title: Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring.
abstract: Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy.
authors.affiliation: Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Ahadome
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.affiliation: Centre for Nephrology, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Suryanarayana
authors.initials: S
authors.lastname: Rayapureddi
authors.affiliation: NIH Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and the UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Saw
authors.affiliation: Duke University School of Medicine, Departments of Ophthalmology and Immunology, Durham, North Carolina, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Saban
authors.affiliation: Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Calder
authors.affiliation: Centre for Nephrology, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Jill T
authors.initials: JT
authors.lastname: Norman
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Markella
authors.initials: M
authors.lastname: Ponticos
authors.affiliation: Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Daniels
authors.affiliation: NIH Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and the UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: John K
authors.initials: JK
authors.lastname: Dart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D002921:Cicatrix / Q000517:prevention & control*; D003228:Conjunctiva / Q000187:drug effects / Q000503:physiopathology; D004221:Disulfiram / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009092:Mucous Membrane / Q000473:pathology*; D010390:Pemphigoid, Benign Mucous Membrane; D014212:Tretinoin
chemical_list: D014212:Tretinoin; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram