Gene expression analysis of conjunctival epithelium of patients with Stevens-Johnson syndrome in the chronic stage

Ueta, Mayumi; Sotozono, Chie; Nishigaki, H; Ohsako, Suzuko; Yokoi, Norihiko; Mizushima, Katsura; Naito, Yuji; Kinoshita, Shigeru

doi:10.1136/bmjophth-2018-000254

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…Squamous metaplasia has been defined as the pathological transition of a nonkeratinized, stratified epithelium into a nonsecretory, keratinized epithelium [ 86 ]. This is an accurate description of the changes that occur in severe ocular surface disease such as Stevens-Johnson Syndrome and vitamin A deficiency, where transformation to a skin phenotype with keratinization is observed [ 87 ]. However, squamous metaplasia in inflammatory diseases like dry eye is primarily characterized by cornification [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation

Suárez

Echenique

López

et al. 2021

IJMS

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Solar damage due to ultraviolet radiation (UVR) is implicated in the development of two proliferative lesions of the ocular surface: pterygium and pinguecula. Pterygium and pinguecula specimens were collected, along with adjacent healthy conjunctiva specimens. RNA was extracted and sequenced. Pairwise comparisons were made of differentially expressed genes (DEGs). Computational methods were used for analysis. Transcripts from 18,630 genes were identified. Comparison of two subgroups of pterygium specimens uncovered evidence of genomic instability associated with inflammation and the immune response; these changes were also observed in pinguecula, but to a lesser extent. Among the top DEGs were four genes encoding tumor suppressors that were downregulated in pterygium: C10orf90, RARRES1, DMBT1 and SCGB3A1; C10orf90 and RARRES1 were also downregulated in pinguecula. Ingenuity Pathway Analysis overwhelmingly linked DEGs to cancer for both lesions; however, both lesions are clearly still benign, as evidenced by the expression of other genes indicating their well-differentiated and non-invasive character. Pathways for epithelial cell proliferation were identified that distinguish the two lesions, as well as genes encoding specific pathway components. Upregulated DEGs common to both lesions, including KRT9 and TRPV3, provide a further insight into pathophysiology. Our findings suggest that pterygium and pinguecula, while benign lesions, are both on the pathological pathway towards neoplastic transformation.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation

Suárez

Echenique

López

et al. 2021

IJMS

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“…Elsewhere 15 we reported that the expression of some genes tended to be up-regulated in the conjunctival epithelium of patients with SJS/TEN with SOC but not in the conjunctival epithelium of the controls. We considered the hypothesis that use of the hsa-miR-455-3p inhibitor may lead to the development of new treatments.…”

Section: Comprehensive Gene Expression Analysis Of Phcjes Transfectedmentioning

confidence: 83%

“…Human conjunctival epithelium was harvested from conjunctival tissue obtained during ocular surface reconstruction for SJS/TEN in the chronic stage or conjunctival chalasis surgery. Samples were immersed overnight at 4 ºC in 1.0 U/ml −1 purified dispase (Roche Diagnostic Ltd., Basel, Switzerland) 15 for comprehensive miRNA analysis, and quantitative miRNA PCR. For transfection with the miRNA inhibitor and RT-qPCR, we cultured primary human conjunctival epithelial cells (PHCjECs) using a modified, previously-described method 16 .…”

Section: Methodsmentioning

confidence: 99%

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Regulation of gene expression by miRNA-455-3p, upregulated in the conjunctival epithelium of patients with Stevens–Johnson syndrome in the chronic stage

Ueta

Nishigaki

Sotozono

et al. 2020

Sci Rep

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To investigate the role of miRNA in the pathogenesis underlying ocular surface complications in patients with Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the chronic stage. Using oligonucleotide microarrays, we performed comprehensive miRNA analysis of the conjunctival epithelium of SJS/TEN patients with severe ocular complications (SOC) in the chronic stage (n = 3). Conjunctival epithelium of patients with conjunctival chalasis (n = 3) served as the control. We confirmed the down- and up-regulation of miRNA of interest by quantitative real-time polymerase chain reaction (RT-PCR) assays using the conjunctival epithelium from 6 SJS/TEN with SOC patients and 7 controls. We focused on miRNA-455-3p, which is significantly upregulated in the conjunctival epithelium of the SJS/TEN patients, and investigated its function by inhibiting miR-455-3p in primary human conjunctival epithelial cells (PHCjEs). Comprehensive miRNA expression analysis showed that the expression of 5 kinds of miRNA was up-regulated more than fivefold, and that the expression of another 5 kinds of miRNA was down-regulated by less than one-fifth. There was a significant difference between the SJS/TEN patients and the controls [analysis of variance (ANOVA) p < 0.05]. Quantitative miRNA PCR assay showed that hsa-miR-31* and hsa-miR-455-3p were significantly up-regulated in the conjunctival epithelium of the SJS/TEN patients. Comprehensive gene expression analysis of PHCjEs transfected with the hsa-miR-455-3p inhibitor and quantitative RT PCR assay showed that ANKRD1, CXCL8, CXCL2, GEM, PTGS2, RNASE8, IL6, and CXCL1 were down-regulated by the hsa-miR-455-3p inhibitor. Quantitative RT-PCR, focused on the genes that tended to be up-regulated in SJS/TEN with SOC, revealed that the expression of IL1A, KPRP, IL36G, PPP1R3C, and ADM was significantly down-regulated in PHCjEs transfected with the hsa-miR-455-3p inhibitor. Our results suggest that miRNA-455-3p could regulate many genes including innate immune related genes in human conjunctival epithelium, and that its up-regulation contributes to the pathogenesis on the ocular surface in SJS/TEN patients with the SOC in the chronic stage. Our findings may lead to the development of new treatments using the miRNA-455-3p inhibitor.

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“… 8 , 11 Extensive transcriptomic studies revealing significant correlation between human and rabbit DED transcriptomes, established it as a robust animal model of DED with the potential of guiding the development of successful therapeutic strategies. 28–32 …”

Section: Discussionmentioning

confidence: 99%

Once-Daily Topical Phosphosulindac Is Efficacious in the Treatment of Dry Eye Disease: Studies in Rabbit Models of Its Main Clinical Subtypes

Huang

et al. 2022

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug phosphosulindac (PS) in rabbit models of DED encompassing its pathogenesis, and its transition to chronicity. Methods: We treated three rabbit models of DED with PS (hydrogel formulation) or vehicle topically applied 1 × /day. We induced aqueous-deficient DED (acute and chronic) by injecting Concanavalin A into lacrimal glands; evaporative DED by injecting into the upper eyelid inactivated Mycobacterium tuberculosis in complete Freund's adjuvant; and mixed DED through desiccative stress, induced by holding open the eye for 3 h. We determined corneal sensitivity, tear break-up time (TBUT), Schirmer's tear test (STT), tear osmolality, and fluorescein staining of the ocular surface. Results: PS reversed all abnormal DED parameters. In acute DED, PS dose dependently normalized corneal sensitivity and tear osmolality; and improved TBUT, STT, and fluorescein staining. PS normalized corneal sensitivity and improved all other parameters in chronic aqueous-deficient DED. In evaporative DED, PS normalized corneal sensitivity and improved TBUT and fluorescein staining (osmolality and STT were not significantly changed in this model). In the desiccative stress model, PS improved TBUT and fluorescein staining but had no effect on STT or tear osmolality. Conclusions: PS rapidly reversed almost all DED parameters in its three subtypes. The normalization of the suppressed corneal sensitivity suggests the possibility of marked symptomatic relief by PS. The hydrogel formulation allows once-daily dosing. PS merits further development as a potential treatment for DED.

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Gene expression analysis of conjunctival epithelium of patients with Stevens-Johnson syndrome in the chronic stage

Cited by 6 publications

References 17 publications

Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation

Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation

Regulation of gene expression by miRNA-455-3p, upregulated in the conjunctival epithelium of patients with Stevens–Johnson syndrome in the chronic stage

Once-Daily Topical Phosphosulindac Is Efficacious in the Treatment of Dry Eye Disease: Studies in Rabbit Models of Its Main Clinical Subtypes

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