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      PPAR-α Agonist Fenofibrate Suppressed the Formation of Ocular Surface Squamous Metaplasia Induced by Topical Benzalkonium Chloride

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          Abstract

          Purpose

          To investigate the effects and mechanisms of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate on the formation of ocular surface squamous metaplasia induced by topical benzalkonium chloride (BAC) in a mouse model.

          Methods

          Ocular surface squamous metaplasia was induced in 16 days by topical BAC application in mice. During the period of induction, mice were divided into four groups: no additional treatment (BAC+UT), topical vehicle (BAC+Vehicle), topical fenofibrate (BAC+Feno), or topical fenofibrate plus intraperitoneal injection of MK886 (BAC+Feno+MK886). The parameters of tear film were evaluated on day 16, and eye specimens were collected. Histologic investigation; PAS assays; immunostaining for cytokeratin 10 (K10), Ki67, and F4/80; and PCR assays for TNF-α and IL-6 were performed. Cell Counting Kit 8 (CCK-8) assays were performed to evaluate the inhibitory effects of fenofibrate on RAW264.7 cells.

          Results

          Fenofibrate suppressed the formation of BAC-induced instable tear film. In the BAC+Feno group, the expression of K10 and Ki67 was lower than in the other three groups. The number of goblet cells was reduced in eyes of the BAC+UT and BAC+Vehicle groups but was maintained in eyes of the BAC+Feno group. The number of F4/80-positive cells and the levels of TNF-α and IL-6 mRNA were significantly reduced in the cornea of the BAC+Feno group. These effects of fenofibrate could be attenuated by MK886. The cell viability of RAW264.7 cells could be significantly inhibited by fenofibrate in a dose-dependent pattern.

          Conclusions

          Topical application of fenofibrate suppressed the formation of ocular surface squamous metaplasia, which might be mediated through the PPAR-α signaling pathway.

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          Most cited references30

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          Staging of conjunctival squamous metaplasia by impression cytology.

          Scheffer C G Tseng (1985)
          We modified the conventional impression cytology technique for conjunctival study by designing a 24-well Teflon sample holder, using cellulose acetate paper cut in an asymmetrical shape, and introducing Gill's modified Papanicolaou stain. Using this modified technique, we studied 35 normal subjects and 67 patients with various ocular surface disorders, 42 of whom were later found to have squamous metaplasia. Six different cytological stages were defined based on changes of goblet cell density, nucleus, and cytoplasm, encompassing three major steps: (1) loss of goblet cells, (2) increase of cellular stratification or enlargement of superficial cells, and (3) keratinization. This staging system allowed us to correlate pathological changes with clinical findings, and to investigate the action mechanism of squamous metaplasia of conjunctival epithelium. This modified impression cytology technique may help increase understanding of various ocular surface disorders.
          Article 0 comments Cited 60 times – based on 0 reviews     Review now
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            A mouse dry eye model induced by topical administration of benzalkonium chloride

            Zhirong Lin, Xiaochen Liu, Tong Zhou … (2011)
            Purpose To develop a dry eye model of mouse induced by topical administration of benzalkonium chloride (BAC) and investigate the possible mechanisms. Methods BAC at concentration of 0.2% was applied to the mouse ocular surface for 7 days. Phenol red thread tear test, tear break-up time (BUT) test, corneal inflammatory index scoring, fluorescein and rose bengal test were performed to evaluate the toxic effects of BAC on the ocular surface. Global specimens were collected on day (D) 7 and labeled with a series of antibodies including cytokeratin 10 (K10) and mucin 5AC (MUC5AC). Apoptosis of ocular surface epithelium was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Histologic analysis and transmission electron microscopy (TEM) were performed on D7. Results BAC at a concentration of 0.2% successfully induced a dry eye condition with decreased tear volume and BUTs, increased corneal fluorescein and rose bengal scores. The Inflammatory index was increased in accompanyment with higher tumor necrosis factor-α (TNF-α) expression and more inflammatory infiltration in the cornea. Immunolabeling revealed positive K10 expression in BAC-treated corneal epithelium and fewer MUC5AC-positive cells in the BAC-treated conjunctival fornix. TUNEL assay showed more apoptotic cells in the corneal basal epithelium. TEM showed that the size and intervals of the microvillis were both reduced in the corneal epithelium. Conclusions Topical administration of 0.2% BAC in mouse induces changes resembling that of dry eye syndrome in humans, and thus, represents a novel model of dry eye.
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              Nuclear receptors versus inflammation: mechanisms of transrepression.

              G. Pascual-Manich, Hannah Glass (2006)
              Inflammation is a beneficial host response to external challenge or cellular injury that leads to the activation of a complex array of inflammatory mediators, finalizing the restoration of tissue structure and function. Although a beneficial response, prolonged inflammation can be detrimental to the host, contributing to the pathogenesis of many disease states. Considerable attention has been focused on the ability of several members of the nuclear receptor superfamily to inhibit transcriptional activation by signal-dependent transcription factors that include nuclear factor kappaB and activator protein 1, thereby, attenuating inflammatory responses to both acute and chronic challenge. An important general mechanism responsible for this activity is referred to as transrepression, in which nuclear receptors interfere with signal-dependent activation of inflammatory response genes through protein-protein interactions with coregulatory proteins and promoter-bound transcription factors, rather than direct, sequence-specific interactions with DNA.
              Article 0 comments Cited 44 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Invest Ophthalmol Vis Sci
                Journal ID (iso-abbrev): Invest. Ophthalmol. Vis. Sci
                Journal ID (pmc): iovs
                Journal ID (publisher-id): IOVS
                Title: Investigative Ophthalmology & Visual Science
                Publisher: The Association for Research in Vision and Ophthalmology
                ISSN (Print): 0146-0404
                ISSN (Electronic): 1552-5783
                Publication date (Electronic): 30 March 2020
                Publication date Collection: March 2020
                Volume: 61
                Issue: 3
                Electronic Location Identifier: 54
                Affiliations
                [1 ] Eye Institute and Affiliated Xiamen Eye Center of Xiamen University , Xiamen, China
                [2 ] Fujian Provincial Key Laboratory of Ophthalmology and Visual Science , Xiamen, China
                Author notes
                Correspondence: Zhirong Lin, Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, 336 Xiahe Rd, Xiamen 361003, China; charlie.lyn668@ 123456foxmail.com .
                Huping Wu, Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, 336 Xiahe Rd, Xiamen 361003, China; wuhuping123@ 123456163.com .

                HH and ML contributed equally to the work presented here and should therefore be regarded as equivalent authors.

                Article
                Publisher ID: IOVS-19-28871
                DOI: 10.1167/iovs.61.3.54
                PMC ID: 7401654
                PubMed ID: 32232349
                SO-VID: ad66037a-5f20-424f-bb81-14f60dc7b5a2
                Copyright © Copyright 2020 The Authors
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                Date accepted : 24 January 2020
                Date received : 15 November 2019
                Page count
                Pages: 9
                Categories
                Subject: Cornea
                Subject: Cornea

                Keywords: squamous metaplasia,peroxisome proliferator-activated receptor-α,fenofibrate,macrophage,inflammation
                Data availability:
                Keywords: squamous metaplasia, peroxisome proliferator-activated receptor-α, fenofibrate, macrophage, inflammation

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