June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Loss of βENaC Function in Meibomian Gland Produces Severe Sex-Biased Ocular Surface Diseases in Mice
Author Affiliations & Notes
  • Dongfang Yu
    Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States
  • Yogesh Saini
    Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana, United States
  • Gang Chen
    Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States
  • Kimberlie A. Burns
    Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States
  • Hong Dang
    Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States
  • Richard Davis
    Department of Ophthalmology, Universisty of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Scott H. Randell
    Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States
  • Charles R. Esther
    Pediatric Pulmonology, Universisty of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Friedrich P Paulsen
    Department of Anatomy II, Friedrich Alexander University Erlangen Nürnberg, Erlangen, Germany
  • Richard C. Boucher
    Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States
  • Footnotes
    Commercial Relationships   Dongfang Yu, None; Yogesh Saini, None; Gang Chen, None; Kimberlie Burns, None; Hong Dang, None; Richard Davis, None; Scott Randell, Gilead Sciences (C), Parion Sciences (F); Charles Esther, None; Friedrich Paulsen, None; Richard Boucher, Parion Sciences (I)
  • Footnotes
    Support  PPG P01HL110873
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4383. doi:
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    • Get Citation

      Dongfang Yu, Yogesh Saini, Gang Chen, Kimberlie A. Burns, Hong Dang, Richard Davis, Scott H. Randell, Charles R. Esther, Friedrich P Paulsen, Richard C. Boucher; Loss of βENaC Function in Meibomian Gland Produces Severe Sex-Biased Ocular Surface Diseases in Mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4383.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To investigate the role of β subunit of epithelial sodium channel (ENaC) in mouse meibomian glands (MG).

Methods : A conditional MG βENaC knockout mouse model was generated by cross breeding Sonic Hedgehog (Shh)-Cre and floxed βENaC mice. Real time RT-PCR confirmed βENaC deletion and quantitated altered expression of genes of interest. Whole eyeballs were excised, fixed, and processed for histopathological analysis and scanning electron microscopy (SEM). Sections were immunostained for cytokeratins, proliferation, and inflammatory cell markers. Conjunctival tissue homogenates were used for cytokine multiplex assays. Tear production was measured with phenol red threads (PRT) test and tears were analyzed for purine metabolites by Mass Spectrometry. Primary mouse MG cell cultures were generated to test the role of ENaC in MG cell growth and proliferation.

Results : MG βENaC KO mice exhibited striking age dependent Meibomian gland dysfunction (MGD). This phenotype was more prevalent in female than male mice, with white toothpaste-like secretions obstructing the MG orifices. In older mice, there were dramatic corneal pathologies, including corneal opacification, ulceration, neovascularization, and ectasis. There was compensatory increase in tear production in MG βENaC KO mice, and tear purine metabolites levels were lower in KO mice. Histologically, inflammatory cell infiltration was observed in both acini and ducts of MG of βENaC MG KO mice, with duct enlargement, and ductal epithelial cells hyperstratification. In older mice, there was MG acinar atrophy, conjunctival epithelial epidermalization, corneal epithelial hyperkeratinization, conjunctivalization, and neovascularization. Structural morphological changes in the cornea as well as the lids were observed by SEM. Inflammation in MG and conjunctiva was confirmed by increased cytokine gene and protein expression, and positive Ly-6B.2 immunostaining. Cell proliferation assays revealed lower proliferation rates of MG cells derived from KO mice than control mice.

Conclusions : βENaC expression in the MG plays a critical role in normal mouse MG function. Loss of βENaC function resulted in MGD, and severe ocular surface damage with time that was sex dependent. Our data suggest a pivotal role of βENaC in the proliferation and regeneration of MG cells. Further investigation on this observation may lead to new therapeutic developments for MGD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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