Stimulation of Matrix Metalloproteinases by Hyperosmolarity via a JNK Pathway in Human Corneal Epithelial Cells

Li, Dequan; Chen, Zhuo; Song, Xiu Jun; Luo, Lihui; Pflugfelder, Stephen C.

doi:10.1167/iovs.04-0299

Cited by 344 publications

(228 citation statements)

References 63 publications

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“…[43][44][45][46][47] Disturbances in secretion or composition of tear film lead to dysfunction of tear film that displays a broad spectrum of symptoms with varying degree of severity associated with many eye pathologies. [48][49][50] The most common is dry eye disease, which can be caused either by deficient tear production or increased tear evaporation.…”

Section: The Tear Filmmentioning

confidence: 99%

“…54,55 Increased tear osmolarity is a significant stress factor that activates several stress-signaling pathways resulting in transcription of stress-related genes, such as proinflammatory cytokines TNF-α, IL-1, IL-6, or matrix metalloproteinases. 46,47 So far, the osmolarity of aniridic tears has not been assessed and the composition of tear fluid, as well as the expression levels of the particular tear components in aniridia has been largely unknown. Recent research, 53 however, revealed different levels of several proteins in aniridic tears when compared with healthy tears.…”

Section: The Tear Filmmentioning

confidence: 99%

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Congenital Aniridia and the Ocular Surface

et al. 2016

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Aniridia is a congenital pan-ocular disorder caused by haplo-insufficiency of Pax6, a crucial gene for proper development of the eye. Aniridia affects a range of eye structures, including the cornea, iris, anterior chamber angle, lens, and fovea. The ocular surface in particular can be severely affected by a progressive pathology termed aniridiaassociated keratopathy (AAK), markedly contributing to impaired vision. The purpose of this review is to provide an update of the current knowledge of the genetic, clinical, micromorphological, and molecular aspects of AAK. We draw upon material presented in the literature and from our own observations in large aniridia cohorts. We summarize signs and symptoms of AAK, describe current options for management, and discuss the latest research 2 findings that may lead to better diagnosis and new treatment or prevention strategies for this debilitating ocular surface condition.

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Section: The Tear Filmmentioning

confidence: 99%

Section: The Tear Filmmentioning

confidence: 99%

Congenital Aniridia and the Ocular Surface

et al. 2016

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“…This initiates the vicious circle of dry eye pathology in a final common pathway. Hyperosmolarity induces inflammatory cascade activation [135][136][137], increases apoptosis [138][139][140], and stimulates expression and activity of MMPs [141,142], causing ocular surface barrier disruption [143,144]. In severe cases, dry eye also leads to squamous metaplasia involving ocular surface epithelial cell transdifferentiation from a wet mucosal phenotype to a keratinized skin-like phenotype [145].…”

Section: Ocular Surface Barrier Function In Dry Eye Diseasementioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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, M. R. (2016). Clusterin in the eye: an old dog with new tricks at the ocular surface. Experimental Eye Research, Clusterin in the eye: an old dog with new tricks at the ocular surface AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Competing Interests: US patent 9,241,974 B2 entitled "Clusterin pharmaceuticals and treatment methods using the same" (inventors: MEF and SJ), assigned to the University of Southern California, is connected with this work. MEF holds a management position with Proteris Biotech, Inc., Pasadena, CA, which is developing Protearin for dry eye based on clusterin. MRW declares that he has no competing interests. Page 3 of 65 AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had bee...

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“…The hyperosmolarity of the cells prompts the production of a cascade of proinflammatory cytokines. 21 Conjunctival hyperemia, superficial punctate keratitis and symptoms of ocular discomfort are just a few of the clinical manifestations of tear cytokine upregulation. 21 In patients topically medicated for glaucoma, TFO have been demonstrated to be elevated compared with normal values.…”

Section: Introductionmentioning

confidence: 99%

“…21 Conjunctival hyperemia, superficial punctate keratitis and symptoms of ocular discomfort are just a few of the clinical manifestations of tear cytokine upregulation. 21 In patients topically medicated for glaucoma, TFO have been demonstrated to be elevated compared with normal values. 22,23 However, the previous studies did not compare these TFO values to a group of normal patients as controls.…”

Section: Introductionmentioning

confidence: 99%

Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity

Lee

Wong

Chua

et al. 2013

Eye

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Purpose To evaluate the tear film osmolarity (TFO) and ocular surface clinical signs and symptoms in chronically medicated glaucoma patients and post-trabeculectomy patients. Methods This is a single-center, prospective case-controlled study. One-hundred and thirty eyes of 130 participants aged Z45 years were included (49 normal controls, 50 glaucoma patients on chronic preserved antiglaucoma medication Z6 months, and 31 post-trabeculectomy patients not on medication Z6 months). TFO, tear break-up time (TBUT), Schirmer's test I and dry eye symptoms were evaluated. Data from both groups of glaucoma patients were compared with age and sex-matched controls. Logistic regression was performed to calculate the odds ratios. Results Mean TFO in the three groups were 301.4 ± 7.7, 307.0 ± 9.3, and 307.4 ± 11.6 mOsm/l, respectively. Compared with normal controls, chronically medicated glaucoma patients and post-trabeculectomy patients were more likely to have a raised TFO, with odds ratios (95% CI) of 4.43 (1.74-11.32) and 2.76 (1.02-7.94), respectively. Both groups of glaucoma patients were also more likely to experience dry eye symptoms, with ORs of 4.72 (1.92-11.59) and 4.24 (1.54-11.72). There was no significant difference in TFO and symptoms between both groups of glaucoma patients, and in TBUT and Schirmer's test across all three groups. Conclusions Patients on chronic topical antiglaucoma medication and posttrabeculectomy patients were more likely to have raised TFO and dry eye symptoms, suggesting significant ocular surface disease. Glaucoma practitioners should be aware that dry eye symptoms and raised TFO may occur in the absence of TBUT and Schirmer's test abnormality.

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Stimulation of Matrix Metalloproteinases by Hyperosmolarity via a JNK Pathway in Human Corneal Epithelial Cells

Cited by 344 publications

References 63 publications

Congenital Aniridia and the Ocular Surface

Congenital Aniridia and the Ocular Surface

Clusterin in the eye: An old dog with new tricks at the ocular surface

Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity

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