Rationale for anti-inflammatory therapy
`in dry eye syndrome
`
`Bases da terapia antiinflamatória em síndrome do olho seco
`
`De Paiva CS1
`Pflugfelder SC2
`
`1 Assistant professor, Ocular Surface Center, Department
`of Ophthalmology, Cullen Eye Institute, Baylor
`College of Medicine, Houston, Texas.
`2 Professor of Ophthalmology, The James and Margaret
`Elkins Chair, Ocular Surface Center, Department of
`Ophthalmology, Cullen Eye Institute, Baylor College
`of Medicine, Houston, Texas.
`Support: NIH Grants EY11915 (SCP), RPB, Oshman
`Foundation, William Stamps Farish Fund, Hamill Foun-
`dation and Allergan.
`Corresponding author: Cintia S. de Paiva. Cullen Eye
`Institute, Baylor College of Medicine, 6565 - Fannin
`Street, NC 205 - Houston, TX 77030
`E-mail: cintiadp@bcm.tmc.edu
`
`ABSTRACT
`
`Dry eye is a multifactorial condition that results in a dysfunctional
`lacrimal functional unit. Evidence suggests that inflammation is involved
`in the pathogenesis of the disease. Changes in tear composition including
`increased cytokines, chemokines, metalloproteinases and the number of
`T cells in the conjunctiva are found in dry eye patients and in animal
`models. This inflammation is responsible in part for the irritation symp-
`toms, ocular surface epithelial disease, and altered corneal epithelial
`barrier function in dry eye. There are several anti-inflammatory therapies
`for dry eye that target one or more of the inflammatory mediators/path-
`ways that have been identified and are discussed in detail.
`
`Keywords: Dry eye syndromes; Inflammation, Concentration /osmolar; Cyclosporine/therapeutic
`use, Doxycycline/therapeutic use; Cytokines/therapeutic use; Metalloproteases; Anti-Inflamma-
`tory agents/therapeutic use
`
`Inflammation in dry eye
`Dry eye is the second most common problem of patients seeking eye
`care, and is characterized by eye irritation symptoms, blurred and fluc-
`tuating vision, tear film instability, increased tear osmolarity and ocular
`surface epithelial disease(1-4). It is often a challenging clinical problem to
`identify because of its varying clinical presentation. Dry eye impacts
`quality of life by decreasing functional vision, i.e. the ability to perform
`daily activities such as reading, using a computer and driving(5).
`There is an increasing evidence that dry eye is an inflammatory di-
`sease. Disease or dysfunction of the tear secretory glands leads to changes
`in tear composition, such as hyperosmolarity that stimulate the produc-
`tion of inflammatory mediators on the ocular surface(6). Inflammation may
`in turn cause dysfunction or disappearance of cells responsible for tear
`secretion or retention(7). Inflammation can also be initiated by chronic
`irritative stress (e.g. contact lenses) and systemic inflammatory/autoim-
`mune disease (e.g. rheumatoid arthritis). Regardless of the initiating cause,
`a vicious cycle of inflammation may develop on the ocular surface in dry
`eye that leads to ocular surface disease. This review will focus on some of
`the recent findings/evidences about dry eye and inflammation.
`
`Increased inflammatory cytokines
`Increased production and activation of pro-inflammatory cytokines (inter-
`leukin [IL]-1 and tumor necrosis factor [TNF]-α) and proteolytic enzymes by
`stressed ocular surface and glandular epithelial cells, as well as by the inflam-
`matory cells that infiltrate these tissues have been reported in dry eye(8-10).
`Increased concentration of pro-inflammatory cytokines and chemokines
`in the tear fluid, such as IL-6, IL-1, TNF-α has been extensively reported(7,11-18).
`
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`90 Rationale for anti-inflammatory therapy in dry eye syndrome
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`Experimental dryness significantly increased the expression of
`IL-1α, IL-6, and TNF-α transcripts in the corneal epithelium and
`conjunctiva of C57BL/6 mice(19).
`In humans, significantly increased levels of IL-1α, IL-6,
`IL-8, TNF-α and transforming growth factor (TGF)-β1 RNA
`transcripts have been found in the conjunctival epithelium of
`Sjögren’s syndrome, the most severe type of dry eye, compa-
`red to controls(12). However, the exact role of these cytokines
`in dry eye have not been fully elucidated.
`
`Tear film osmolarity
`Hyperosmolarity of the tear fluid has been recognized for
`decades as a common feature of all types of dry eye and it has
`been referred to as the “gold standard” for the diagnosis of
`dry eye(20). It is also recognized as a pro-inflammatory stimu-
`lus(21-22). Exposure of cultured corneal epithelial cells to me-
`dia of increasing sodium chloride concentration results in a
`concentration dependent increase in the production of the
`same pro-inflammatory factors that have been detected in the
`conjunctival epithelium and tear fluid of dry eye patients
`(i.e. IL-1, IL-8, TNF-α, and MMP-9)(23-24). In vivo and in vitro,
`hyperosmolarity was shown to stimulate the production of
`these inflammatory mediators by activating mitogen activa-
`ted protein kinases(6,24-25).
`
`Increased metallproteinases
` Another pathologic change is an increased concentration
`and activity of matrix metalloproteinases (MMPs) in the tear
`fluid of dry eye patients(13,26-27). These enzymes, such as
`MMP-9, lyse a variety of different substrates including com-
`ponents of the corneal epithelial basement membrane and
`tight junction proteins (such as ZO-1 and occludin) that
`maintain corneal epithelial barrier function(28-29). In a group
`of dry eye patients, we observed that tear MMP-9 activity
`levels increased as the severity of corneal disease progressed.
`Tear MMP-9 activity levels also correlated positively with
`corneal fluorescein staining scores and with low contrast
`visual acuity(30).
`MMP-9 appears to play a physiological role in regulating
`corneal epithelial desquamation. In systemic vitamin A defi-
`ciency, there is reduced expression of MMP-9 and hyperstra-
`tification of the corneal epithelium. In contrast, the increased
`MMP-9 activity in keratoconjunctivitis sicca (KCS) is asso-
`ciated with deranged corneal epithelial barrier function (in-
`creased fluorescein permeability), increased corneal epi-
`thelial desquamation (punctate epithelial erosions) and cor-
`neal surface irregularity(6,28-29).
`
`Chemokines and chemokine receptors
`Chemokines are small peptides that can induce recruit-
`ment of nearby responsive cells. They are important in sites
`of inflammation because they can amplify the cascade by
`attracting more and more inflammatory cells.
`In human cystic fibrosis patients, the tear levels of the
`chemokine macrophage inflammatory protein 1α (MIP-1α)
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`Arq Bras Oftalmol. 2008;71(6 Supl):89-95
`
`were significantly higher when compared with healthy con-
`trols and correlated with dry eye findings in these patients(31).
`In an animal experimental dry eye model, desiccating
`stress significantly increased concentrations of MIP-1α,
`MIP-1β, monokine induced by interferon (MIG)-gamma, and
`interferon-gamma-inducible protein (IP)-10 proteins in the
`corneal epithelium and conjunctiva of C57BL/6 mice(32).
`
`Inflammatory cascade and immune system
`The increase in soluble and cellular inflammatory media-
`tors in the tear fluid, conjunctiva and lacrimal glands initia-
`tes an inflammatory cascade on the ocular surface, evidenced
`by increased expression of immune activation and adhesion
`molecules (HLA-DR and ICAM-1) by the conjunctival epi-
`thelium. These molecules function to attract and retain in-
`flammatory cells in the conjunctiva.
`Upregulation of expression of HLA-DR and ICAM-1 has
`been reported in a variety of dry eye diseases, such as ocular
`rosacea, non-Sjögren’s syndrome (SS) aqueous tear deficient
`and SS patients(33-36), but the highest expression of HLA-DR
`was found in the conjunctival epithelium of SS patients(33,36).
`Increased HLA-DR antigen expression by the conjunctival
`epithelium detected by flow cytometry has been observed as
`a universal feature of dry eye(37-38).
`
`Role of T cells
`Sjögren’s syndrome is characterized by dry eyes, dry
`mouth, vasculitis and neurologic disease. The cardinal mani-
`festation of SS is dryness, resulting from exocrine gland dys-
`function. At the cellular level, the involved exocrine tissues
`(including the lacrimal gland) are infiltrated with lympho-
`cytes, monocytes and plasma cells(39). T cell infiltration of
`the conjunctiva has been observed in both SS and non-SS
`KCS(40-41).
`There is increased evidence that CD4+ T cells are invol-
`ved in the pathogenesis of dry eye. In an animal model,
`increased infiltration of CD4+T cells in the goblet cell rich
`area was accompanied by increased expression of IFN-y, go-
`blet cell loss and conjunctival metaplasia(17). Inflammation
`in the lacrimal glands, cornea, and conjunctiva, resulting in
`decreased tear production and conjunctival goblet cell loss,
`was transferable from wild type mice subjected to expe-
`rimental dry eye to T-cell-deficient nude mice that have not
`been exposed to desiccating stress(7). Using a similar ap-
`proach, CD4+ T cells adoptively transferred from animals
`deficient in the autoimmune regulator (aire) gene to immuno-
`deficient recipients mice caused advanced ocular surface
`keratinization(42).
`
`Anti-inflammatory therapy in dry eye
`Clinical evidence indicates that anti-inflammatory thera-
`pies that inhibit these inflammatory mediators reduce the
`signs and symptoms of keratoconjunctivis sicca (KCS). Our
`review will therefore focus on the current available anti-
`inflammatory therapy of dry eye.
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`Rationale for anti-inflammatory therapy in dry eye syndrome
`
` 91
`
`Corticosteroids
`Corticosteroids are potent anti-inflammatory agents that
`are routinely used to control inflammation in many organs.
`Corticosteroids have multiple mechanisms of action. They
`work through traditional glucocorticoid receptor mediated
`pathways to directly regulate gene expression and they also
`work through non-receptor pathways to interfere with trans-
`criptional regulators of pro-inflammatory genes, such as NF-
`kB. Among their multiple biological activities, corticoste-
`roids inhibit inflammatory cytokine and chemokine produc-
`tion, decrease the synthesis of matrix metalloproteinases and
`lipid mediators of inflammation (e.g. prostaglandins), de-
`crease expression of cell adhesion molecules (e.g. ICAM-1)
`and stimulate lymphocyte apoptosis(43-48). They have been
`reported to decrease the production of a number of inflam-
`matory cytokines (IL-1, IL-6, IL-8, TNF-α, GM-CSF) and
`MMP-9 by the corneal epithelium(49).
`Corticosteroids have been successfully used to treat the
`corneal epithelial disease in dry eye(50-52) in several clinical
`studies. In a retrospective clinical series, topical adminis-
`tration of a 1% solution of non-preserved methylpredniso-
`lone, given 3-4 times daily for two weeks to patients with
`Sjögren syndrome KCS, provided moderate to complete re-
`lief of symptoms in all patients(51). In addition, there was a
`decrease in corneal fluorescein staining and complete resolu-
`tion of filamentary keratitis. This therapy was effective even
`for patients suffering from severe KCS who had no improve-
`ment with maximum aqueous enhancement therapies. In a
`prospective, randomized clinical trial, topical treatment of
`dry eye patients with non-preserved methylprednisolone and
`punctual plugs significantly decreased the severity of ocular
`irritation symptoms and corneal fluorescein staining com-
`pared to the group that received punctual occlusion alone(53).
`No steroid related complications were observed in this study.
` A randomized, double-masked, placebo-controlled study
`of loteprednol etabonate showed that a subset of patients
`with the most severe inflammatory signs at entry, treated
`topically with loteprednol, showed a significantly greater
`decrease in central corneal fluorescein staining scores when
`compared to its vehicle (31% vs. 0%, respectively). There was
`also a significant decrease in inferior bulbar conjunctival
`hyperemia (25%) in the loteprenol treated group compared to
`the vehicle treated group that had a 33% increase. There was
`no change in intraocular pressure in the steroid treated group.
`In another open-label randomized study, patients with
`KCS that received fluorometholone plus artificial tear substi-
`tutes experienced lower symptom severity scores, fluorescein
`and rose bengal staining than either patients receiving either
`artificial tear substitute alone, or artificial tear substitute plus
`flurbiprofen(54).
`The corticosteroid methylprednisolone was noted to
`preserve corneal epithelial smoothness and barrier function
`in an experimental murine model of dry eye(55). This was
`attributed to its ability to maintain the integrity of corneal
`epithelial tight junctions and decrease desquamation of api-
`
`cal corneal epithelial cells (de Paiva et al. 2006)(55). A concur-
`rent study showed that methylprednisolone prevented an in-
`crease in MMP-9 protein in the corneal epithelium, as well as
`gelatinase activity in the corneal epithelium in response to
`experimental dry eye(29).
`Taken together, these studies indicate that topical corti-
`costeroids are an important tool in the management of dry
`eye. While no steroid related complications were observed in
`these short-term clinical trials, there is the potential for toxi-
`city with long term use, such as increase on intraocular pres-
`sure and cataracts. This may limit the use of more potent
`steroids for chronic therapy of dry eye. The risk-benefit ratio
`may be better with “soft steroids” such as fluorometholone
`and loteprednol etabonate that have less intraocular activity
`and a lower likelihood of raising intraocular pressure.
`
`Cyclosporine
`Cyclosporine A (CsA) is a lipophilic cyclic undecapep-
`tide isolated from the fungus Hypocladium inflatum gams(56).
`It was first introduced for clinical use in 1983, as an immu-
`nosuppressant drug to prevent organ rejection after trans-
`plant. The immunomodulatory effect of the drug has proved
`to be beneficial for treatment of a broad group of diseases that
`have in common an underlying inflammatory response in
`their pathophysiology (psoriasis, rheumatoid arthritis, ulce-
`rative colitis, etc).
`One of the mechanisms of action of CsA is the inhibition
`of calcineurin, (a serine/threonine phosphatase) with subse-
`quent restriction in the expression of certain genes involved
`in T-cell activation (IL-2, IL-4, IL-12p40). CsA also can bind
`cyclophiline D, and the complex formed can prevent the
`opening of the mitochondrial permeability transition pore in
`response to stress stimuli, thus preventing apoptosis. There is
`evidence that CsA blocks JNK and p38 signaling pathways as
`well and it has been shown to induce the synthesis of TGF-β
`in vivo and in vitro(56).
`The potential of cyclosporine-A (CsA) for treating dry eye
`disease was initially recognized in dogs that develop sponta-
`neous KCS(57). Since the initial description, the therapeutic
`efficacy of CsA for human KCS has been well documented,
`with evidence ranging from several small single center ran-
`domized double-masked clinical trials to several large
`multicenter randomized, double-masked clinical trials(58-60).
`Two independent phase 3 clinical trials compared twice
`daily treatment with 0.05% or 0.1% CsA or vehicle in 877
`patients with moderate to severe dry eye disease(60-61). When
`the results of the two phase 3 trials were combined for statis-
`tical analysis, patients treated with CsA, 0.05% or 0.1%,
`showed significantly (P≤0.05) greater improvement in two
`objective signs of dry eye disease (corneal fluorescein stai-
`ning and anesthetized Schirmer test values) than those trea-
`ted with vehicle. An increased Schirmer test score was obser-
`ved in 59% of patients treated with CsA, with 15% of patients
`having an increase of 10 mm or more. In contrast, only 4% of
`vehicle-treated patients had this magnitude of change in
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`92 Rationale for anti-inflammatory therapy in dry eye syndrome
`
`their Schirmer test scores (P<0.0001). CsA 0.05% treatment
`also produced significantly greater improvements (P<0.05)
`in three subjective measures of dry eye disease (blurred vi-
`sion symptoms, need for concomitant artificial tears, and the
`global response to treatment). No dose-response effect was
`noted. Both doses of CSA exhibited an excellent safety pro-
`file with no significant systemic or ocular adverse events,
`except for transient burning symptoms after instillation in
`17% of patients. Burning was reported in 7% of patients
`receiving the vehicle. No CsA was detected in the blood of
`patients treated with topical CsA for 12 months. Clinical
`improvement that was observed in these trials from CsA was
`accompanied by improvement in other disease parameters.
`Treated eyes had an approximately 200% increase in con-
`junctival goblet cell density(62). Furthermore, there was de-
`creased expression of immune activation markers (i.e. HLA-
`DR), apoptosis markers (i.e. Fas), and the inflammatory cyto-
`kine IL-6 by the conjunctival epithelial cells(63-64). The num-
`bers of CD3, CD4, and CD8-positive T lymphocytes in the
`conjunctiva decreased in cyclosporine-treated eyes, while
`vehicle-treated eyes showed an increased number of cells
`expressing these markers(62). Following treatment with 0.05%
`cyclosporine, there was a significant decrease in the number
`of cells expressing the lymphocyte activation markers
`CD11a and HLA-DR, indicating less activation of lymphocy-
`tes compared with vehicle-treated eyes.
`Topical CsA significantly reduced conjunctival epithe-
`lial apoptosis and protected against goblet cell loss in ex-
`perimental murine dry eye(65-66), while reducing the number of
`CD4+ T cells infiltrating the conjunctiva. It also retained the
`intraepithelial lymphocyte population in the same area(66).
` In December 2002, the US Food and Drug Administration
`approved CsA 0.05% ophthalmic emulsion for treatment of
`dry eye disease and it has been a record number of prescrip-
`tions in the USA and worldwide.
`
`Tetracyclines and their derivatives
`The tetracyclines have anti-inflammatory as well as anti-
`bacterial properties that may make them useful for the manage-
`ment of chronic inflammatory diseases. These agents decrease
`the activity of collagenase, phospholipase A2, and several
`matrix metalloproteinases. They also decrease the production
`of IL-1α and TNF-α in a wide range of tissues, including the
`corneal epithelium(67-69). At high concentrations, tetracyclines
`inhibit staphylococcal exotoxin-induced cytokines and che-
`mokines(70-71). Tetracyclines are also known to inhibit matrix
`metalloproteinase expression, suggesting a rationale for their
`use in ocular rosacea(72). Tetracyclines can also inhibit angio-
`genesis, that may develop in benign conditions (e.g., rosacea)
`and malignant processes (e.g., cancer). Minocycline and doxy-
`cycline were found to inhibit angiogenesis induced by im-
`planted tumors in rabbit cornea(73).
`Tetracyclines have been used extensively to treat rosa-
`cea(74-77). Rosacea, including its ocular manifestations, is an
`inflammatory disorder, occurring mainly in adults with peak
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`Arq Bras Oftalmol. 2008;71(6 Supl):89-95
`
`severity in the third and fourth decades. It is characterized by
`vasomotor instability (flushing) of the face, neck, and upper
`chest. Chronic facial inflammation may lead to persistent
`facial erythema and telangiectasia formation, and, ultima-
`tely, significant deformity of the central face. Current recom-
`mendations are to treat rosacea with long-term doxycycline,
`minocycline, tetracycline, or erythromycin. These recom-
`mendations may be tempered by certain recent reports that in
`women, the risk of developing breast cancer and breast can-
`cer morbidity increases cumulatively with duration of anti-
`biotic use, including tetracyclines78-79. Another large study
`did not substantiate these findings(80).
`The already mentioned anti-inflammatory effects of tetra-
`cycline may explain, at least in part, their beneficial effects in
`rosacea. Inhibition of angiogenesis may be a contributory factor
`in the therapeutic effect of tetracycline in this group of disor-
`ders. Factors that promote angiogenesis may contribute to the
`telangiectasia of rosacea. These include protease-triggered re-
`lease of angiogenic factors stored in the extracellular matrix,
`inactivation of endothelial growth factor inhibitors, and release
`of angiogenic factors from activated macrophages(81-82). Tetra-
`cycline derivatives (e.g. minocycline, doxycycline) have been
`recommended as treatment options for chronic blepharitis be-
`cause of their high concentration in tissues, low renal clearance,
`long half-life, high level of binding to serum proteins, and de-
`creased risk of photosensitization(83).
`Doxycycline was discovered in the early 1960’s as a semi-
`synthetic long-acting tetracycline derivative useful as a bac-
`terial ribosome inhibitor in a wide variety of microbes. In
`subantimicrobial doses it is also an effective primary treatment
`for rosacea, sterile corneal ulceration, and effective adjunctive
`treatment for adult periodontitis(84-86). Doxycycline has been
`shown to effectively inhibit MMP-9 in a wide variety of mouse
`and human cells including prostate epithelium, epidermal
`keratinocytes, and the aortic endothelium(87-90).
`Previously reported studies using experimental dry eye
`model demonstrated that doxycycline was efficacious in de-
`creasing gelatinolytic activity in the ocular surface epithelia,
`as well as decreasing levels of MMP-9 mRNA transcripts, and
`preventing experimental dry eye-induced increase in inflam-
`matory cytokines IL-1 and TNF-α(29). Doxycycline also im-
`proved corneal surface regularity and improved corneal bar-
`rier function(55). At the cellular level, doxycycline preserved
`apical epithelial cell area and the tight-junction protein oc-
`cludin, resulting in a decreased number of desquamating
`epithelial cells from the surface of the cornea(55,91). These fin-
`dings were also confirmed in cultured human corneal epi-
`thelial cells treated with doxycycline subjected to osmotic
`stress that increases their production of MMP-9(28).
`A phase 3 FDA clinical trial is underway to evaluate the
`efficacy of a topical novel preparation of doxycycline in dry
`eye patients.
`One randomized controlled clinical trial of tetracycline in
`ocular rosacea compared symptom improvement in 24 pa-
`tients treated with either tetracycline or doxycycline(77). All
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`but one patient reported an improvement in symptoms after 6
`weeks of therapy. No placebo group was included in this trial.
`A prospective, randomized, double-blind, placebo-control-
`led, partial crossover trial compared the effect of oxytetracy-
`cline to provide symptomatic relief of blepharitis with or
`without rosacea. Only 25% of the patients with blepharitis
`without rosacea responded to the antibiotic, whereas 50%
`responded when both diseases were present(92). In another
`trial of 10 patients with both acne rosacea and concomitant
`meibomianitis, acne rosacea without concomitant ocular in-
`volvement, or seborrheic blepharitis, minocycline 50 mg
`daily for 2 weeks followed by 100 mg daily for a total of 3
`months significantly decreased bacterial flora. Clinical im-
`provement was seen in all patients with meibomianitis(93).
`Because of the improvement observed in small clinical
`trials of patients with meibomianitis, the American Academy
`of Ophthalmology recommends the chronic use of either doxy-
`cycline or tetracycline for the management meibomianitis(94).
`Larger randomized placebo-controlled trials assessing symp-
`tom improvement rather than surrogate markers are needed to
`clarify the role of this antibiotic in blepharitis treatment(71).
`Several studies have described the beneficial effects of mino-
`cycline and other tetracycline derivatives (e.g. doxycycline)
`in the treatment of chronic blepharitis(83,95-97). Studies have
`shown significant changes in the aqueous tear parameters,
`such as tear volume and tear flow following treatment that
`with tetracycline derivatives (e.g. minocycline). One study
`also demonstrated a decrease in the aqueous tear production
`that occurred along with clinical improvement(98).
`The randomized prospective study by Yoo and collea-
`gues(99) compared 2 different doxycycline doses (200 mg and
`20 mg/day) in patients who had chronic meibomian gland
`dysfunction and who did not respond to lid hygiene and
`topical therapy for more than 2 months. Both the high and
`low dose group had statistically significant improvement in
`TBUT after treatment. This implies that low dose doxycy-
`cline (20 mg twice a day) therapy may be effective in patients
`with chronic meibomian gland dysfunction.
`
`Essential fatty acids
`Essential fatty acids are necessary for complete health and
`they cannot be synthesized by vertebrates and must be obtai-
`ned from dietary sources. Among the essential fatty acids are
`18 carbon omega-6 and omega-3 fatty acids. In the typical
`western diet, 20-25 times more omega-6 than omega-3 fatty
`acids are consumed. Omega-6 fatty acids are precursors for
`arachidonic acid and certain pro-inflammatory lipid media-
`tors (PGE2 and LTB4). In contrast, certain omega-3 fatty acids
`(e.g. EPA found in fish oil) inhibit the synthesis of these lipid
`mediators as well as block production of IL-1 and TNF-
`alpha(100-101). A beneficial clinical effect of fish oil omega-3
`fatty acids on rheumatoid arthritis has been observed in seve-
`ral double-masked placebo-controlled clinical trials(102-103). In
`a prospective placebo-controlled clinical trial of the essen-
`tial fatty acids linoleic acid and gamma-linoleic acid admi-
`
`nistered orally twice daily produced significant improve-
`ment in ocular irritation symptoms and ocular surface lissa-
`mine green staining(104). Decreased conjunctival HLA-DR
`staining also was observed.
`In dry eye induced animal, topical treatment with alpha-
`linolenic acid significantly decreased corneal fluorescein
`staining compared with both vehicle and untreated controls
`and decreased CD11b(+) cell number, expression of corneal
`IL-1α and TNF-α, and conjunctival TNF-α(105).
`
`RESUMO
`
`Olho seco é uma doença multifatorial que resulta em disfunção
`da unidade lacrimal glandular. Evidências sugerem que infla-
`mação está involvida na patogênese da doença. Mudanças na
`composição das lágrimas, incluindo aumento de citocinas,
`quimiocinas, metaloproteinases e o número de células T na
`conjuntiva são encontrados em pacientes com olho seco e em
`modelos animais. Esta inflamação é responsável em parte pe-
`los sintomas de irritação, doença epitelial de surperfície ocular
`e função epitelial de barreira alterada em olho seco. Existem
`várias terapias antiinflamatórias que se direcionam para um ou
`mais mediadores/vias que foram identificados e são discutidos
`em detalhe.
`
`Descritores: Síndromes do olho seco; Inflamação; Concen-
`tração osmolar; Ciclosporina/uso terapêutico; Doxiciclina/
`uso terapêutico; Citocinas/uso terapêutico; Metaloprotea-
`ses; Antiinflamatórios/uso terapêutico
`
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