Experimental Dry Eye Stimulates Production of Inflammatory Cytokines and MMP-9 and Activates MAPK Signaling Pathways on the Ocular Surface

Luo, Lihui; Li, Dequan; Doshi, Amish; Farley, William J.; Corrales, Rosa M.; Pflugfelder, Stephen C.

doi:10.1167/iovs.03-1145

Cited by 512 publications

(412 citation statements)

References 44 publications

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“…18 Previous studies showed that inflammatory cytokines including IL-1, IL-6, IL-8, and TNF-a, are important mediators in both human and animal DEDs. [19][20][21][22] Recent reports indicated that pro-inflammatory cytokines were significantly increased in the conjunctiva tissue and tears of NSSDE and SSDE patients. 21,22 Th17 cells are the newly recognized CD4 þ T-cell subset, which mainly produces cytokines, including IL-17A, IL-17F, and IL-22, and is involved in a wide range of autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22] Recent reports indicated that pro-inflammatory cytokines were significantly increased in the conjunctiva tissue and tears of NSSDE and SSDE patients. 21,22 Th17 cells are the newly recognized CD4 þ T-cell subset, which mainly produces cytokines, including IL-17A, IL-17F, and IL-22, and is involved in a wide range of autoimmune diseases. [11][12][13] The level of IL-17 was found to be correlated with both activity and severity of various autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome

Tan

Sun

Liu³

et al. 2014

Eye

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Purpose To determine the levels of Th17-associated cytokines, particularly interleukin (IL)-17 and IL-22 in tears of patients with dry eye syndrome. Methods Tear samples were collected from 20 healthy volunteers, 20 dry eye (DE) patients with non-Sjö gren's syndrome (NSSDE) and 20 DE patients with Sjö gren's syndrome (SSDE). Symptom questionnaire was self-administered and multiple dry eye disease (DED)-related clinical tests were performed. The levels of IL-17 and IL-22 in tears were measured by enzyme-linked immunosorbent assay. Results The levels of IL-17 and IL-22 were significantly increased in tears of DE patients compared with those of controls and also higher in SSDE patients compared with those of NSSDE patients (Po0.05). Moreover, the levels of IL-17 and IL-22 were positively correlated with questionnaire score and keratopathy score but negatively correlated with tear film break-up time and Schirmer I test in both NSSDE and SSDE patients (Po0.05). Conclusions The levels of IL-17 and IL-22 in tears were significantly increased in DE patients, which were associated with the disease severity. Therefore, Th17 cellassociated cytokines, particularly IL-17 and IL-22, may have important roles in the immunopathogenesis of the DED.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome

Tan

Sun

Liu³

et al. 2014

Eye

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“…These findings are consistent with experimental models of DED, where both the conjunctiva and cornea were inflamed because of local production of inflammatory cytokines, such as interleukin-1β), tumor necrosis factor-α, and matrix metalloproteinase-9. 41 We speculate that the improved symptoms in MGD patients who had been treated with doxycycline and/or corticosteroids were in part due to the reduction in palpebral conjunctival epithelial immune cells, not made possible with mechanical and thermal gland expression procedures alone. Our speculation is supported by the highly significant correlation between EIC and OSDI found in this study.…”

Section: Discussionmentioning

confidence: 91%

In vivo detection of clinically non-apparent ocular surface inflammation in patients with meibomian gland dysfunction-associated refractory dry eye symptoms: a pilot study

Qazi

Kheirkhah

Blackie

et al. 2015

Eye

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Purpose The utility of in vivo confocal microscopy (IVCM) in the investigation of palpebral conjunctival and corneal inflammation in patients with meibomian gland dysfunction (MGD)-associated refractory dry eye symptoms following gland expression, despite objective clinical improvement. Methods A retrospective, observational pilot study was conducted evaluating five patients with MGD-associated refractory dry eye symptoms and three control groups: symptomatic untreated MGD patients (n = 3), treatment-responsive MGD patients with improved symptoms (n = 3) and asymptomatic healthy normals (n = 11). Ocular surface disease index (OSDI) scores, tear break-up time (TBUT), the number of meibomian glands yielding liquid secretion (MGYLS), palpebral conjunctival epithelial and substantia propria immune cell (EIC, SIC), and corneal dendritic cell (DC) densities were measured. Results Despite clinical improvement (TBUT: 6.4 ± 1.2 s to 10.1 ± 2.1 s, P = 0.03; MGYLS: 3.5 ± 0.8 glands to 7.0 ± 1.1 glands, P = 0.13) and a normal clinical examination post treatment, MGD patients remained symptomatic. IVCM revealed increased immune cells in the palpebral conjunctiva (refractory MGD EIC = 592.6 ± 110.1 cells/ mm 2 ; untreated MGD EIC = 522.6 ± 104.7 cells/mm 2 , P = 0.69; responsive MGD EIC = 194.9 ± 119.4 cells/mm 2 , Po0.01; normals EIC = 123.7 ± 19.2 cells/mm 2 , Po 0.001), but not the cornea (refractory MGD DC = 60.9 ± 28.3 cells/mm 2 ; normals DC = 25.9 ± 6.3 cells/mm 2 ; P = 0.43). EIC did not correlate with TBUT (R s = − 0.26, P = 0.33). OSDI scores correlated with both EIC (R s = 0.76, Po0.001) and TBUT (R s = − 0.69, Po0.01) but not SIC. Intraglandular immune cells were also seen. Conclusion MGD-associated refractory symptoms and the symptom-sign disparity may be explained by clinically non-apparent, active inflammation of the palpebral conjunctiva as detected by IVCM. These patients may benefit from anti-inflammatory therapy.

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“…Higher levels of dye uptake in the same punctate pattern are associated with dry eye syndrome [129,132,133].…”

Section: Ocular Surface Barrier Function In Dry Eye Diseasementioning

confidence: 97%

“…Elevated gelatinolytic activity was detected within the ocular surface epithelia by in situ zymography [132].…”

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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Experimental Dry Eye Stimulates Production of Inflammatory Cytokines and MMP-9 and Activates MAPK Signaling Pathways on the Ocular Surface

Cited by 512 publications

References 44 publications

Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome

Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome

In vivo detection of clinically non-apparent ocular surface inflammation in patients with meibomian gland dysfunction-associated refractory dry eye symptoms: a pilot study

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

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