June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Aldehyde dehydrogenase (ALDH) inhibition is a novel potential therapy for conjunctival fibrosis in ocular mucous membrane pemphigoid (OcMMP)
Author Affiliations & Notes
  • John Kenneth George Dart
    Corneal and External Disease, Moorfields Eye Hospital, London, United Kingdom
    Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom
  • Sarah Dale
    Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom
  • Julie T Daniels
    Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom
  • Valerie P J Saw
    Corneal and External Disease, Moorfields Eye Hospital, London, United Kingdom
    Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom
  • David Abraham
    Research Department of Inflammation, Royal Free and University College Medical School University College London - Royal Free Campus, London, United Kingdom
  • Footnotes
    Commercial Relationships John Dart, UCL Business (P); Sarah Dale, UCL Business (P); Julie Daniels, UCL Business (P); Valerie Saw, None; David Abraham, UCL Business (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3038. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      John Kenneth George Dart, Sarah Dale, Julie T Daniels, Valerie P J Saw, David Abraham; Aldehyde dehydrogenase (ALDH) inhibition is a novel potential therapy for conjunctival fibrosis in ocular mucous membrane pemphigoid (OcMMP). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3038. doi: https://doi.org/.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: We have previously shown that OcMMP human conjunctival fibroblasts (HCF) maintain their phenotype in culture. We hypothesize that in vitro models of OcMMP HCF activity may predict conjunctival scarring mechanisms in-vivo and allow us to identify profibrotic targets, and analyse their therapeutic potential. We have used gene expression, proteomics and western blots of whole OcMMP conjunctival tissue, and OcMMP HCF, to identify putative conjunctival scarring inhibitors. We investigated the therapeutic potential of these inhibitors in our in vitro HCF model.

Methods: Gene expression on whole OcMMP conjunctiva and on cultured OcMMP HCF was carried out by microarray to identify over expressing genes in OcMMP. Western blots were used to confirm over expression of targets in OcMMP fibroblasts. Kinexus whole tissue proteomics, enabled identification of downstream signaling molecules associated with the target protein. A range of in vitro HCF assays including collagen secretion and production, matrix contraction, proliferation, chemotaxis, and myofibroblast differentiation were used to analyse the role of target proteins.

Results: Gene expression studies identified 14 overexpressed genes in OcMMP. ALDH1A3 was chosen for further study, as being potentially relevant to fibrosis pathways. Protein phosphorylation profiling, in whole OcMMP conjunctiva, identified NF-κBp50, p53 and Bcl-XL as potential ALDH1A3 signaling pathways. Western blot of MMP fibroblasts showed increased ALDH1A3. OcMMP HCF showed increased collagen production, decreased matrix contraction, reduced rates of proliferation, and myofibroblast differentiation. Addition of both DEAB (diethylaminobenzaldehyde) and disulfiram, two selective ALDH inhibitors, restored the functionality of OcMMP HCF to that of Control HCF. Conversely, adding retinoic acid (a downstream product in the ALDH pathway) to Control HCF promoted OcMMP like HCF dysfunction.

Conclusions: These findings taken together show that ALDH1A3 is a novel target involved in the scarring process in OcMMP. In addition they demonstrate that ALDH inhibition may provide a therapeutic approach to fibrosis with application in OcMMP that should be evaluated in other scarring disorders. Disulfiram is licenced for human use, and can be repurposed for this indication.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×