Purpose: To study the association between different types of mediators in the tear fluid and topographic indices characterizing the severity of keratoconus (KC). Methods: In this study, nonstimulated tear fluid samples were collected from 14 eyes of 11 patients with KC. The following indices were measured by corneal topography: maximum K value, average K value, Klyce/Maeda keratoconus index (KCI), Smolek/Klyce keratoconus severity index, opposite sector index, center/surround index, keratoconus prediction index and standard deviation of corneal power. The concentrations of interleukin (IL)-6, IL-13, CXCL8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5, regulated and normal T cell expressed and secreted), matrix metalloproteinase-9 (MMP-9), MMP-13, tissue inhibitor of metalloproteinase-1, nerve growth factor (NGF) and epidermal growth factor were measured by cytometric bead array technology. Release of mediators was calculated from their concentrations and the volume of tears collected over 2 min. Results: Significant positive associations were found between CCL5, MMP-13 and NGF and several topographic indices. Significant negative correlations were found between IL-6 and KCI. Age-dependent associations were observed between IL-13, CXCL8, CCL5 and MMP-13 and the topographic data. Conclusion: Several correlations were observed between the mediators and the topographic indices, suggesting possible roles in the pathophysiology of KC. Our data indicate that some mediators have different effects on the severity of disease in an age-dependent manner.

Keywords:
Keratoconus, Mediators, Tears, Topographic indices
1.
Krachmer JH, Eagle RC, Belin MW: Keratoconus and related non-inflammatory corneal thinning disorders. Surv Ophthalmol 1984;28:293-322.
2.
Rabinowitz YS: Keratoconus. Surv Ophthalmol 1998;42:297-319.
3.
Jun AS, Cope L, Speck C, et al: Subnormal cytokine profile in the tear fluid of keratoconus patients. PLoS One 2011;6:e16437.
4.
Balasubramanian SA, Mohan S, Pye DC, Willcox MD: Proteases, proteolysis and inflammatory molecules in the tears of people with keratoconus. Acta Ophthalmol 2012;90:e303-e309.
5.
Kao WW, Vergnes JP, Ebert J, Sundar-Raj CV, Brown SI: Increased collagenase and gelatinase activities in keratoconus. Biochem Biophys Res Commun 1982;107:929-936.
6.
Kenney MC, Chwa M, Atilano SR, et al: Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder. Invest Ophthalmol Vis Sci 2005;46:823-832.
7.
Lema I, Sobrino T, Durán JA, Brea D, Díez-Feijoo E: Subclinical keratoconus and inflammatory molecules from tears. Br J Ophthalmol 2009;93:820-824.
8.
Lambiase A, Merlo D, Mollinari C, et al: Molecular basis for keratoconus: lack of TrkA expression and its transcriptional repression by Sp3. Proc Natl Acad Sci USA 2005;102:16795-16800.
9.
Abalin JH, Dossou H, Colin J, Floch HH: Levels of collagen degradation products (telopeptides) in the tear film of patients with keratoconus. Cornea 2000;19:474-476.
10.
Maier P, Broszinski A, Heizmann U, Böhringer D, Reinhard T: Active transforming growth factor-β2 is increased in the aqueous humor of keratoconus patients. Mol Vis 2007;13:1198-1202.
11.
Zhou L, Sawaguchi S, Twining SS, Sugar J, Feder RS, Yue BY: Expression of degradative enzymes and protease inhibitors in corneas with keratoconus. Invest Ophthalmol Vis Sci 1998;39:1117-1124.
12.
Mackiewicz Z, Määttä M, Stenman M, Konttinen L, Tervo T, Konttinen YT: Collagenolytic proteinases in keratoconus. Cornea 2006;25:603-610, erratum in Cornea 2006;25:760.
13.
Balasubramanian SA, Pye DC, Willcox MD: Are proteinases the reason for keratoconus? Current Eye Research 2010;35:185-191.
14.
Lema I, Durán JA: Inflammatory molecules in the tears of patients with keratoconus. Ophthalmology 2005;112:654-659.
15.
Pannebaker C, Chandler HL, Nichols JJ: Tear proteomics in keratoconus. Mol Vis 2010;16:1949-1957.
16.
Smolek MK, Klyce SD: Current keratoconus detection methods compared with a neural network approach. Invest Ophthalmol Vis Sci 1997;38:2290-2299.
17.
Maeda N, Klyce SD, Smolek MK, Thompson HW: Automated keratoconus screening with corneal topography analysis. Invest Ophthalmol Vis Sci 1994;35:2749-2757.
18.
Lee HK, Lee KS, Kim HC, Lee SH, Kim EK: Nerve growth factor concentration and implications in photorefractive keratectomy vs laser in situ keratomileusis. Am J Ophthalmol 2005;139:965-971.
19.
Lema I, Durán JA, Ruiz C, Díez-Feijoo E, Acera A, Merayo J: Inflammatory response to contact lenses in patients with keratoconus compared with myopic subjects. Cornea 2008;27:758-763.
20.
Fodor M, Gogolák P, Rajnavölgyi É, et al: Long-term kinetics of cytokine responses in human tears after penetrating keratoplasty. J Interferon Cytokine Res 2009;29:375-380.
21.
Smith VA, Matthews FJ, Majid MA, Cook SD: Keratoconus: matrix metalloproteinase-2 activation and TIMP modulation. Biochim Biophys Acta 2006;1762:431-439.
22.
Collier SA: Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin Experiment Ophthalmol 2001;29:340-344.
23.
Matthews FJ, Cook SD, Majid MA, Dick AD, Smith VA: Changes in the balance of the tissue inhibitor of matrix metalloproteinases (TIMPs)-1 and -3 may promote keratocyte apoptosis in keratoconus. Exp Eye Res 2007;84:1125-1134.
24.
Lambiase A, Micera A, Sacchetti M, Cortes M, Mantelli F, Bonini S: Alterations of tear neuromediators in dry eye disease. Arch Ophthalmol 2011;129:981-986.
25.
Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L: Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000;107:1347-1351.
26.
Brookes NH, Loh IP, Clover GM, Poole CA, Sherwin T: Involvement of corneal nerves in the progression of keratoconus. Exp Eye Res 2003;77:515-524.
27.
Niederer RL, Perumal D, Sherwin T, McGhee CN: Laser scanning in vivo confocal microscopy reveals reduced innervation and reduction in cell density in all layers of the keratoconic cornea. Invest Ophthalmol Vis Sci 2008;49:2964-2970.
28.
Saghizadeh M, Chwa M, Aoki A, et al: Altered expression of growth factors and cytokines in keratoconus, bullous keratopathy and diabetic human corneas. Exp Eye Res 2001;73:179-189.
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2013
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