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Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

Ahadome, S; Abraham, DJ; Rayapureddi, S; Saw, VP; Saban, DR; Calder, VL; Norman, JT; ... Dart, JK; + view all (2016) Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. Journal of Clinical Investigation insight , 1 (12) , Article e87001. 10.1172/jci.insight.87001. Green open access

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Abstract

Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase (ALDH) family 1 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, 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.

Type: Article
Title: Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.87001
Publisher version: http://dx.doi.org/10.1172/jci.insight.87001
Language: English
Additional information: Copyright © 2016, American Society for Clinical Investigation
Keywords: Human, mouse, fibrosis, mucosa, mucous membrane pemphigoid, aldehyde dehydrogenase, disulfiram
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1507974
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