{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:29:14Z","timestamp":1790634554379,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T00:00:00Z","timestamp":1668816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31671210"],"award-info":[{"award-number":["31671210"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022A1515011140"],"award-info":[{"award-number":["2022A1515011140"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Guangdong Province, China","award":["31671210"],"award-info":[{"award-number":["31671210"]}]},{"name":"Natural Science Foundation of Guangdong Province, China","award":["2022A1515011140"],"award-info":[{"award-number":["2022A1515011140"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dry eye disease (DED) is a multifactorial disease with an incidence of approximately 50% worldwide. DED seriously affects quality of life and work. The prevalence of environmental DED (eDED) ranges from 35 to 48%. Conjunctival fluid secretion dysfunction may be one of the major causes of DED. Notably, the Cl\u2013 flux corresponds to the conjunctival fluid secretion and could be affected by ATP. Both the cystic fibrosis transmembrane conductance regulator (CFTR) and the Ca2+-activated Cl\u2013 channel (CaCC) are Cl\u2013 channels involved in epithelial fluid secretion. Conjunctival fluid secretion could be increased by activating P2Y2R (an ATP receptor) in DED. However, the role of the CaCC and CFTR channels regulated by P2Y2R in eDED remains unclear. In this study, we established a rabbit eDED model using a controlled drying system. A Ussing chamber was used to perform a conjunctival short-circuit current induced by ATP to evaluate the reactivity of the ion channels to the ATP. Our results revealed that eDED accompanied by conjunctival fluid secretion impairment was caused by a P2Y2R dysfunction, which is related to CaCC-CFTR signaling in the conjunctiva epithelium. Notably, the coupling effect of the ATP-induced CaCC-CFTR activation and intracellular Ca2+ may represent a promising therapeutic target for treating eDED.<\/jats:p>","DOI":"10.3390\/ijms232214399","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T03:05:11Z","timestamp":1668999911000},"page":"14399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Conjunctival Fluid Secretion Impairment via CaCC-CFTR Dysfunction Is the Key Mechanism in Environmental Dry Eye"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-6374","authenticated-orcid":false,"given":"Jinyu","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limian","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangjian","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Institute for Vision and Eye Research, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyou","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II Epidemiology Report","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.jtos.2017.05.011","article-title":"TFOS DEWS II pathophysiology report","volume":"15","author":"Bron","year":"2017","journal-title":"Ocul Surf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jtos.2017.05.001","article-title":"TFOS DEWS II Diagnostic Methodology report","volume":"15","author":"Wolffsohn","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1016\/j.ophtha.2008.06.022","article-title":"Prevalence of dry eye disease among Japanese visual display terminal users","volume":"115","author":"Uchino","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1097\/ICO.0b013e31826671ab","article-title":"The effect of low humidity on the human tear film","volume":"32","author":"Abusharha","year":"2013","journal-title":"Cornea"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"C595","DOI":"10.1152\/ajpcell.2001.281.2.C595","article-title":"Rabbit conjunctival epithelium transports fluid, and P2Y22 receptor agonists stimulate Cl2 and fluid secretion","volume":"281","author":"LI","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_7","first-page":"7","article-title":"Changes of chloride channels in the lacrimal glands of a rabbit model of Sjgren syndrome","volume":"31","author":"Nandoskar","year":"2011","journal-title":"Cornea"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lee, H.K., Park, J., Kim, B.R., Jun, I., Kim, T.I., and Namkung, W. (2021). Isorhamnetin Ameliorates Dry Eye Disease via CFTR Activation in Mice. Int J Mol Sci, 22.","DOI":"10.3390\/ijms22083954"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1096\/fj.201500180","article-title":"Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease","volume":"30","author":"Flores","year":"2016","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S0022-3476(73)80221-5","article-title":"Tear sodium, potassium, chloride, and calcium at various flow rates: Children with cystic fibrosis and unaffected siblings with and without corneal staining","volume":"83","author":"Botelho","year":"1973","journal-title":"J Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1076\/ceyr.21.4.782.5550","article-title":"P2Y(2) receptor stimulation increases tear fluid secretion in rabbits","volume":"21","author":"Murakami","year":"2000","journal-title":"Curr. Eye Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1089\/jop.2016.0193","article-title":"Diquafosol Delivery from Silicone Hydrogel Contact Lenses: Improved Effect on Tear Secretion","volume":"34","author":"Carracedo","year":"2018","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1165\/rcmb.2003-0183OC","article-title":"Apical and basolateral ATP-induced anion secretion in polarized human airway epithelia","volume":"30","author":"Son","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Centeio, R., Ousingsawat, J., Schreiber, R., and Kunzelmann, K. (2021). CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105133"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1006\/exer.1997.0459","article-title":"Modulation of chloride secretion across the pigmented rabbit conjunctiva","volume":"66","author":"Shiue","year":"1998","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"C767","DOI":"10.1152\/ajpcell.00195.2012","article-title":"Regional differences in rat conjunctival ion transport activities","volume":"303","author":"Yu","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s00424-008-0606-2","article-title":"CFTR is activated through stimulation of purinergic P2Y2 receptors","volume":"457","author":"Faria","year":"2009","journal-title":"Pflugers Arch."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"F544","DOI":"10.1152\/ajprenal.00709.2010","article-title":"Activation of P2Y1 and P2Y2 receptors induces chloride secretion via calcium-activated chloride channels in kidney inner medullary collecting duct cells","volume":"301","author":"Rajagopal","year":"2011","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"G1004","DOI":"10.1152\/ajpgi.90382.2008","article-title":"Extracellular nucleotides stimulate Cl- currents in biliary epithelia through receptor-mediated IP3 and Ca2+ release","volume":"295","author":"Dutta","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mikolajewicz, N., Smith, D., Komarova, S.V., and Khadra, A. (2021). High-affinity P2Y2 and low-affinity P2X7 receptor interaction modulates ATP-mediated calcium signaling in murine osteoblasts. PLoS Comput. Biol., 17.","DOI":"10.1101\/2021.03.16.435624"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.niox.2020.04.004","article-title":"Cellular mechanisms underlying carbon monoxide stimulated anion secretion in rat epididymal epithelium","volume":"100","author":"Peng","year":"2020","journal-title":"Nitric Oxide"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1083\/jcb.200608073","article-title":"Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels","volume":"175","author":"Szabadkai","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.mam.2012.07.016","article-title":"Water channels and their roles in some ocular tissues","volume":"33","author":"Fischbarg","year":"2012","journal-title":"Mol. Aspects Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1124\/jpet.103.049221","article-title":"Nucleotide-induced restoration of conjunctival chloride and fluid secretion in adenovirus type 5-infected pigmented rabbit eyes","volume":"305","author":"Kulkarni","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.3109\/02713689309033501","article-title":"Active chloride transport in the pigmented rabbit conjunctiva","volume":"12","author":"Kompella","year":"1993","journal-title":"Curr. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"927","DOI":"10.3109\/02713689508995132","article-title":"Active sodium and chloride transport across the isolated rabbit conjunctiva","volume":"14","author":"Shi","year":"1995","journal-title":"Curr. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"F483","DOI":"10.1152\/ajprenal.00062.2012","article-title":"Differential effects of extracellular ATP on chloride transport in cortical collecting duct cells","volume":"303","author":"Rajagopal","year":"2012","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1095\/biolreprod.108.068346","article-title":"Stimulating effects of dopamine on chloride transport across the rat caudal epididymal epithelium in culture","volume":"80","author":"Du","year":"2009","journal-title":"Biol. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.4196\/kjpp.2014.18.2.89","article-title":"DA-6034 Induces [Ca(2+)]i Increase in Epithelial Cells","volume":"18","author":"Yang","year":"2014","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s11302-017-9556-5","article-title":"Hyperosmotic stress induces ATP release and changes in P2X7 receptor levels in human corneal and conjunctival epithelial cells","volume":"13","author":"Pintor","year":"2017","journal-title":"Purinergic Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1152\/physrev.00039.2011","article-title":"Structure and function of TMEM16 proteins (anoctamins)","volume":"94","author":"Pedemonte","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4435","DOI":"10.1073\/pnas.1503474112","article-title":"Infection by Toxoplasma gondii, a severe parasite in neonates and AIDS patients, causes impaired anion secretion in airway epithelia","volume":"112","author":"Guo","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cellsig.2014.11.015","article-title":"Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells","volume":"27","author":"Khajavi","year":"2015","journal-title":"Cell Signal"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ceca.2017.05.003","article-title":"Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death","volume":"69","author":"Marchi","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"C817","DOI":"10.1152\/ajpcell.00139.2004","article-title":"Calcium, ATP, and ROS: A mitochondrial love-hate triangle","volume":"287","author":"Brookes","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1167\/tvst.10.4.32","article-title":"A Novel Rabbit Dry Eye Model Induced by a Controlled Drying System","volume":"10","author":"Chen","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1089\/jop.2021.0015","article-title":"Novel Lipids of the Rabbit Harderian Gland Improve Tear Stability in an Animal Model of Dry Eye Disease","volume":"37","author":"Butovich","year":"2021","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_38","first-page":"1169","article-title":"Silencing of P2Y2 receptor delays Ap4A-corneal re-epithelialization process","volume":"15","author":"Crooke","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1111\/j.1476-5381.2011.01586.x","article-title":"Silencing of P2Y(2) receptors reduces intraocular pressure in New Zealand rabbits","volume":"165","author":"Crooke","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.niox.2019.05.011","article-title":"The gasotransmitter hydrogen sulfide inhibits transepithelial anion secretion of pregnant mouse endometrial epithelium","volume":"90","author":"Xu","year":"2019","journal-title":"Nitric Oxide"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3748\/wjg.v8.i1.40","article-title":"Nitric oxide and calcium ions in apoptotic esophageal carcinoma cells induced by arsenite","volume":"8","author":"Shen","year":"2002","journal-title":"World J. Gastroenterol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14399\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:02Z","timestamp":1760145722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,19]]},"references-count":41,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214399"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214399","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,19]]}}}