Serine Protease Inhibitor A3K Suppressed the Formation of Ocular Surface Squamous Metaplasia in a Mouse Model of Experimental Dry Eye

Zhong, Lin; Yan, Zhou; Wang, Yuqian; Zhou, Tong; Li, Jie; Luo, Pingping; He, Hui; Wu, Huping; Liu, Zuguo

doi:10.1167/iovs.13-13546

Cited by 18 publications

(16 citation statements)

References 37 publications

(43 reference statements)

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“…Given the fact that epithelial cell hyperplasia was observed in the saline- but not the α-MSH-treated dry eye corneas ( Fig. 4 ), the α-MSH’s promotion on cell proliferation appears unlikely, although Ki67 or 5-Bromo-2´-Deoxyuridine staining is needed to exclude this possibility 40 . Therefore, TUNEL staining was performed to examine the effects of α-MSH on apoptosis.…”

Section: Discussionmentioning

confidence: 96%

α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways

Huang

Liu

et al. 2015

Sci Rep

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Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10−4 μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH’s protective effects, suggesting that both pathways are necessary for α-MSH’s protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED.

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Section: Discussionmentioning

confidence: 96%

α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways

Huang

Liu

et al. 2015

Sci Rep

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“…2 Abnormal differentiation is an important feature of squamous metaplasia, which causes the pathological transition of a nonkeratinized, stratified epithelium into a nonsecretory, keratinized epithelium. 1,24,48 The emergence of epidermisspecific K10 protein, a lower level of Pax6 expression and goblet cell loss indicates that the epithelium has lost its secretory function and has been replaced by squamous epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Many ocular surface diseases such as dry eye, Stevens-Johnson syndrome, mucous membrane pemphigoid, chemical/thermal burns, pterygium, and vitamin A deficiency often show chronic inflammation of the ocular surface. [3][4][5][6] Chronic inflammation can lead to squamous metaplasia of the ocular surface epithelium through a signaling pathway.…”

mentioning

confidence: 99%

“…Squamous metaplasia may, in turn, exacerbate inflammation by dysfunction or loss of cells responsible for tear secretion. 1,2,7 Antiinflammatory therapy has become a common and important therapeutic strategy for treating chronic inflammation in ocular surface diseases. 8,9 Topical corticosteroids and cyclosporine A are effective to treat chronic inflammation of ocular surface diseases.…”

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confidence: 99%

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Minocycline Inhibits Inflammation and Squamous Metaplasia of Conjunctival Tissue Culture in Airlift Conditions

Xiao

Tan

Zhong

et al. 2016

Cornea

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“…Interestingly, activation of PAR2 by serine proteases plays an important role in innate and inflammatory responses of corneal infection and inflammation 25 . It has been reported that the serine protease inhibitor A3K has promising experimental in vivo results in a mouse and rabbit model for dry eye 29,49 . In addition, KLK13 has also recently been discovered as a potential target for DES 11 .…”

Section: Discussionmentioning

confidence: 99%

A novel serine protease inhibitor as potential treatment for dry eye syndrome and ocular inflammation

Joossen

Baán

Moreno-Cinos

et al. 2020

Sci Rep

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Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options. In this study, a newly developed trypsin-like serine protease inhibitor (UAMC-00050) in a tear drop formulation was evaluated to treat ocular inflammation. A surgical animal model of dry eye was employed to investigate the potential of UAMC-00050 on dry eye pathology. Animals treated with UAMC-00050 displayed a significant reduction in ocular surface damage after evaluation with sodium fluorescein, compared to untreated, vehicle treated and cyclosporine-treated animals. The concentrations of IL-1α and TNF-α were also significantly reduced in tear fluid from UAMC-00050-treated rats. Additionally, inflammatory cell infiltration in the palpebral conjunctiva (CD3 and CD45), was substantially reduced. An accumulation of pro-MMP-9 and a decrease in active MMP-9 were found in tear fluid from animals treated with UAMC-00050, suggesting that trypsin-like serine proteases play a role in activating MMP-9 in ocular inflammation in this animal model. Comparative qRT-PCR analyses on ocular tissue indicated the upregulation of tryptase, urokinase plasminogen activator receptor (uPAR) and protease-activated receptor 2 (PAR2). The developed UAMC-00050 formulation was stable up to 6 months at room temperature in the absence of light, non-irritating and sterile with compatible pH and osmolarity. These results provide a proof-of-concept for the in vivo modifying potential of UAMC-00050 on dry eye pathology and suggest a central role of trypsin-like serine proteases and PAR2 in dry eye derived ocular inflammation.

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Serine Protease Inhibitor A3K Suppressed the Formation of Ocular Surface Squamous Metaplasia in a Mouse Model of Experimental Dry Eye

Abstract: Topical application of SERPINA3K ameliorated the severity of ocular surface squamous metaplasia and suppressed the formation of BAC-induced dry eye.

Cited by 18 publications

References 37 publications

α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways

α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways

Minocycline Inhibits Inflammation and Squamous Metaplasia of Conjunctival Tissue Culture in Airlift Conditions

A novel serine protease inhibitor as potential treatment for dry eye syndrome and ocular inflammation

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