Increased Levels of Diadenosine Polyphosphates in Dry Eye

Thumbnail Image
Full text at PDC
Publication Date
Peral Cerdá, Assumpta
Acosta Boj, Mª Carmen
Gallar Martínez, Juana
Pintor, Jesús
Advisors (or tutors)
Journal Title
Journal ISSN
Volume Title
The Association for Research in Vision and Ophthalmology, Inc.
Google Scholar
Research Projects
Organizational Units
Journal Issue
Purpose. To analyze the levels of the diadenosine polyphosphates Ap4A and Ap5A in tears, in a set of control subjects and in groups of symptomatic and nonsymptomatic persons with dry eye. Methods. Ninety-seven subjects participated in the study. The subjects were divided into five experimental groups: control subjects; symptomatic patients with normal tear secretion; symptomatic patients with low tear secretion; forced blink; and corneal mechanical stimulation provided by a gas esthesiometer. The Schirmer I test was used to measure and collect tear secretions from each subject. All samples were processed by high pressure liquid chromatography (HPLC) and their Ap4A and Ap5A levels determined. Results. The levels of Ap4A and Ap5A in tears were greater in all symptomatic patients than in control subjects, especially in symptomatic subjects with low tear secretion. Within the symptomatic subjects with normal tear secretion, significant differences in concentrations of Ap4A and Ap5A were found between men and women. In the forced blink experiments, concentrations of the Ap4A and Ap5A rose with increasing blink frequency. When the cornea was mechanically stimulated, the levels of Ap4A and Ap5A rose significantly during both moderate and high-flow rate tests. Conclusions. The increased levels of Ap4A and Ap5A in tears of patients with dry eye allow these dinucleotides to be used as objective biomarkers in dry eye conditions.
En Open Access en la web del editor
1. RecordsRE. Tear film.RecordsRE eds. Physiology of the Eye and Visual System. 1979;47–67.Harper & Row Hagerstown, MD. 2. DillyPN. Structure and function of the tear film. Adv Exp Med Biol. 1994;350:239–247. 3. NicholsKK, NicholsJJ, MitchellGL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea. 2004;23:762–770. 4. McCartyCA, BansalAK, LivingstonePM, StanislavskyYL, TaylorHR. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology. 1998;105:1114–1119. 5. ScheinOD, TielschJM, MunozB, Bandeen-RocheK, WestS. Relationship between signs and symptoms of dry eye in the elderly: a population-based perspective. Ophthalmology. 1997;104:1395–1401. 6. LempMA. Epidemiology and classification of dry eye. Adv Exp Med Biol. 1998;438:791–803. 7. LempMA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J. 1995;21:221–232. 8. GrusFH, PodustVN, BrunsK, et al. SELDI-TOF-MS ProteinChip array profiling of tears from patients with dry eye. Invest Ophthalmol Vis Sci. 2005;46:863–876. 9. PintorJ, CarracedoG, AlonsoMC, BautistaA, PeralA. Presence of diadenosine polyphosphates in human tears. Pflügers Arch Eur J Physiol. 2002;443:432–436. 10. McLennanAG. Dinucleoside polyphosphates: friends or foe?. Pharmacol Ther. 2000;87:73–89. 11. HoyleCHV, HildermanR, PintorJJ, SchlüterH, KingBF. Diadenosine polyphosphates as extracellular signal molecules. Drug Dev Res. 2002;52:260–273. 12. PintorJ, PeralA, PeláezT, MartínS, HoyleCHV. Presence of diadenosine polyphosphates in the aqueous humour: their effect on intraocular pressure. J Pharmacol Exp Ther. 2002;304:342–348. 13. PintorJ, BautistaA, CarracedoG, PeralA. UTP and diadenosine tetraphosphate accelerate wound healing in the rabbit cornea. Ophthalmic Physiol Opt. 2004;24:186–193. 14. PintorJ, PeralA, HoyleCHV, et al. Effects of diadenosine polyphosphates on tear secretion in New Zealand white rabbits. J Pharmacol Exp Ther. 2002;300:1–7. 15. McMonniesCW, HoA, WakefieldD. Optimum dry eye classification using questionnaire responses. Adv Exp Med Biol. 1998;438:835–838. 16. SchirmerO. Studien zur Physiologie and Pathologie der Träneab-sonderung und Tränenabfuhr. Graefes Arch Ophthalmol. 1903;56:197–291. 17. BelmonteC, AcostaMC, ShmelzM, GallarJ. Measurements of corneal sensitivity to mechanical and chemical stimuli with a CO2 esthesiometer. Invest Ophthalmol Vis Sci. 1999;40:513–519. 18. AcostaMC, PeralA, LunaC, PintorJ, BelmonteC, GallarJ. Tear secretion induced by selective stimulation of corneal and conjunctival sensory nerve fibers. Invest Ophthalmol Vis Sci. 2004;45:2333–2336. 19. PintorJ, Díaz-ReyMA, TorresM, Miras-PortugalMT. Presence of diadenosine polyphosphates Ap4A and Ap5A in rat brain synaptic terminals: Ca+2 dependent release evoked by 4-aminopyridine and veratridine. Neurosci Lett. 1992;136:114–144. 20. RotllánP, RamosA, PintorJ, Miras-PortugalMT. Di(1, N6-ethenoadenosine) 5′,5‴-P1,P4-tetraphosphate, a fluorescent enzymatically active derivative of Ap4A. FEBS Lett. 1991;280:371–374. 21. TsubotaK, HataS, OkusawaY, EgamiF, OhtsukiT, NakamoriK. Quantitative videographic analysis of blinking in normal subjects and patients with dry eye. Arch Ophthalmol. 1996;114:715–720. 22. SrinivasSP, MutharasanR, FleiszigS. Shear-induced ATP release by cultured rabbit corneal epithelial cells. Adv Exp Med Biol. 2002;506:677–685. 23. TaylorAL, KudlowBA, MarrsKL, GruenertDC, GugginoWB, SchwiebertEM. Bioluminescence detection of ATP release mechanisms in epithelia. Am J Physiol. 1998;275:C1391–C1406. 24. WilsonPD, HovaterJS, CaseyCC, FortenberryJA, SchwiebertEM. ATP release mechanisms in primary cultures of epithelia derived from the cysts of polycystic kidneys. J Am Soc Nephrol. 1999;10:218–229. 25. MitchellCH, CarreDA, McGlinnAM, StoneR, CivanMM. A release mechanism for stored ATP in ocular ciliary epithelial cells. Proc Natl Acad Sci USA. 1998;95:7174–7178. 26. BorstP, ElferinkRO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71:537–592. 27. LazarowskiER, BoucherRC, HardenTK. Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol. 2003;64:785–795. 28. AbrahamEH, PratAG, GerweckL, et al. The multidrug resistance (mdr1) gene product functions as an ATP channel. Proc Natl Acad Sci USA. 1993;90:312–316. 29. GomesP, SrinivasSP, DriesscheWV, VereeckeJ, HimpensB. ATP release through connexin hemichannels in corneal endothelial cells. Invest Ophthalmol Vis Sci. 2005;46:1208–1218. 30. RecordsR. The tear film.DuaneT JaegerE eds. Biomedical Foundations of Ophthalmology. 1982;2:1–22.Harper & Row Publishers Inc. New York. 31. DoanneM. Interaction of eyelids and tears in corneal wetting and the dynamics of the normal human eye blink. Am J Ophthalmol. 1980;89:507–516. 32. AcostaMC, BelmonteC, GallarJ. Sensory experience in humans and single-unit activity in cats evoked by polymodal stimulation of the cornea. J Physiol. 2001;534:511–525. 33. CowlenMS, ZhangVZ, WarnockL, MoyerCF, PetersonWM, YerxaBR. Localization of ocular P2Y2 receptor gene expression by in situ hybridization. Exp Eye Res. 2003;77:77–84.