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Open Access Journal of Ophthalmology Research Article 10 min read

The Conjunctiva Plays an Important Role in Modulating Ocular Surface Tear

Bhattacharya D* and Wang M*
* Corresponding author
ISSN: 2578-465X  10.23880/oajo-16000102  Received: May 20, 2016  Published: May 25, 2016
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Keywords
Dry eye Conjunctival epithelium Cornea
Abstract

Manifestation of dry eye disease (DED) includes tear film (TF) instability and hyperosmolar condition, leading to immunoinflammatory and mechanical injuries to the ocular surface [1, 2]. Specifically, DED involves defects in aqueous, lipid and/or mucin layers of the TF [3, 4]. Etiologically DED is categorized into aqueous teardeficient and evaporative dry eye [5]. In the United States, 3.23 million women and 1.68 million men 50 years and older suffer from varied severity of DED [6, 7]. Most importantly, DED largely impairs the activities of daily living, thus negatively impacting vision related quality of life [8]. Since ocular surface plays a significant role in modulating tear volume and composition, [9] maintaining and/or restoring the normal function of ocular surface tissues could be a novel treatment strategy for DED.

Introduction

Manifestation of dry eye disease (DED) includes tear film (TF) instability and hyperosmolar condition, leading to immunoinflammatory and mechanical injuries to the ocular surface [1, 2]. Specifically, DED involves defects in aqueous, lipid and/or mucin layers of the TF [3, 4]. Etiologically DED is categorized into aqueous tear- deficient and evaporative dry eye [5]. In the United States, 3.23 million women and 1.68 million men 50 years and older suffer from varied severity of DED [6, 7]. Most importantly, DED largely impairs the activities of daily living, thus negatively impacting vision related quality of life [8]. Since ocular surface plays a significant role in modulating tear volume and composition, [9] maintaining and/or restoring the normal function of ocular surface tissues could be a novel treatment strategy for DED. The ocular surface is a collection of anatomically continuous epithelial and glandular tissues that are functionally linked to maintain the TF [10]. The main lacrimal gland (LG) has been considered the major source of tears [11]. However, there is strong evidence that ocular surface tissues are competent to maintain adequate tear secretion in the absence of the main LG [12]. In fact, contributions from accessory LGs, corneal and conjunctival epithelia to tear volume have being widely recognized [13, 14, 15, 16]. The conjunctiva, and to a very small extent the cornea, are involved in basal tear production [9]. The conjunctiva in particular has the ability to modify the TF by absorbing/ secreting electrolytes and water and by secreting proteins such as mucin [17]. It has also been previously speculated that conjunctival fluid flow may play an important role in hydrating the mucus secreted by goblet cells [18]. Previous studies supported that rabbit conjunctival epithelium has the capacity to be the primary source of TF [19, 20, 21]. In rabbits, the basal conjunctival fluid secretion rate is 0.79 ml/min whereas the basal tear production rate is 0.72 ml/min [19] and conjunctival fluid secretion was reported to be 175% greater than tear turnover [20, 21]. The conjunctiva occupies 17 times more surface area than the cornea in human and about 9 times more in rabbits [22]. Given such a large surface area ratio, the role played by the conjunctiva in modulating the TF should not be underestimated [2, 22]. The conjunctival fluid flow can either be paracellular [23] or transcellular [24] and both pathways are driven by either active Cl- secretion or an osmotic gradient. The osmotic gradient (which regulates the direction of water flow across plasma membranes) is established by the net influx of Na+ , K+ and Cl- into cells and efflux of H+ and HCO3- out of cells; [25] both corneal and conjunctival epithelia have the ability to secrete Cl- and absorb Na+ [17]. In fact, in conjunctival epithelium, Cl- secretion (basolateral to apical movement) accounts for nearly 60% and Na+ reabsorption (apical to basolateral) accounts for about 40% of net ionic transport [17, 26]. This ionic transport determines the amount of tears collected in the conjunctiva sac which possibly affects the stability of TF [27]. It has been reported that uridine triphosphate analog such as Diquafosol (targeting surface epithelial P2Y2 receptors) stimulates Cl- and fluid secretion from the mucosal surface of isolated rabbit conjunctiva [19, 28] as well as increases mucin-like glycoprotein secretion from the ocular surface of rats and rabbits [29, 30]. Topical ocular instillation of 3% diquafosol ophthalmic solution has been shown efficacious in human DED treatment [31, 32]. This again strongly supports the involvement of conjunctival epithelium in ocular fluid secretion.

The ionic gradient across ocular surface is regulated by ionic transporters across the conjunctival epithelium such as cystic fibrosis transmembrane conductance regulator (CFTR), sodium potassium chloride co-transporter, sodium potassium ATPase, and epithelial sodium channels (ENaC) [25]. The CFTR, a c-AMP activated Cl- channel, functions as potential major pathways for Cl- transport at the ocular surface [9]. The competence for CFTR facilitated Cl- transport has been previously shown at the ocular surface in mice [33] and subsequently in rat conjunctiva [34]. Similarly, the ENaC in mouse, [35] rabbit and human conjunctiva [36] mediates active Na+ re- absorption to maintain the electrolyte/water homeostasis [27]. Further, the transcellular flow is potentially mediated in parts by the membranous aquaporins (AQPs) type water selective channels in the ocular surface, [21] supporting their possible role in water/fluid transport and TF homeostasis [37]. The AQP-3, [38] AQP-4 [16] and AQP-5 [16, 39] have been detected in the conjunctiva. Our research demonstrated that tear secretion was not affected in the absence of the main LG, nictitating membrane and Harderian gland in rabbits [16, 40]. A spontaneous improvement of dry eye phenotypes and ocular surface inflammation (with no external intervention) were also observed in this mixed- mechanism rabbit dry eye model. Our findings strongly suggested the presence of a compensatory mechanism in the remaining ocular surface tissues. Our group demonstrated for the first time that APQ-4 is expressed by rabbit conjunctival epithelium and in addition, revealed the potential role of AQP-4 and AQP-5 in the tear fluid secretion by the conjunctival epithelium [16, 40]. Interestingly, it has been concluded that water transport facilitated by conjunctiva encoded AQP-3 does not play any role in transconjunctival fluid movement [37]. Overall, across conjunctival epithelium, AQPs and CFTR have been identified as the principal molecular pathways for water and Cl- transport, respectively, [2, 40] thus serving as attractive targets for drug development in the treatment of DED [40, 41]. A recent report demonstrated in mice the potential utility and efficacy of newly identified small-molecule CFTR activators as a novel prosecretory treatment for DED [2].

Conclusion

In conclusions, significant contributions from the conjunctival epithelium in tear secretion are being increasingly recognized. The conjunctiva possibly plays a pivotal role in the maintenance of ocular surface homeostasis. Thus, understanding the physiology of conjunctival epithelium in order to optimize its fluid and mucin secretion capacity is imperative for developing alternative DED treatments. Further research will be crucial to delineate specific mechanisms by which the conjunctival epithelium modulates tear quality and quantity, and to identify potential novel treatment strategies for DED.

References

  1. Stevenson W, Chauhan SK, Dana R (2012) Dry eye disease: an immune-mediated ocular surface disorder. Archives of ophthalmology 130, 90-100, doi:10.1001/archophthalmol.2011.364.
  2. Flores AM, et al. (2016) Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 30, 1789-1797.
  3. (2007) The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). The ocular surface 5, 75-92.
  4. Sambursky R, Davitt WF 3rd, Latkany R, Tauber S, et al. (2013) Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA ophthalmology 131, 24-28.
  5. (2007) The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). The ocular surface 5, 93- 107.
  6. Schaumberg DA, Sullivan DA, Buring JE, Dana MR (2003) Prevalence of dry eye syndrome among US women. American journal of ophthalmology 136, 318-326.
  7. Schaumberg DA, Dana R, Buring JE, Sullivan DA (2009) Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. Archives of ophthalmology 127, 763-768.
  8. Miljanovic B, Dana R, Sullivan DA, Schaumberg DA (2007) Impact of dry eye syndrome on vision-related quality of life. American journal of ophthalmology 143, 409-415.
  9. Levin MH, Verkman AS (2005) CFTR-regulated chloride transport at the ocular surface in living mice measured by potential differences. Investigative ophthalmology & visual science 46, 1428- 1434.
  10. Asbell PA, Spiegel S (2010) Ophthalmologist perceptions regarding treatment of moderate-to- severe dry eye: results of a physician survey. Eye & contact lens 36, 33-38.
  11. Thorig L, van Agtmaal EJ, Glasius E, Tan KL, van Haeringen (1985) NJ Comparison of tears and lacrimal gland fluid in the rabbit and guinea pig. Current eye research 4, 913-920.
  12. Stevenson W, Pugazhendhi S, Wang M (2016) Is the main lacrimal gland indispensable? Contributions of the corneal and conjunctival epithelia. Survey of ophthalmology,doi:10.1016/j.survophthal.2016.02.00 6.
  13. Gilbard JP, Rossi SR, Gray KL, (1987) A new rabbit model for keratoconjunctivitis sicca. Investigative ophthalmology & visual science 28, 225-228.
  14. Gilbard JP, Rossi SR, Gray KL, Hanninen LA, Kenyon KR, (1988) Tear film osmolarity and ocular surface disease in two rabbit models for keratoconjunctivitis sicca. Investigative ophthalmology & visual science 29, 374-378.
  15. Chen ZY, Liang QF, Yu GY, (2011) Establishment of a rabbit model for keratoconjunctivitis sicca. Cornea 30, 1024-1029, doi:10.1097/ICO.0b013e3181f1b0fc.
  16. Bhattacharya D, Ning Y, Zhao F, Stevenson W, Chen R, et al. (2015) Tear Production After Bilateral Main Lacrimal Gland Resection in Rabbits. Investigative ophthalmology & visual science 56, 7774-7783.
  17. Dartt DA (2002) Regulation of mucin and fluid secretion by conjunctival epithelial cells. Progress in retinal and eye research 21, 555-576.
  18. Kessler TL, Mercer HJ, Zieske JD, McCarthy DM, Dartt DA (1995) Stimulation of goblet cell mucous secretion by activation of nerves in rat conjunctiva. Current eye research 14, 985- 992.
  19. Li Y, Kuang K, Yerxa B, Wen Q, Rosskothen H et al. (2001) Rabbit conjunctival epithelium transports fluid, and P2Y2(2) receptor agonists stimulate Cl(-) and fluid secretion. American journal of physiology. Cell physiology 281, C595- 602.
  20. Chrai SS, Patton TF, Mehta A, Robinson JR (1973) Lacrimal and instilled fluid dynamics in rabbit eyes. J Pharm Sci 62, 1112-1121.
  21. Shiue MH, Kulkarni AA, Gukasyan HJ, Swisher JB, Kim KJ et al. (2000) Pharmacological modulation of fluid secretion in the pigmented rabbit conjunctiva. Life sciences 66, PL105-111.
  22. Watsky MA, Jablonski MM, Edelhauser HF, (1988) Comparison of conjunctival and corneal surface areas in rabbit and human. Current eye research **7**, 483- 486.
  23. Loeschke K, Bentzel CJ, (1994) Osmotic water flow pathways across Necturus gallbladder: role of the tight junction. The American journal of physiology 266, G722-730.
  24. Carpi-Medina P, Whittembury G (1988) Comparison of transcellular and transepithelial water osmotic permeabilities (Pos) in the isolated proximal straight tubule (PST) of the rabbit kidney. Pflugers Arch 412, 66-74.
  25. Ding C, Leili P, Prachi N, Ping Zhao, Kaijin W et al. (2010) Duct system of the rabbit lacrimal gland: structural characteristics and role in lacrimal secretion. Investigative ophthalmology & visual science 51, 2960-2967.
  26. Candia OA, (2004) Electrolyte and fluid transport across corneal, conjunctival and lens epithelia. Experimental eye research 78, 527-535.
  27. Hara S, Hazama A, Miyake M, Kojima T, Sasaki Y, et al. (2010) The effect of topical amiloride eye drops on tear quantity in rabbits. Molecular vision 16, 2279- 2285.
  28. Murakami T, Fujihara T, Horibe Y, Nakamura M (2004) Diquafosol elicits increases in net Cl- transport through P2Y2 receptor stimulation in rabbit conjunctiva. Ophthalmic research 36(2): 89- 93.
  29. Fujihara T, Murakami T, Fujita H, Nakamura M, Nakata K (2001)Improvement of corneal barrier function by the P2Y(2) agonist INS365 in a rat dry eye model. Investigative ophthalmology & visual science 42(1): 96-100.
  30. Fujihara T, Murakami T, Nagano T, Nakamura M, Nakata K (2002) INS365 suppresses loss of corneal epithelial integrity by secretion of mucin-like glycoprotein in a rabbit short-term dry eye model. J Ocul Pharmacol Ther. The official journal of the Association for Ocular Pharmacology and Therapeutics 18(4): 363-370.
  31. Matsumoto Y, Ohashi Y, Watanabe H, Tsubota K & Diquafosol Ophthalmic Solution Phase 2 Study, G. (2012) Efficacy and safety of diquafosol ophthalmic solution in patients with dry eye syndrome: a Japanese phase 2 clinical trial. Ophthalmology 119(10): 1954-1960, doi:10.1016/j.ophtha.2012.04.010.
  32. Takamura E, Tsubota K, Watanabe H, Ohashi, Y & Diquafosol Ophthalmic Solution Phase 3 Study, Group (2012) A randomised, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients. The British journal of ophthalmology 96(10): 1310-1315.
  33. Levin MH, Kim JK, Hu J, Verkman AS (2006) Potential difference measurements of ocular surface Na+ absorption analyzed using an electrokinetic model. Invest Ophthalmol Vis Sci. 47(1): 306-316.
  34. Yu D, Thelin WR, Rogers TD, Stutts MJ, Randell SH, et al. (2012) Regional differences in rat conjunctival ion transport activities. Am J Physiol Cell Physiol.303 (7): C767-780.
  35. Schechter JE, Warren DW, Mircheff AK, (2010) A lacrimal gland is a lacrimal gland, but rodent's and rabbit's are not human. The ocular surface 8(3): 111- 134.
  36. Candia OA, Alvarez LJ, (2008) Fluid transport phenomena in ocular epithelia. Progress in retinal and eye research 27(2): 197-212 .
  37. Levin MH, Verkman AS (2004) Aquaporin-dependent water permeation at the mouse ocular surface: in vivo microfluorimetric measurements in cornea and conjunctiva. Investigative ophthalmology & visual science 45, 4423-4432.
  38. Frigeri A, Gropper MA, Turck CW & Verkman AS (1995) Immunolocalization of the mercurial- insensitive water channel and glycerol intrinsic protein in epithelial cell plasma membranes. Proceedings of the National Academy of Sciences of the United States of America 92, 4328-4331.
  39. Oen H, Cheng P, Turner HC, Alvarez LJ & Candia OA (2006) Identification and localization of aquaporin 5 in the mammalian conjunctival epithelium. Experimental eye research 83, 995- 998, doi: 10.1016/j.exer.2006.04.006.
  40. Levin MH, Verkman AS (2006) Aquaporins and CFTR in ocular epithelial fluid transport. The Journal of membrane biology 210, 105-115, doi: 10.1007/s00232-005-0849-1.
  41. Zhang D, Vetrivel L, Verkman AS (2002) Aquaporin deletion in mice reduces intraocular pressure and aqueous fluid production. The Journal of general physiology 119(6) 561-569.
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@article{bhattacharya2016,
  title   = {The Conjunctiva Plays an Important Role in Modulating Ocular Surface Tear},
  author  = {Bhattacharya D* and Wang M},
  journal = {Open Access Journal of Ophthalmology},
  year    = {2016},
  volume  = {1},
  number  = {1},
  doi     = {10.23880/oajo-16000102}
}
Bhattacharya D* and Wang M (2016). The Conjunctiva Plays an Important Role in Modulating Ocular Surface Tear. Open Access Journal of Ophthalmology, 1(1). https://doi.org/10.23880/oajo-16000102
TY  - JOUR
TI  - The Conjunctiva Plays an Important Role in Modulating Ocular Surface Tear
AU  - Bhattacharya D* and Wang M
JO  - Open Access Journal of Ophthalmology
PY  - 2016
VL  - 1
IS  - 1
DO  - 10.23880/oajo-16000102
ER  -