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Original Articles

Pathophysiology of Corneal Endothelial Cell Loss in Dry Eye Disease and Other Inflammatory Ocular Disorders

, , BScORCID Icon, , MD, PhD, FRCSC & , MD, PhD, FRCSC
Pages 21-31 | Received 11 Jan 2021, Accepted 09 Sep 2021, Published online: 22 Oct 2021

References

  • Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017;15(3):334–365.
  • Calonge M, Enríquez-de-salamanca A, Diebold Y, et al. Dry eye disease as an inflammatory disorder. Ocul Immunol Inflamm. 2010;18(4):244–253.doi:10.3109/09273941003721926.
  • Chia E, Mitchell P, Rochtchina E, Lee AJ, Maroun R, Wang JJ. Prevalence and associations of dry eye syndrome in an older population: the blue mountains eye study. Clin Exp Ophthalmol. 2003;31(3):229–232. doi:10.1046/j.1442-9071.2003.00634.x
  • Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol. 2000;118(9):1264–1268. doi:10.1001/archopht.118.9.1264.
  • Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136(2):318–326. doi:10.1016/s0002-9394(03)00218-6.
  • Pflugfelder SC, de Paiva CS. The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology. 2017;124(11S):S4–S13.
  • Wan KH, Chen LJ, Young AL. Depression and anxiety in dry eye disease: a systematic review and meta-analysis. Eye. 2016;30(12):1558–1567. doi:10.1038/eye.2016.186.
  • McDonald M, Patel DA, Keith MS, Snedecor SJ. Economic and humanistic burden of dry eye disease in europe, north america, and asia: a systematic literature review. Ocul Surf. 2016;14(2):144–167.
  • Clayton JA. Dry eye. N Engl J Med. 2018;378(23):2212–2223. doi:10.1056/NEJMra1407936.
  • Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130(1):90–100. doi:10.1001/archophthalmol.2011.364.
  • Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32(1):19–41. doi:10.3109/08830185.2012.748052.
  • Kheirkhah A, Saboo US, Abud TB, et al. Reduced corneal endothelial cell density in patients with dry eye disease. Am J Ophthalmol. 2015;159(6):1022–1026.e2.doi:10.1016/j.ajo.2015.03.011.
  • Kheirkhah A, Satitpitakul V, Hamrah P, Dana R. Patients with dry eye disease and low subbasal nerve density are at high risk for an accelerated corneal endothelial cell loss. Cornea. 2017;36(2):196–201. doi:10.1097/ICO.0000000000001057.
  • Milner MS, Beckman KA, Luchs JI, et al. Ophthalmology. Ophthalmology. 1978;28(Suppl1):3–47.
  • Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571–579. doi:10.2147/OPTH.S45921.
  • He J, Ogawa Y, Mukai S, et al. In vivo confocal microscopy evaluation of ocular surface with graft-versus-host disease-related dry eye disease. Sci Rep. 2017;7(1):1–10.doi:10.1038/s41598-017-10237-w.
  • Pellegrini M, Giannaccare G, Bernabei F, et al. Longitudinal corneal endothelial cell changes in patients undergoing hematopoietic stem cell transplantation. Cornea. 2020. doi:10.1097/ICO.0000000000002441.
  • Kheirkhah A, Qazi Y, Arnoldner MA, Suri K, Dana R. In vivo confocal microscopy in dry eye disease associated with chronic graft-versus-host disease. Invest Ophthalmol Vis Sci. 2016;57(11):4686–4691. doi:10.1167/iovs.16-20013.
  • Steger B, Speicher L, Philipp W, Bechrakis NE. In vivo confocal microscopic characterisation of the cornea in chronic graft-versus-host disease related severe dry eye disease. Br J Ophthalmol. 2015;99(2):160–165. doi:10.1136/bjophthalmol-2014-305072.
  • Villani E, Galimberti D, Viola F, Mapelli C, Ratiglia R. The cornea in sjögren’s syndrome: an in vivo confocal study. Invest Ophthalmol Vis Sci. 2007;48(5):2017–2022. doi:10.1167/iovs.06-1129.
  • Zhang M, Chen J, Luo L, Xiao Q, Sun M, Liu Z. Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy. Cornea. 2005;24(7):818–824. doi:10.1097/01.ico.0000154402.01710.95.
  • Tepelus T, Chiu G, Maram J, et al. Corneal features in ocular graft-versus-host disease by in vivo confocal microscopy. Graefes Arch Clin Exp Ophthalmol. 2017;255(12):2389–2397.doi:10.1007/s00417-017-3759-x.
  • Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of sjögren syndrome. Arch Intern Med. 2004;164(12):1275–1284. doi:10.1001/archinte.164.12.1275.
  • Tuominen ISJ, Konttinen YT, Vesaluoma MH, Moilanen JAO, Helintö M, Tervo TMT. Corneal innervation and morphology in primary sjögren’s syndrome. Invest Ophthalmol Vis Sci. 2003;44(6):2545–2549. doi:10.1167/iovs.02-1260.
  • Castillo JM, Benítez del WMAS, Fernandez C, Garcia-Sanchez J. An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci. 2004;45(9):3030–3035. doi:10.1167/iovs.04-0251.
  • Villani E, Mantelli F, Nucci P. In-vivo confocal microscopy of the ocular surface: ocular allergy and dry eye. Curr Opin Allergy Clin Immunol. 2013;13:569–576.
  • Machetta F, Fea AM, Actis AG, De Sanctis U, Dalmasso P, Grignolo FM. In vivo confocal microscopic evaluation of corneal langerhans cells in dry eye patients. Open Ophthalmol J. 2014;8:51.
  • Wakamatsu TH, Sato EA, Matsumoto Y, et al. Conjunctival in vivo confocal scanning laser microscopy in patients with sjögren syndrome. Invest Ophthalmol Vis Sci. 2010;51(1):144–150.
  • Vera LS, Gueudry J, Delcampe A, Roujeau J, Brasseur G, Muraine M. In vivo confocal microscopic evaluation of corneal changes in chronic stevens-johnson syndrome and toxic epidermal necrolysis. Cornea. 2009;28:401–407.
  • Resch MD, Marsovszky L, Németh J, Bocskai M, Kovács L, Balog A. Dry eye and corneal langerhans cells in systemic lupus erythematosus. J Ophthalmol. 2015;2015:543835. doi:10.1155/2015/543835.
  • Marsovszky L, Németh J, Resch MD, et al. Corneal langerhans cell and dry eye examinations in ankylosing spondylitis. Innate Immun. 2014;20(5):471–477.doi:10.1177/1753425913498912.
  • Guthoff RF, Wienss H, Hahnel C, Wree A. Epithelial innervation of human cornea: a three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea. 2005;24(5):608–613.
  • Müller LJ, Vrensen GF, Pels L, Cardozo BN, Willekens B. Architecture of human corneal nerves. Invest Ophthalmol Vis Sci. 1997;38:985–994.
  • Srinivasan S, Lyall DAM. 27 - neurotrophic keratopathy. In: Holland EJ, Mannis MJ, Lee WB eds. Ocular Surface Disease: Cornea, Conjunctiva and Tear Film. London: W.B. Saunders; 2013:205–211. doi:10.1016/B978-1-4557-2876-3.00027-4.
  • Müller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76(5):521–542.
  • Marfurt C, Anokwute MC, Fetcko K, et al. Comparative anatomy of the mammalian corneal subbasal nerve plexus. Invest Ophthalmol Vis Sci. 2019;60(15):4972–4984.doi:10.1167/iovs.19-28519.
  • Guerrero-Moreno A, Baudouin C, Melik Parsadaniantz S, Réaux-Le Goazigo A. Morphological and functional changes of corneal nerves and their contribution to peripheral and central sensory abnormalities. Front Cell Neurosci. 2020;14:436. doi:10.3389/fncel.2020.610342.
  • Belmonte C, Nichols JJ, Cox SM, et al. TFOS DEWS II pain and sensation report. Ocul Surf. 2017;15(3):404–437.
  • Parra A, Madrid R, Echevarria D, et al. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med. 2010;16(12):1396–1399.doi:10.1038/nm.2264.
  • Koh SW, Guo Y, Bernstein SL, Waschek JA, Liu X, Symes AJ. Vasoactive intestinal peptide induction by ciliary neurotrophic factor in donor human corneal endothelium in situ. Neurosci Lett. 2007;423(2):89–94.
  • Brenneman DE. Neuroprotection: a comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Peptides. 2007;28(9):1720–1726.
  • Moody TW, Ito T, Osefo N, Jensen RT. VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Curr Opin Endocrinol Diabetes Obes. 2011;18(1):61–67. doi:10.1097/MED.0b013e328342568a.
  • Lambiase A, Micera A, Sacchetti M, Cortes M, Mantelli F, Bonini S. Alterations of tear neuromediators in dry eye disease. Arch Ophthalmol. 2011;129(8):981–986. doi:10.1001/archophthalmol.2011.200.
  • Yoon HJ, Li L, Li Y, Jin R, You I, Kc Y. Tear neuromediators according to the ocular sensitivity in patients with dry eye and normal participants. Invest Ophthalmol Vis Sci. 2020;61:158.
  • Koh SM, Waschek JA. Corneal endothelial cell survival in organ cultures under acute oxidative stress: effect of VIP. Invest Ophthalmol Vis Sci. 2000;41:4085–4092.
  • Koh SM, Yue BY. VIP stimulation of cAMP production in corneal endothelial cells in tissue and organ cultures. Cornea. 2002;21:270–274.
  • Koh SW, Cheng J, Dodson RM, Ku CY, Abbondandolo CJ. VIP down-regulates the inflammatory potential and promotes survival of dying (neural crest-derived) corneal endothelial cells ex vivo: necrosis to apoptosis switch and up-regulation of bcl-2 and N-cadherin. J Neurochem. 2009;109(3):792–806. doi:10.1111/j.1471-4159.2009.06012.x.
  • Koh SW, Chandrasekara K, Abbondandolo CJ, Coll TJ, Rutzen AR. VIP and VIP gene silencing modulation of differentiation marker N-cadherin and cell shape of corneal endothelium in human corneas ex vivo. Invest Ophthalmol Vis Sci. 2008;49(8):3491–3498. doi:10.1167/iovs.07-1543.
  • Koh SM, Coll T, Gloria D, Sprehe N. Corneal endothelial cell integrity in precut human donor corneas enhanced by autocrine vasoactive intestinal peptide. Cornea. 2017;36(4):476–483. doi:10.1097/ICO.0000000000001136.
  • Koh SW, Gloria D, Molloy J. Corneal endothelial autocrine VIP enhances its integrity in stored human donor corneoscleral explant. Invest Ophthalmol Vis Sci. 2011;52(8):5632–5640. doi:10.1167/iovs.10-5983.
  • Satitpitakul V, Sun Z, Suri K, et al. Vasoactive intestinal peptide promotes corneal allograft survival. Am J Pathol. 2018;188(9):2016–2024.doi:10.1016/j.ajpath.2018.05.010.
  • Santavirta N, Konttinen YT, Törnwall J, et al. Neuropeptides of the autonomic nervous system in sjögren’s syndrome. Ann Rheum Dis. 1997;56(12):737–740.doi:10.1136/ard.56.12.737.
  • de Paiva CS, Pflugfelder SC. Mechanisms of disease in sjögren syndrome-new developments and directions. Int J Mol Sci. 2020;21(2):650. doi:10.3390/ijms21020650.
  • Waring GOIII, Bourne WM, Edelhauser HF, Kenyon KR. The corneal endothelium: normal and pathologic structure and function. Ophthalmology. 1982;89:531–590.
  • Walkenbach RJ, Ye G, Boney F, Dueker DK. Muscarinic cholinoceptors in native and cultured human corneal endothelium. Curr Eye Res. 1993;12:155–162.
  • Grueb M, Reinthal E, Rohrbach JM, Bartz-Schmidt K. Muscarinic acetylcholine receptor subtypes in human corneal epithelium and endothelium. Graefes Arch Clin Exp Ophthalmol. 2006;244(9):1191–1195. doi:10.1007/s00417-006-0263-0.
  • Sarkar J, Chaudhary S, Namavari A, et al. Corneal neurotoxicity due to topical benzalkonium chloride. Invest Ophthalmol Vis Sci. 2012;53(4):1792–1802.doi:10.1167/iovs.11-8775.
  • Guzmán M, Miglio M, Keitelman I, et al. Transient tear hyperosmolarity disrupts the neuroimmune homeostasis of the ocular surface and facilitates dry eye onset. Immunology. 2020;161(2):148–161.doi:10.1111/imm.13243.
  • Joubert F, Acosta MDC, Gallar J, et al. Effects of corneal injury on ciliary nerve fibre activity and corneal nociception in mice: a behavioural and electrophysiological study. Eur J Pain. 2019;23(3):589–602.doi:10.1002/ejp.1332.
  • Kovács I, Luna C, Quirce S, et al. Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease. Pain. 2016;157:2.
  • Fakih D, Zhao Z, Nicolle P, et al. Chronic dry eye induced corneal hypersensitivity, neuroinflammatory responses, and synaptic plasticity in the mouse trigeminal brainstem. J Neuroinflammation. 2019;16(1):268.doi:10.1186/s12974-019-1656-4.
  • Ishida N, Rao GN, del Cerro M, Aquavella JV. Corneal nerve alterations in diabetes mellitus. Arch Ophthalmol. 1984;102:1380–1384.
  • Hamrah P, Cruzat A, Dastjerdi MH, et al. Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology. 2010; 117(10):1930–1936. doi:10.1016/j.ophtha.2010.07.010.
  • Zheng X, Shiraishi A, Okuma S, et al. In vivo confocal microscopic evidence of keratopathy in patients with pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci. 2011; 52(3):1755–1761. doi:10.1167/iovs.10-6098.
  • Ahuja Y, Baratz KH, McLaren JW, Bourne WM, Patel SV. Decreased corneal sensitivity and abnormal corneal nerves in fuchs endothelial dystrophy. Cornea. 2012;31(11):1257–1263. doi:10.1097/ICO.0b013e31823f7888.
  • Al-Aqaba M, Alomar T, Lowe J, Dua HS. Corneal nerve aberrations in bullous keratopathy. Am J Ophthalmol. 2011;151(5):840–849.e1. doi:10.1016/j.ajo.2010.11.013.
  • Aggarwal S, Cavalcanti BM, Regali L. et al. In vivo confocal microscopy shows alterations in nerve density and dendritiform cell density in fuchs’ endothelial corneal dystrophy. Am J Ophthalmol. 2018;196:136–144. doi:10.1016/j.ajo.2018.08.040.
  • Alomar TS, Al-Aqaba M, Gray T, Lowe J, Dua HS. Histological and confocal microscopy changes in chronic corneal edema: implications for endothelial transplantation. Invest Ophthalmol Vis Sci. 2011;52(11):8193–8207. doi:10.1167/iovs.11-8047.
  • Bucher F, Adler W, Lehmann HC, et al. Corneal nerve alterations in different stages of fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study. Graefes Arch Clin Exp Ophthalmol. 2014;252(7):1119–1126.doi:10.1007/s00417-014-2678-3.
  • Mustonen RK, McDonald MB, Srivannaboon S, Tan AL, Doubrava MW, Kim CK. In vivo confocal microscopy of fuchs’ endothelial dystrophy. Cornea. 1998;17(5):493–503.
  • Rowland FN, Donovan MJ, Lindsay M, Weiss WI, O’rourke J, Kreutzer DL. Demonstration of inflammatory mediator-induced inflammation and endothelial cell damage in the anterior segment of the eye. Am J Pathol. 1983;110:1.
  • Jurkunas UV, Bitar MS, Funaki T, Azizi B. Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy. Am J Pathol. 2010;177(5):2278–2289. doi:10.2353/ajpath.2010.100279.
  • Hu J, Kovtun A, Tomaszewski A, et al. A new tool for the transfection of corneal endothelial cells: calcium phosphate nanoparticles. Acta Biomater. 2012;8(3):1156–1163.doi:10.1016/j.actbio.2011.09.013.
  • Leonardi A, Modugno RL, Salami E. Allergy and dry eye disease. Ocul Immunol Inflamm. 2021;1–9. doi:10.1080/09273948.2020.1841804.
  • Schaumburg CS, Siemasko KF, De Paiva CS, et al. Ocular surface APCs are necessary for autoreactive T cell-mediated experimental autoimmune lacrimal keratoconjunctivitis. J Immunol. 2011; 187(7):3653–3662. doi:10.4049/jimmunol.1101442.
  • Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in aqueous tear–deficient dry eye. Invest Ophthalmol Vis Sci. 2010;51(1):122–128.
  • Kheirkhah A, Darabad RR, Cruzat A, et al. Corneal epithelial immune dendritic cell alterations in subtypes of dry eye disease: a pilot in vivo confocal microscopic study. Invest Ophthalmol Vis Sci. 2015;56(12):7179–7185.doi:10.1167/iovs.15-17433.
  • Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252. doi:10.1038/32588.
  • Kheirkhah A, Saboo US, Abud TB, et al. Reduced corneal endothelial cell density in patients with dry eye disease. Am J Ophthalmol. 2015; 159(6):1022–1026.e2. doi:10.1016/j.ajo.2015.03.011.
  • Willrodt A, Salabarria A, Schineis P, et al. ALCAM mediates DC migration through afferent lymphatics and promotes allospecific immune reactions. Front Immunol. 2019;10:759.
  • Elgebaly SA, Forouhar F, Gillies C, Williams S, O’Rourke J, Kreutzer DL. Leukocyte-mediated injury to corneal endothelial cells. A model of tissue injury. Am J Pathol. 1984;116:407–416.
  • Matsumoto Y, Ibrahim OMA, Kojima T, Dogru M, Shimazaki J, Tsubota K. Corneal in vivo laser-scanning confocal microscopy findings in dry eye patients with sjögren’s syndrome. Diagnostics. 2020;10:7. doi:10.3390/diagnostics10070497.
  • Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in aqueous Tear–Deficient dry eye. Invest Ophthalmol Vis Sci. 2010;51(1):122–128.doi:10.1167/iovs.09-3629.
  • Wakamatsu TH, Sato EA, Matsumoto Y, et al. Conjunctival in vivo confocal scanning laser microscopy in patients with sjögren syndrome. Invest Ophthalmol Vis Sci. 2010;51(1):144–150.doi:10.1167/iovs.08-2722.
  • Villani E, Magnani F, Viola F, et al. In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye. Optom Vis Sci. 2013;90(6):576–586.doi:10.1097/OPX.0b013e318294c184.
  • Kobayashi Y, Matsumoto M, Kotani M, Makino T. Possible involvement of matrix metalloproteinase-9 in langerhans cell migration and maturation. J Immunol. 1999;163:5989.
  • Dekaris I, Zhu S, Dana MRTNF. α regulates corneal langerhans cell migration. J Immunol. 1999;162:4235.
  • Cannon JG. Inflammatory cytokines in nonpathological states. News Physiol Sci. 2000;15:298–303. doi:10.1152/physiologyonline.2000.15.6.298.
  • Sagoo P, Chan G, Larkin DFP, George AJT. Inflammatory cytokines induce apoptosis of corneal endothelium through nitric oxide. Invest Ophthalmol Vis Sci. 2004;45(11):3964–3973. doi:10.1167/iovs.04-0439.
  • Shivanna M, Rajashekhar G, Srinivas SP. Barrier dysfunction of the corneal endothelium in response to TNF-alpha: role of p38 MAP kinase. Invest Ophthalmol Vis Sci. 2010;51(3):1575–1582. doi:10.1167/iovs.09-4343.
  • Eom Y, Kwon J, Heo J. et al. The effects of proinflammatory cytokines on the apoptosis of corneal endothelial cells following argon laser iridotomy. Exp Eye Res. 2016;145:140–147. doi:10.1016/j.exer.2015.11.022.
  • Kim JC, Cheong TB, Park GS, Park MH, Kwon NS, Yoon HY. The role of nitric oxide in ocular surface diseases. Adv Exp Med Biol. 2002;506(PtA):687–695. doi:10.1007/978-1-4615-0717-8_96.
  • Buddi R, Lin B, Atilano SR, Zorapapel NC, Kenney MC, Brown DJ. Evidence of oxidative stress in human corneal diseases. J Histochem Cytochem. 2002;50(3):341–351. doi:10.1177/002215540205000306.
  • Ohta K, Kikuchi T, Arai S, Yoshida N, Sato A, Yoshimura N. Protective role of heme oxygenase-1 against endotoxin-induced uveitis in rats. Exp Eye Res. 2003;77(6):665–673.
  • Yilmaz G, Sizmaz S, Yilmaz ED, Duman S, Aydin P. Aqueous humor nitric oxide levels in patients with behçet disease. Retina. 2002;22(3):330–335. doi:10.1097/00006982-200206000-00012.
  • Keinänen R, Vartiainen N, Koistinaho J. Molecular cloning and characterization of the rat inducible nitric oxide synthase (iNOS) gene. Gene. 1999;234(2):297–305.
  • Dana MR, Yamada J, Streilein JW. Topical interleukin 1 receptor antagonist promotes corneal transplant survival. Transplantation. 1997;63(10):1501–1507. doi:10.1097/00007890-199705270-00022.
  • Rayner SA, King WJ, Comer RM, et al. Local bioactive tumour necrosis factor (TNF) in corneal allotransplantation. Clin Exp Immunol. 2000;122(1):109–116.
  • Enríquez-de-salamanca A, Castellanos E, Stern ME, et al. Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease. Mol Vis. 2010;16:862–873.
  • Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147(2):198–e1. doi:10.1016/j.ajo.2008.08.032.
  • Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001;42(10):2283–2292.
  • Massingale ML, Li X, Vallabhajosyula M, Chen D, Wei Y, Asbell PA. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea. 2009;28(9):1023–1027. doi:10.1097/ICO.0b013e3181a16578.
  • Corrales RM, Villarreal A, Farley W, Stern ME, Li D, Pflugfelder SC. Strain-related cytokine profiles on the murine ocular surface in response to desiccating stress. Cornea. 2007;26(5):579–584. doi:10.1097/ICO.0b013e318033a729.
  • Rashid S, Jin Y, Ecoiffier T, Barabino S, Schaumberg DA, Dana MR. Topical omega-3 and omega-6 fatty acids for treatment of dry eye. Arch Ophthalmol. 2008;126(2):219–225. doi:10.1001/archophthalmol.2007.61.Accessed Nov 16, 2020.
  • Zhu L, Shen J, Zhang C, et al. Inflammatory cytokine expression on the ocular surface in the botulium toxin B induced murine dry eye model. Mol Vis. 2009;15:250–258.
  • Pflugfelder SC, Jones D, Ji Z, Afonso A, Monroy D. Altered cytokine balance in the tear fluid and conjunctiva of patients with sjögren’s syndrome keratoconjunctivitis sicca. Curr Eye Res. 1999;19(3):201–211. doi:10.1076/ceyr.19.3.201.5309.
  • Yoon K, Jeong I, Park Y, Yang S. Interleukin-6 and tumor necrosis factor-alpha levels in tears of patients with dry eye syndrome. Cornea. 2007;26(4):431–437.
  • Jung JW, Han SJ, Song MK, et al. Tear cytokines as biomarkers for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(12):2079–2085.
  • Riemens A, Stoyanova E, Rothova A, Kuiper J. Cytokines in tear fluid of patients with ocular graft-versus-host disease after allogeneic stem cell transplantation. Mol Vis. 2012;18:797–802.
  • Lee SY, Han SJ, Nam SM, et al. Analysis of tear cytokines and clinical correlations in sjögren syndrome dry eye patients and non-sjögren syndrome dry eye patients. Am J Ophthalmol. 2013;156(2):247–253.e1.
  • Kang MH, Kim MK, Lee HJ, Lee HI, Wee WR, Lee JH. Interleukin-17 in various ocular surface inflammatory diseases. J Korean Med Sci. 2011;26(7):938–944. doi:10.3346/jkms.2011.26.7.938.
  • De Paiva CS, Chotikavanich S, Pangelinan SB, et al. IL-17 disrupts corneal barrier following desiccating stress. Mucosal Immunol. 2009;2(3):243–253.doi:10.1038/mi.2009.5.
  • Zheng X, de Paiva CS, Li DQ, Farley WJ, Pflugfelder SC. Desiccating stress promotion of Th17 differentiation by ocular surface tissues through a dendritic cell-mediated pathway. Invest Ophthalmol Vis Sci. 2010;51(6):3083–3091. doi:10.1167/iovs.09-3838.
  • Chauhan SK, Dana R. Role of Th17 cells in the immunopathogenesis of dry eye disease. Mucosal Immunol. 2009;2(4):375–376. doi:10.1038/mi.2009.21.
  • Sugita S, Kawazoe Y, Yamada Y, et al. Inhibitory effect of corneal endothelial cells on IL-17-producing Th17 cells. Br J Ophthalmol. 2012;96(2):293–299.doi:10.1136/bjophthalmol-2011-300769.
  • El Annan J, Goyal S, Zhang Q, Freeman GJ, Sharpe AH, Dana R. Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry Eye–Associated corneal inflammation. Invest Ophthalmol Vis Sci. 2010;51(7):3418–3423. doi:10.1167/iovs.09-3684.
  • Yoon K, De Paiva CS, Qi H, et al. Expression of th-1 chemokines and chemokine receptors on the ocular surface of C57BL/6 mice: effects of desiccating stress. Invest Ophthalmol Vis Sci. 2007; 48(6):2561–2569. Accessed Nov 16, 2020. doi:10.1167/iovs.07-0002.
  • Yoon K, Park C, You I, et al. Expression of CXCL9, −10, −11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. Invest Ophthalmol Vis Sci. 2010;51(2):643–650.doi:10.1167/iovs.09-3425.
  • Cocho L, Fernández I, Calonge M, et al. Biomarkers in ocular chronic graft versus host disease: tear cytokine- and chemokine-based predictive model. Invest Ophthalmol Vis Sci. 2016;57(2):746–758.doi:10.1167/iovs.15-18615.
  • Lahdou I, Engler C, Mehrle S, et al. Role of human corneal endothelial cells in T-Cell–Mediated alloimmune attack in vitro. Invest Ophthalmol Vis Sci. 2014;55(3):1213–1221.doi:10.1167/iovs.13-11930.
  • Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–573. doi:10.1016/j.cardiores.2005.12.002.
  • Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea. 1999;18(4):403–407.
  • Brejchova K, Liskova P, Hrdlickova E, Filipec M, Jirsova K. Matrix metalloproteinases in recurrent corneal melting associated with primary sjörgen’s syndrome. Mol Vis. 2009;15:2364–2372.
  • Acera A, Rocha G, Vecino E, Lema I, Durán JA. Inflammatory markers in the tears of patients with ocular surface disease. Ophthalmic Res. 2008;40(6):315–321. doi:10.1159/000150445.
  • Chotikavanich S, CSd P, Li DQ, et al. Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009;50(7):3203–3209. doi:10.1167/iovs.08–2476.
  • Pflugfelder SC, Farley W, Luo L, et al. Matrix metalloproteinase-9 knockout confers resistance to corneal epithelial barrier disruption in experimental dry eye. Am J Pathol. 2005;166(1):61–71.
  • Arafat SN, Robert MC, Abud T. et al. Elevated neutrophil elastase in tears of ocular graft-versus-host disease patients. Am J Ophthalmol. 2017;176:46–52.
  • Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea. 1999;18(4):403–407.
  • Kook KY, Jin R, Li L, Yoon HJ, Yoon KC. Tear osmolarity and matrix metallopeptidase-9 in dry eye associated with sjögren’s syndrome. Korean J Ophthalmol. 2020;34(3):179–186. doi:10.3341/kjo.2019.0145.
  • Rajashekhar G, Shivanna M, Kompella UB, Wang Y, Srinivas SP. Role of MMP-9 in the breakdown of barrier integrity of the corneal endothelium in response to TNF-α. Exp Eye Res. 2014;122:77–85. doi:10.1016/j.exer.2014.03.004.
  • Zhang J, Dai Y, Wu D, Xu J. Calcitriol, the active metabolite of vitamin D3, inhibits dry eye related corneal inflammation in vivo and in vitro. Ocul Immunol Inflamm. 2019;27(2):257–265. doi:10.1080/09273948.2017.1372486.
  • Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopulations in sjögren’s and non-sjögren’s patients with dry eye. Invest Ophthalmol Vis Sci. 2002;43(8):2609–2614. Accessed Nov 16, 2020.
  • Ogawa Y, Kuwana M, Yamazaki K, et al. Periductal area as the primary site for T-cell activation in lacrimal gland chronic graft-versus-host disease. Invest Ophthalmol Vis Sci. 2003;44(5):1888–1896.doi:10.1167/iovs.02-0699.
  • Tsubota K, Fujihara T, Saito K, Takeuchi T. Conjunctival epithelium expression of HLA-DR in dry eye patients. Ophthalmologica. 1999;213(1):16–19. doi:10.1159/000027387.
  • Yagi-Yaguchi Y, Yamaguchi T, Higa K, et al. Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor. Sci Rep. 2017;7(1):1–8.doi:10.1038/s41598-017-14131-3.
  • Kim JJ, Lee SB, Park JK, Yoo YD. TNF-α-induced ROS production triggering apoptosis is directly linked to Romo1 and bcl-X L. Cell Death & Differentiation. Cell Death and Differentiation. 2010; 17(9):1420–1434.
  • Khan SY, Awad EM, Oszwald A. et al. Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin. Sci Rep. 2017;7:39501. doi:10.1038/srep39501.
  • Hara T, Mahadevan J, Kanekura K, Hara M, Lu S, Urano F. Calcium efflux from the endoplasmic reticulum leads to β-cell death. Endocrinology. 2014;155:758–768.
  • Okumura N, Hashimoto K, Kitahara M, et al. Activation of TGF-β signaling induces cell death via the unfolded protein response in fuchs endothelial corneal dystrophy. Sci Rep. 2017;7(1):6801–6803.doi:10.1038/s41598-017-06924-3.
  • Kharroubi I, Ladrière L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 2004;145:5087–5096.

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