50Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011Review ArticleA review on recent advances in dry eye: Pathogenesis and managementAnkita S. Bhavsar, Samir G. Bhavsar1, Sunita M. JainDepartment of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, 1Department of Ophthalmology,S. K. Hospital and P. S. Medical College, Karamsad, Anand 388 325, Gujarat, IndiaCorrespondence:Dr. Sunita M. Jain, Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India.E-mail: sunitalmcp@yahoo.comIntroductionDryeyeisoneofthemostfrequentlyencounteredocular morbidities,agrowingpublichealthproblemandoneofthe mostcommonconditionsseenbyeyecarepractitioners.[1]In thelightofnewknowledgeabouttherolesofocularsurface inflammation and tear hyperosmolarity in dry eye and the effects of dry eye on visual function, the International Dry Eye Workshop (DEWS) defined dry eye as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.[2] Overthepastfewyears,asaresultofnumerousstudies,new concepts of pathogenesis have shown that dry eye seems to be caused by inflammation mediated by T-cell lymphocytes.[3-5] This finding hasalsobeenaugmentedbythestudiesinvestigatingtheroleof antiinflammatory therapies. Consequently, because of the increasing importanceoftheroleofinflammationinetiopathogenesis,we have included recent understanding of pathogenesis and treatment of dry eye disease (DED) in the present article.Lacrimal Functional Unit The Newer ConceptDEWSin2007recognizeddryeyeasadisturbanceofthe Copyright: 2011 Bhavsar AS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Keratoconjunctivitissicca,morecommonly knownasdryeye,isanextremelycommonand oftenunrecognizeddisease.Itistheconditionin ophthalmologythatinitsmildgradeofseveritywill affect most of the population at one time or other. Due toawidevarietyofpresentationsandsymptoms,it often frustrates the ophthalmologists as well as patients. Duetomultifactorialandelusiveetiology,itisoften challenging to treat dryeye. Ocularsurface disorders are also clinically important to treat especially in terms of visual acuity. Xero-dacryology is therefore becoming averyimportantbranchofophthalmology.Recent studieshavegiveninsightintotheinflammatory etiologyofdryeye.Theconventionalandmain approachtothetreatmentofdryeyeisproviding lubricating eye drops or tear substitutes. However, the newertreatmentapproachistotargettheunderlying cause of dry eye instead of conventional symptomatic relief.Inlightoftheaboveknowledge,thepresent articlefocusesonnewertheoriesonpathogenesisof dry eye and their impact on dry eye management. Method of Literature Search: A systematic literature review was performed using PubMed databases in two steps. The first step was oriented to articles published fordryeye.Thesecondstepwasfocusedontherole ofinflammationandanti-inflammatorytherapyfor dryeye.Thesearchstrategywasnotlimitedbyyear ofpublication.Amanualliteraturesearchwasalso undertakenfromauthenticreferencebooksonocular surface disease.Keywords: Apoptosis, inflammation, pathogenesis Access this article onlineQuick Response Code:Website:www.ojoonline.orgDOI:10.4103/0974-620X.83653[Downloadedfreefromhttp://www.ojoonline.orgonFriday,August22,2014,IP:223.255.230.33]||ClickheretodownloadfreeAndroidapplicationforthisjournalOman Journal of Ophthalmology, Vol. 4, No. 2, 201151Lacrimal Functional Unit (LFU) whose parts act together and not inisolation.Itisanintegratedsystemcomprisingthelacrimal glands,ocularsurface(cornea,conjunctivaandmeibomian glands) and lids, and the sensory and motor nerves that connect them[2] [Figure 1].Abnormality of any of several subparts of the lacrimal functional unitcanbetransferredacrosstheentiresystemthroughits extensiveneuralconnectionstoresultinanunstableand unrefreshedtearfilmhavingalteredcompositionlikeelevated tearosmolarity,presenceofproinflammatorymediatorsand proteases,whichnolongersupportsthenormalfunctioningof the ocular surface.[6]Etiology and Risk Factors of Dry Eye DiseaseThelastdecadehasbroughtaboutsignificantimprovementin theunderstandingoftheetiologyandpathogenesisofDED.[7] AppreciationoftheroleofinflammationinDEDwasoneof themostimportantfactorsthataidedintheunderstandingand treatment of DED. The findings of the association of inflammation with reduced tear secretion and subsequent damage to the ocular surface led to the proposal of a unified concept of DED.[8] Older ageandfemalesex(particularlyperiandpostmenopausalage) are wellknown risk factors for DED.[9,10] Hormonal studies suggest thatsexhormonesinfluenceocularsurfaceconditionsthrough theireffectsontearsecretion,meibomianglandfunction,and conjunctivalgobletcelldensity.[11]Chronicandrogendeficiency is associated with meibomian gland dysfunction. Postmenopausal women who use hormonal replacement therapy (HRT) especially estrogen alone, have a higher prevalence of DED compared with those who have never used HRT.[12,13]Otherfactorsthatprecipitateand/orexacerbateDEDinclude long-termcontactlenswear,refractivesurgeriessuchaslaser-assistedinsitukeratomileusis(LASIK)orphotorefractive keratectomy(PRK),[9,14,15]smoking,[16] extendedvisualtasking during computer use, television watching and prolonged reading provoke symptoms of dry eye.[17,18] Dry eye can be worsened by low relative humidity (RH) conditions like office environment, air-conditioned cars, airplane cabins and extremehotorcoldweather.[19,20]Certainsystemicmedications can cause dry eye.[9] Frequent use (>4-6 times daily) of preserved eyedrops(includingglaucomamedicationsandartificialtears) may contribute to DED because of the well established toxicity of preservatives like benzalkonium chloride.[21] Role of Infammation in Etiopathogenesis of Dry EyeTherehasbeenconsiderableincreaseinknowledgeregarding pathogenesisofdryeye.Thoughthetermkeratoconjunctivitis sicca (KCS) was used for more than 50 years, it is only recently recognizedthatinflammationoftheocularsurfaceispartof thepathophysiologyofdryeye.InKCSpatients,ocularsurface inflammationcanbeevaluatedasboththecauseandthe consequenceofcelldamage.Adangerousviciouscycleensures betweenocularinflammationanddryeye,whichinturnmay leadtosightthreateningcomplications[Figure2].Theroleof inflammatorycytokinesandmatrixmetalloproteinases(MMPs) inthepathogenesisofdryeyeseemstobeveryimportantfor both the easier understanding of KCS and for the discovery of new therapeutic agents.[22-24]Asmentionedearlier,diseaseordysfunctionofanycomponent of lacrimal functional unit disrupts the delicate balance between secretionanddegradationoftearcomponentsontheocular surfacewhichdestabilizesthetearfilmwithdelayedtear clearance that causes ocular irritation and epithelial abnormalities leadingtoKCSorDED.[25] Anyconditionthatresultsinrapid stimulationofthelacrimalfunctionalunit(e.g.duetodryness) will induce neurogenic inflammation within the acini of lacrimal gland resulting in antigen presentation and cytokine production, ultimately leading to activation of T cells. Normally when there is no inflammation, these T lymphocytes undergo apoptosis. But in Bhavsar, et al.: Dry eye diseaseFigure 1: The lacrimal functional unit Figure 2: Vicious cycle of ocular surface infammation[Downloadedfreefromhttp://www.ojoonline.orgonFriday,August22,2014,IP:223.255.230.33]||ClickheretodownloadfreeAndroidapplicationforthisjournal52Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011the presence of inflammation, they are activated, become resistant to apoptosis and secrete proinflammatory cytokines which results in even more Tcell activation.[26,27] One of the causes of lacrimal dysfunctioninSjogrensyndromeislymphocyticinfiltrationof the lacrimal gland with damage to secretory acini. The presence offocallymphocyticinfiltratesandincreasedproductionof proinflammatory cytokines are characteristic findings of lacrimal glandinflammation.[28]Releaseofinflammatorycytokinesby infiltratinginflammatorycellsanddiseasedlacrimalepithelial cellsthemselvesfurthercausesepithelialcelldysfunctionor apoptosis.[29]Apoptosis of the ocular surface epithelium which may serve as one of the initiating events is further exacerbated by the inflammatory process and the decreasing levels of lacrimal gland derived factors. Thisisevidentbyincreasedexpressionofproapopticmarkers (e.g.Fas,Fasligand,CD40,CD40ligand)bytheconjunctival epithelium.[30]Diseaseordysfunctionofthelacrimalfunctionalunitleads tochangesintearfilmcompositionandstability,whichhave adverse consequences for the ocular surface. Common feature of dysfunctional unit is elevated tear osmolarity.[31] There are several reports suggesting that hyperosmolarity induces inflammation.[31,32] The role of inflammation in the etiopathogenesis of DED is briefly summarized in Figure 3.Androgensareimportantforprovidingtrophicsupportto thelacrimalfunctionalunitaswellascreatingageneralanti-inflammatoryenvironment.[33,34]Decreaseinandrogenlevels cancauselossoftheanti-inflammatoryenvironmentwithin thelacrimalgland.Meibomianglandsarealsoandrogentarget organs. As circulatory androgen level drops (e.g. in menopause), thelacrimaltissuebecomesvulnerabletoimmunogenic inflammation.[26] Relative androgen deficiency might explain the greater prevalence of dry eye in women. Alteration of either mucin distributionormucinglycosylationonthesurfacesofapical epithelial cells is also involved in the pathogenesis of dry eye.[35]Thus, it can be summarized that the dysfunction of any component oflacrimalfunctionalunitcanresultinunstabletearfilmwith alteredtearfilmcomposition,oculardiscomfortandocular surfacedisease.Theendresultisocularsurfaceinflammation starting a vicious cycle of dryness and more inflammation. Diagnosis of Dry EyeCurrently, there are no uniform criteria for the diagnosis of DED. Traditionally, combinations of diagnostic tests have been used to assess symptoms and clinical signs.[36] Common DED symptoms are dry, scratchy, gritty or sandy feeling, foreignbodysensation,painorsoreness,burning,itchingand increasedblinking.[37]Twocomplaintsprovideimportantclues thatpatientsmaybesufferingfromdryeye:exacerbationof irritationbyenvironmentalstressandexacerbationofirritation by activities that require prolonged visual attention.[38] A number of questionnaires are available for evaluation of various aspects of DED symptomatology, including severity, effect on daily activities andqualityoflife.Theocularsurfacediseaseindex(OSDI)[39] permitsquantificationofcommonsymptomsandprovidesa reasonably objective approach to the evaluation of symptoms over time. It is a valuable tool in clinical treatment trials.[40]Physicalexaminationincludesvisualacuitymeasurement, externalexamination,andslit-lampbiomicroscopyforgrading theseverityofDED.[25]Dryeyeisclassifiedaccordingtothe clinical severity into three grades.[41]Grade1ormild:Patientshavesymptomsofdrynessinnormal environmental conditions but no signs on slit-lamp examination. However,otherelectrophysiologicalorinvasivetests,suchas hyperosmolarity,hypolysozymeorinflammatorycytokines,may be positive.Grade2ormoderate:Inadditiontosymptoms,patienthas reversibleslitlampsignssuchasepithelialerosion,punctate keratopathy,filamentarykeratitis,shorttearbreakuptime (TBUT), etc.Grade3orsevere:Thepatienthas,besidesthesymptomsof oculardryness,signsthathaveevolvedtopermanentsequelae such as corneal ulcer, corneal opacity, corneal neovascularization orsquamousepithelialmetaplasia.Thesesignsarecommonly seen in untreated patients.Additional diagnostic tests may be performed to assess tear film instability, ocular surface damage and aqueous tear flow.Tear film stability assessmentItiscommonlydonebyperformingTBUT.[38]Valuesof