Towards a closed eye model of the pre-ocular tear layer

Sack, Robert A.; Beaton, Ann; Sathe, Sonal; Morris, Carol A.; Willcox, Mark; Bogart, Bruce Ian

doi:10.1016/s1350-9462(00)00006-9

Cited by 125 publications

(100 citation statements)

References 68 publications

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“…11 Consistent with this finding is the observation that tear MMP-9 concentration increases in the nocturnal closed eye. 21 We previously observed that among dry eye patients, the highest tear MMP-9 concentrations were in patients with Sjö gren's syndrome, the most severe dry eye condition in which the ability to reflex tear is lost, similar to the scopolamine-treated mice in this study. 10 Among these eyes, the highest MMP-9 concentrations were observed in patients who developed corneal epithelial defects and sterile stromal ulceration.…”

Section: Discussionsupporting

confidence: 73%

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Pflugfelder

Farley

Luo

et al. 2005

The American Journal of Pathology

276

239

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Altered corneal epithelial barrier function is the cause for ocular irritation and visual morbidity in dry eye disease. Increased matrix metalloproteinase (MMP)-9 activity has been observed in the tear fluid of dry eye patients. To determine the pathogenic role of MMP-9 in the corneal epithelial disease of dry eye, the effects of experimentally induced dry eye on corneal epithelial morphology and barrier function were compared in MMP-9 knockout mice and their wild-type littermates. Dry eye was created through cholinergic blockade and exposure to a desiccating environment. The tear fluid MMP-9 concentration increased in response to dryness in wild-type mice. Corneal epithelial permeability to three different-sized molecules increased in dry eye wild-type mice, but not in MMP-9 knockout mice. Topical administration of active MMP-9 to dry eye MMP-9 knockout mice significantly increased corneal epithelial permeability. Compared to MMP-9 knockout mice, wild-type mice showed greater desquamation of differentiated apical corneal epithelial cells that expressed the tight junction protein occludin in response to dryness. This was accompanied by an increase in lower sized (50 kd) occludin in the corneal epithelia of wild-type mice. These findings could be replicated in cultured human corneal epithelial cells that were treated with active MMP-9. These studies indicate that increased MMP-9 activity on the ocular surface in response to dryness disrupts corneal epithelial barrier function. This appears to be because Corneal epithelial disease, termed keratitis sicca, is a severe and sight-threatening complication of dry eye. 1 A key clinical feature of keratitis sicca is disruption of corneal epithelial barrier function. [2][3][4] This results in eye irritation, corneal surface irregularity, blurred and fluctuating vision, and increased risk for corneal ulceration. 4 -8 Ocular surface inflammation has been implicated in the pathogenesis of keratitis sicca. Elevated levels of proinflammatory cytokines, such as interleukin (IL)-1, have been detected in the tear fluid of patients with this condition. 9 -11 Furthermore, the concentration and activity of matrix metalloproteinase (MMP)-9 in the tear fluid was found to be significantly increased in these eyes, with the highest concentrations observed in eyes with the severe corneal epithelial disease or sterile corneal ulcers. 10 -12 We hypothesize that MMP-9 plays an important role in the disruption of corneal epithelial barrier function in dry eye. We previously reported an experimental murine model of dry eye that disrupts corneal epithelial barrier function similar to human dry eye disease. 13 The purpose of this study was to compare the effects of experimentally induced dry eye (EIDE) on corneal epithelial morphology and barrier function in MMP-9 knockout mice and their wild-type (WT) littermates. Materials and Methods MiceThis research protocol was approved by the Baylor College of Medicine Center for Comparative Medicine and it conformed to the standards in the Association...

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Section: Discussionsupporting

confidence: 73%

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Pflugfelder

Farley

Luo

et al. 2005

The American Journal of Pathology

276

239

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“…Both sites are repeatedly exposed to a variety of foreign substances and organisms and possess efficient mechanisms that limit infection. The eyes and the oral cavity are bathed in fluid that is secreted by the tear or salivary glands, which secrete mucins and antimicrobial peptides and proteins, including MUC7, histatin, lysozyme, and, as is now known, gp340 (13,22).…”

Section: Discussionmentioning

confidence: 99%

“…The ocular surface is constantly exposed to environmental pathogens that are prevented from colonizing the mucosal surface by the tear film antimicrobial defenses and the sweeping actions of the eyelids. Known antimicrobial components of the tear film include, defensins, MUC7, histatin, lysozyme, lactoperoxidase, transferrin, and surfactant protein D (SPD) (8,13,20,22,25).…”

mentioning

confidence: 99%

Glycoprotein 340 in Normal Human Ocular Surface Tissues and Tear Film

Jumblatt¹,

Imbert²,

Young³

et al. 2006

Infect Immun

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The tear film is a complex mixture of secreted fluid, ions, proteins, glycoproteins, and lipids that lubricates and protects the ocular surface. Recently, several antimicrobial peptides have been described in the tear fluid. In this study, we describe the presence of the large secreted glycoprotein gp340 in the tear film. Western blot analysis showed that gp340 is abundant in secreted tears and in the lacrimal glands. Lesser amounts of gp340 were detected in the cornea and conjunctiva. Consistent with Western blot data, reverse transcription-PCR and real-time quantitative PCR showed that gp340 transcripts were abundant in lacrimal gland tissue and were also present in the cornea and conjunctiva. Immunohistochemistry localized gp340 to the acinar cells of the lacrimal gland and the deeper layers of the conjunctival epithelium. gp340 was not detected in conjunctival goblet cells. In the cornea, gp340 was present only in a peripheral band of basal epithelial cells, suggesting that gp340 may play a role in the cycle of corneal epithelial renewal. To determine if tear film gp340 may function as a bacterial agglutinin as it does in saliva, tears were incubated with streptococcal cells and the formation of bacterial aggregates was monitored. Addition of tears to late-exponential-phase Streptococcus mutans cells resulted in time-and dose-dependent aggregation of the bacteria. Furthermore, Western blot analysis confirmed the presence of cell-associated gp340 in isolated bacterial aggregates. The ocular pathogen Staphylococcus aureus, but not Pseudomonas aeruginosa, also aggregated when incubated with tears. These results suggest that gp340 is a normal component of the tear film and that the glycoprotein may function as a bacterial agglutinin.

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“…42 While this mechanism for corneal epithelial desquamation has not been confirmed in human corneas, increased levels of MMP-2 and -9 have been found in cornea epithelium and tear fluid obtained from eyes with recurrent corneal epithelial erosion, 43,44 and increased proand active forms of MMP-9 have also been found in tears sampled from the closed eye during sleep when recurrent erosions typically occur while tear production and clearance are decreased. 45 There is mounting evidence that MMPs contribute to the altered cornea barrier function that is observed in dry eye. [46][47][48] Increased cornea epithelial permeability to fluorescent dyes is observed in human dry eye (sodium fluorescein) and experimental mouse models (fluorescent dextran conjugates).…”

mentioning

confidence: 99%

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

Pflugfelder¹,

Bian²,

Paiva³

2017

MNM

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Dry eye and tear dysfunction are common ocular disorders that cause cornea barrier disruption resulting in a poorly lubricated and irregular cornea epithelium, eye irritation and blurred vision. Increased levels and activities of matrix metalloproteinases (MMPs), particularly MMP-9, have been detected in the tears and ocular surface epithelial and inflammatory cells in dry eye. MMPs have been found to participate in disruption of tight junctions in the apical cornea epithelium leading to their accelerated desquamation and barrier disruption. This review summarizes evidence showing the contribution of MMPs to dry eye pathogenesis and their roles as biomarkers and therapeutic targets. Keywords: matrix metalloproteinase, dry eye, keratitis sicca, cornea, barrier function, Sjögren syndrome Dry eye overviewDry eye and tear dysfunction are common ocular disorders that cause cornea barrier disruption resulting in a poorly lubricated and irregular cornea epithelium, eye irritation and blurred vision. It affects millions of people worldwide and is one of the most frequent conditions for which patients seek eye care.1 Aging and female sex are significant risk factors for dry eye which increases in prevalence around the fifth decade, with further increase every decade thereafter.2-13 Prevalence of dry eye varies from 2% to 50%, depending on the population studied and the diagnostic criteria for dry eye (symptom questionnaire vs. objective signs). [1][2][3]6,7,[9][10][11][14][15][16][17][18][19][20][21][22][23] There is scarce information about the natural history of dry eye, but there is a recognized disconnection between signs and symptoms; patients tend to be more symptomatic at early stages.24,25 Dry eye causes corneal irregularity [26][27][28] and decreases functional vision by altering contrast sensitivity [29][30][31] and, therefore, decreases quality of life with a significant burden on the individual as well as the society. 23,[32][33][34][35] A meta-analysis of 22 published studies showed increased odds ratio for depression and anxiety in patients with ocular Sjögren syndrome (SS). 36 There is increased evidence that dry eye is an inflammatory disease, and this review will focus on matrix metalloproteinases (MMPs) and their role in the pathogenesis of dry eye. Cornea barrier disruption is a feature of dry eyeAs the principal lens of the eye, the cornea has unique features to maintain its transparency and smooth surface that include a lack of blood vessels and a multilayered stratified, non-cornifying epithelium. The differentiated apical epithelial cells produce

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Towards a closed eye model of the pre-ocular tear layer

Cited by 125 publications

References 68 publications

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Glycoprotein 340 in Normal Human Ocular Surface Tissues and Tear Film

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

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