Modulation of Inflammation-Related Genes in the Cornea of a Mouse Model of Dry Eye upon Treatment with Cyclosporine Eye Drops

Daull, Philippe; Barabino, Stefano; Feraille, Laurence; Kessal, Karima; Docquier, Mylène; Mélik-Parsadaniantz, Stéphane; Baudouin, Christophe; Garrigue, Jean-Sébastien

doi:10.1080/02713683.2018.1563197

Cited by 20 publications

(18 citation statements)

References 53 publications

(70 reference statements)

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“…8 Previous studies had indicated the increased corneal IL-6 levels in a BAC-induced dry eye rabbit model and scopolamine-induced mouse dry eye model. 36,37 Similarly, an increased IL-6 expression was detected in both cornea and conjunctiva of BAC-induced dry eye mice. Therefore, the abnormal STAT3 activation may be caused by the increased IL-6 expression in the ocular surface of dry eye.…”

Section: Discussionmentioning

confidence: 88%

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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Section: Discussionmentioning

confidence: 88%

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Wang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Animal studies in a dry eye mouse model have demonstrated that CsA formulations were effective at reducing the severity of the corneal epithelium lesions [17][18][19] or at restoring tear secretion. 20 However, in these studies, CsA eye drops are generally instilled at dosing regimens that are higher than the recommended human posology, and at volumes substantially in excess, when considering the small size of the eye in the mouse.…”

Section: Introductionmentioning

confidence: 99%

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Daull

Nagano

Gros³

et al. 2021

Current Eye Research

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Purpose/Aim: Dry eye (DE) disease is a multifactorial disease in which uncontrolled inflammation can lead to corneal epithelium lesions and symptoms of discomfort. The aim of the present study was to evaluate the efficacy of two cyclosporine emulsions in a mouse model of DE with corneal epithelium lesions. Materials and Methods: Six-to 9-week-old female C57BL/6 N mice were housed in a controlledenvironment room to induce DE. Following DE development, mice were instilled with: QD 0.1%CsA cationic emulsion (CaEm), BID 0.05%CsA anionic emulsion (AEm), or left untreated. Aqueous tear production and corneal epithelium lesions were assessed throughout the experiment. At the end of the treatment period, left eyes were sampled, fixed, and stained for histology, while the cornea, conjunctiva, and lacrimal gland of right eyes were sampled for transcriptomic analysis. Results: Corneal lesion scores were reduced by 10.4%, 18.4%, and 10.9% at day 6, 10, and 14, respectively, with CaEm (QD), and by 2.6%, 3.0%, and 5.5% at day 6, 10, and 14, respectively, with AEm (BID). Histology demonstrated that 7 out of 10 DE mice presented moderate to severe ocular lesions, while only 2 and 5 out of 10 mice presented slight to moderate ocular lesions when treated with the CaEm (QD) and AEm (BID), respectively. The transcriptomic profile analysis suggests that a different set of inflammatory genes are modulated in the cornea, conjunctiva, and lacrimal gland upon DE development. In addition, the two emulsions distinctively modulate the gene expression profile. Conclusions: This study demonstrates that both emulsions were effective at reducing corneal lesions, with the CaEm (QD) being slightly better than the AEm (BID). Interestingly, this study suggests that ocular tissues may not respond similarly to a dry environment and that a different set of genes is modulated by the two formulations in the ocular tissues.

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“…Results showed that the CFS scores of mice with induced DED were reduced by 36% for the group treated with CE alone (CE-CsA vehicle) and by 59% for the group treated with CE-CsA when compared to the untreated group 62 (Figure 2b), however, only CE-CsA was found to significantly increase tear fluid volume of mice. 64 CE-CsA also exhibited a greater reduction of CFS scores compared to other corticosteroids including 1% methylprednisolone 62 and 0.5% loteprednol etabonate (LE, Lotemax®, Baush+Lomb) 60 as well as 5% lifitegrast solution (Xiidra®, Shire), a lymphocyte functionassociated antigen-1 (LFA-1) antagonist. 61 Interestingly, CE alone was found to be more efficient at reducing CFS scores compared to 5% lifitegrast solution.…”

Section: Effect On the Ded Signsmentioning

confidence: 99%

“…Effects of CE-CsA and CE alone on signs of DED have also been tested using in vivo mice models. [59][60][61][62][63][64] DED was induced in mice using a controlled environment room with low humidity, as previously described in the literature. 67 Clinically, two Ref.…”

Section: Effect On the Ded Signsmentioning

confidence: 99%

Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases

Daull

Baudouin

Liang

et al. 2021

Ocular Immunology and Inflammation

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Background: Cyclosporine A (CsA) has been used as a topical treatment for various ocular surface diseases including dry eye disease (DED). Several CsA formulations are available as solutions or emulsions. Purpose: This review describes the development and the preclinical testing of a cationic oil-in-water emulsion of CsA (CE-CsA) in terms of pharmacodynamics, pharmacokinetics, and ocular tolerance. Due to the cationic charge, CE electrostatically interacts with the negatively-charged ocular surface, improving its residence time. Compared to other CsA formulations, CE-CsA and CE itself were found to reduce the signs and symptoms of DED, by restoring tear film stability and properties, and inhibiting the expression and secretion of pro-inflammatory factors. No delay in wound healing nor ocular toxicity were observed using CE formulations. Conclusion: these findings indicate that the type of vehicle can significantly affect the performance of eye drops and play an ancillary role in DED treatment. CE appears as a promising strategy to deliver drugs to the ocular surface while maintaining its homeostasis.

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Modulation of Inflammation-Related Genes in the Cornea of a Mouse Model of Dry Eye upon Treatment with Cyclosporine Eye Drops

Cited by 20 publications

References 53 publications

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Therapeutic Effects of STAT3 Inhibition on Experimental Murine Dry Eye

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases

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