MAPKs","volume":"292","author":"Mountain","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/jcp.20992","article-title":"Interleukin-1beta induces MMP-9 expression via p42\/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells","volume":"211","author":"Liang","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1167\/iovs.03-0476","article-title":"Inhibition by triptolide of IL-1-induced collagen degradation by corneal fibroblasts","volume":"44","author":"Lu","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6576","DOI":"10.4049\/jimmunol.164.12.6576","article-title":"Prolonged elevation of IL-1 in Pseudomonas aeruginosa ocular infection regulates macrophage-inflammatory protein-2 production, polymorphonuclear neutrophil persistence, and corneal perforation","volume":"164","author":"Rudner","year":"2000","journal-title":"J. Immunol."},{"key":"ref_84","first-page":"1107","article-title":"Aged mice fail to upregulate ICAM-1 after Pseudomonas aeruginosa corneal infection","volume":"36","author":"Hobden","year":"1995","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.exer.2010.08.007","article-title":"ICAM-1 mediates surface contact between neutrophils and keratocytes following corneal epithelial abrasion in the mouse","volume":"91","author":"Gagen","year":"2010","journal-title":"Exp. Eye Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.4049\/jimmunol.0902023","article-title":"Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression","volume":"184","author":"Ren","year":"2010","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1167\/iovs.10-5459","article-title":"Lipopolysaccharide regulation of toll-like receptor-4 and matrix metalloprotease-9 in human primary corneal fibroblasts","volume":"52","author":"Wong","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4910","DOI":"10.1167\/iovs.06-0537","article-title":"TLR4 is required for host resistance in Pseudomonas aeruginosa keratitis","volume":"47","author":"Huang","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1006\/exer.1996.0190","article-title":"Lipopolysaccharide induced acute red eye and corneal ulcers","volume":"64","author":"Schultz","year":"1997","journal-title":"Exp. Eye Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1093\/clind\/15.5.840","article-title":"Antibiotic-induced release of endotoxin: A reappraisal","volume":"15","author":"Hurley","year":"1992","journal-title":"Clin. Infect. Dis."},{"key":"ref_91","first-page":"1110","article-title":"Citrate or ascorbate\/citrate treatment of established corneal ulcers in the alkali-injured rabbit eye","volume":"29","author":"Pfister","year":"1988","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1128\/AAC.34.11.2065","article-title":"Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide","volume":"34","author":"Burns","year":"1990","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_93","first-page":"107","article-title":"Inhibition of alkali-induced corneal ulceration and perforation by a thiol peptide","volume":"31","author":"Burns","year":"1990","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1001\/archopht.1970.00990030352013","article-title":"Collagenase inhibitors in prevention of ulcers of alkali-burned cornea","volume":"83","author":"Brown","year":"1970","journal-title":"Arch. Ophthalmol."},{"key":"ref_95","first-page":"2174","article-title":"Effect of a metalloproteinase inhibitor on established corneal ulcers after an alkali burn","volume":"33","author":"Wentworth","year":"1992","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.cvsm.2003.12.005","article-title":"Matrix metalloproteinase inhibition in corneal ulceration","volume":"34","author":"Brooks","year":"2004","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1167\/iovs.04-0299","article-title":"Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells","volume":"45","author":"Li","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1167\/iovs.02-0874","article-title":"Regulated expression of collagenases MMP-1, -8, and -13 and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells","volume":"44","author":"Li","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1001\/archopht.1987.01060020122043","article-title":"Systemic tetracycline treatment of alkali-induced corneal ulceration in rabbits","volume":"105","author":"Seedor","year":"1987","journal-title":"Arch. Ophthalmol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0002-9394(01)00913-8","article-title":"Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids","volume":"132","author":"Dursun","year":"2001","journal-title":"Am. J. Ophthalmol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1097\/01.icl.0000086490.38331.58","article-title":"Doxycycline in the management of pseudomonas corneal melting: Two case reports and a review of the literature","volume":"29","author":"McElvanney","year":"2003","journal-title":"Eye Contact Lens"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jtos.2015.11.006","article-title":"Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye","volume":"14","author":"Bian","year":"2016","journal-title":"Ocul. Surf."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1001\/archophthalmol.2008.504","article-title":"Rationale for adjunctive topical corticosteroids in bacterial keratitis","volume":"127","author":"Hindman","year":"2009","journal-title":"Arch. Ophthalmol."},{"key":"ref_104","first-page":"3415","article-title":"Inhibition by female sex hormones of collagen degradation by corneal fibroblasts","volume":"17","author":"Zhou","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1167\/iovs.11-8822","article-title":"Inhibition by medroxyprogesterone acetate of interleukin-1beta-induced collagen degradation by corneal fibroblasts","volume":"53","author":"Zhou","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1001\/archophthalmol.2009.221","article-title":"The steroid controversy in bacterial keratitis","volume":"127","author":"Acharya","year":"2009","journal-title":"Arch. Ophthalmol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1136\/bjophthalmol-2015-307955","article-title":"Corticosteroids as a therapy for bacterial keratitis: An evidence-based review of \u2018who, when and why\u2019","volume":"100","author":"Tallab","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1001\/archophthalmol.2011.315","article-title":"Corticosteroids for bacterial keratitis: The Steroids for Corneal Ulcers Trial (SCUT)","volume":"130","author":"Srinivasan","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1167\/iovs.19-27306","article-title":"Inhibition by Epigallocatechin Gallate of IL-1-Induced Urokinase-Type Plasminogen Activator Expression and Collagen Degradation by Corneal Fibroblasts","volume":"60","author":"Sugioka","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.2147\/OPTH.S253750","article-title":"Self-Retained Cryopreserved Amniotic Membrane for the Management of Corneal Ulcers","volume":"14","author":"Brocks","year":"2020","journal-title":"Clin. Ophthalmol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1097\/ICO.0b013e3181a2abad","article-title":"Sutureless amniotic membrane transplantation for severe bacterial keratitis","volume":"28","author":"Sheha","year":"2009","journal-title":"Cornea"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8979\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:47:56Z","timestamp":1760165276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,20]]},"references-count":111,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168979"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168979","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,20]]}}}