0.005% Preservative-Free Latanoprost Induces Dry Eye-Like Ocular Surface Damage via Promotion of Inflammation in Mice

Yang, Yiran; Huang, Caihong; Lin, Xiang; Wu, Yang; Ouyang, Wei; Tang, Liying; Ye, Sihao; Wang, Yuhong; Li, Wei; Zhang, Xiaobo; Liu, Zuguo

doi:10.1167/iovs.18-24013

Cited by 34 publications

(25 citation statements)

References 33 publications

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“…The fluorescein score was analyzed as previously described 22 and as follows: absent, 0; slightly punctate staining less than 30 spots, 1; dense punctate staining more than 30 spots, 2; severe diffuse staining, but no positive plaque, 3; positive fluorescein plaque, 4. www.nature.com/scientificreports/ Measurement of tear production. Tear production (12 eyes of six mice per group) was determined with phenol red-impregnated cotton threads (AYUMI Pharmaceutical Corporation, Tokyo, Japan) as previous description with minimal modification 40 . Briefly, the thread was placed in the medial of the lower conjunctival fornix for 20 s. The length of the wet red thread was photographed and measured.…”

Section: Extracellular Vesicles Labeling and Tracking In Vitro And Inmentioning

confidence: 99%

hADSCs derived extracellular vesicles inhibit NLRP3inflammasome activation and dry eye

Chen

et al. 2020

Sci Rep

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The present study was set out to address the therapeutic efficacy of human adipose tissue stem cells derived extracellular vesicles (hADSC-Evs) in a mouse model of dry eye disease and to investigate the underlying mechanisms involved. hADSC-Evs eye drops were topically administered to mice that subjected to desiccating stress (DS). Clinical parameters of ocular surface damage were assessed with fluorescein staining, tear production and PAS staining. For in vitro studies, cell viability assay and TUNEL staining were performed in human corneal epithelial cells (HCECs) treated with hADSC-Evs under hyperosmotic media. In addition, immunofluorescent staining, Real-time PCR (qRT-PCR) and Western blots were used to evaluated NLRP3, ASC, caspase-1, and IL-1β expression levels. Compared with vehicle control mice, topical hADSC-Evs treated mice showed decreased corneal epithelial defects, increased tear production, decreased goblet cell loss, as well as reduced inflammatory cytokines production. In vitro, hADSC-Evs could protect HCECs against hyperosmotic stress-induced cell apoptosis. Mechanistically, hADSC-Evs treatment suppressed the DS induced rises in NLRP3 inflammasome formation, caspase-1 activation and IL-1β maturation. In conclusion, hADSC-Evs eye drops effectively suppress NLRP3 inflammatory response and alleviate ocular surface damage in dry eye disease. Dry eye disease (DED) is a highly prevalent ocular surface disorder in the world 1. It is estimated that more than 16 million adults are diagnosed DED in US, and the prevalence in Asia is even higher than in western countries 2,3. According to the reports of Dry Eye Workshop (DEWS II), DED is a multifactorial disease that characterized by loss of homeostasis of the tear film 4. The tear film instability causes symptoms of discomfort, itching, eye irritation, glare and blurry vision, leading to a reduction in quality of life. Although the pathogenesis of DED is not yet fully understood, mounting evidence showed that the "vicious cycle of inflammation", including tear film instability, tear hyperosmolarity, apoptosis of cornea/conjunctiva and elevated levels of pro-inflammatory cytokines, play a core driver in its initiation and progression 5,6. Accordingly, most of the treatments to date are focused on reducing inflammation and restoring normal tear film 7. Mesenchymal stem cells (MSCs) are self-renewing multipotent stromal cells that can be isolated from mesenchymal tissues such as bone marrow, adipose, umbilical cord, as well as other tissues 8. Due to their immunomodulatory and trophic characteristics, MSC-based therapeutic intervention has been explored in a variety of immune-mediated disorders, including dry eye disease 9-12. Although most of the results were promising, safety issues regarding MSC-based therapy are still a matter of concern. Extracellular vesicles, with nanosized diameter of 30-150 nm, are known as intercellular communication mediators by transferring various bioactive molecules (proteins, lipids and RNAs) 13. Recent studies revealed that MS...

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Section: Extracellular Vesicles Labeling and Tracking In Vitro And Inmentioning

confidence: 99%

hADSCs derived extracellular vesicles inhibit NLRP3inflammasome activation and dry eye

Chen

et al. 2020

Sci Rep

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“…Increased production of MMPs, particularly MMP-3 and -9, has been reported to be associated with the disruption of corneal epithelial barrier in dry eye. 26,27 Therefore, the expression of MMP-3 and -9 was examined in corneal epithelium using immunofluorescence staining and qRT-PCR. Immunofluorescence staining showed a strong fluorescence density in the corneal epithelium of BAC-induced mice and vehicle DMSO treatment, while it was alleviated after S3I-201 treatment (Fig.…”

Section: Stat3 Inhibition Decreases Mmp-3 and -9 Expression In Corneamentioning

confidence: 99%

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Wang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate the therapeutic effects of targeting signal transducer and activator of transcription-3 (STAT3) activation on the ocular surface damage of dry eye in mice. METHODS. Adult Balb/C and C57BL/6 mice with benzalkonium chloride (BAC) treatment, lacrimal gland excision, and meibomian gland dysfunction were used as dry eye models. The levels of phosphorylated STAT3 (p-STAT3) were detected with immunofluorescence staining and Western blotting. STAT3 inhibition was performed by topical application of STAT3 inhibitor S3I-201. Corneal epithelial barrier function, tear production, and conjunctival goblet cell density were quantified with fluorescein sodium staining, phenol red cotton test, and histochemical staining. The expressions of matrix metalloproteinase (MMP)-3/9, TUNEL, and inflammation cytokines were assessed with immunofluorescence staining, qPCR, and ELISA assays. The therapeutic effect of S3I-201 was further compared with the Janus kinase inhibitor tofacitinib and ruxolitinib. RESULTS. Elevated levels of nuclear p-STAT3 were detected in the corneal and conjunctival epithelium of three dry eye models. Topical application of S3I-201 improved corneal epithelial barrier function, increased tear production and conjunctival goblet cell density in BACinduced dry eye mice. Moreover, S3I-201 decreased the expression of MMP-3/9, suppressed the apoptosis of corneal and conjunctival epithelial cells, and reduced the levels of IL-1b, IL-6, IL-17A, and IFN-c. Compared with tofacitinib and ruxolitinib, the STAT3 inhibitor S3I-201 showed superior improvement of tear production and inflammatory cytokine expression in lacrimal gland. CONCLUSIONS. Elevated STAT3 activation is involved in the pathogenesis of dry eye, while targeting STAT3 effectively alleviates BAC-induced ocular surface damage.

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“…PGF2α analogues have also been linked with intraocular inflammation, [14,15] reactivation of herpes simplex keratitis, and macular edema particularly in patients with a history of uveitis or those in the post-operative period [16]. Furthermore, treatment with PGF2α analogues has been associated with an increase in markers of ocular surface inflammation in patients [17] and in animal models [18].…”

Section: Introductionmentioning

confidence: 99%

Stanniocalcin-1 (STC-1), a downstream effector molecule in latanoprost signaling, acts independent of the FP receptor for intraocular pressure reduction

et al. 2020

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Prostaglandin F2 alpha (PGF2α) analogues such as latanoprost are common first-line intraocular pressure (IOP) lowering medications. However, their clinical use is limited in some patient populations due to minimal or no IOP lowering response or side effects. In searching for a more targeted approach for IOP reduction, our lab recently identified Stanniocalcin-1 (STC-1) as a molecule that was required for latanoprost-mediated IOP reduction and also acted as a stand-alone IOP lowering agent. In order to determine whether latanoprost and STC-1 were equivalent and/or additive for IOP reduction, we treated C57BL/6J mice with one or a combination of these agents and measured IOP. Importance of the FP receptor for latanoprost-and STC-1-mediated IOP reduction was examined in C57BL/6J mice utilizing the pharmacologic FP receptor inhibitor AL-8810 as well as FP receptor knockout mice generated in our laboratory. Latanoprost-free acid (LFA) and STC-1 reduced IOP to a similar degree and were non-additive in C57BL/6J mice. As expected, the IOP lowering effects of LFA were abrogated by pharmacologic inhibition of the FP receptor with AL-8810 and in FP receptor knockout mice. In contrast, STC-1 maintained IOP-lowering effects in the presence of AL-8810 and also in FP receptor knockout mice. These results suggest that LFA and STC-1 show equivalent and non-additive IOP reduction in C57BL/6J mice and that unlike LFA, STC-1-mediated IOP reduction occurs independent of the FP receptor.

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0.005% Preservative-Free Latanoprost Induces Dry Eye-Like Ocular Surface Damage via Promotion of Inflammation in Mice

Abstract: 0.005% latanoprost induced dry eye-like ocular surface damage via promotion of inflammation in mice.

Cited by 34 publications

References 33 publications

hADSCs derived extracellular vesicles inhibit NLRP3inflammasome activation and dry eye

hADSCs derived extracellular vesicles inhibit NLRP3inflammasome activation and dry eye

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Stanniocalcin-1 (STC-1), a downstream effector molecule in latanoprost signaling, acts independent of the FP receptor for intraocular pressure reduction

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