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Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring
Sarah D. Ahadome, … , Julie T. Daniels, John K. Dart
Sarah D. Ahadome, … , Julie T. Daniels, John K. Dart
Published August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e87001. https://doi.org/10.1172/jci.insight.87001.
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Research Article Inflammation Ophthalmology

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

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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 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

Sarah D. Ahadome, David J. Abraham, Suryanarayana Rayapureddi, Valerie P. Saw, Daniel R. Saban, Virginia L. Calder, Jill T. Norman, Markella Ponticos, Julie T. Daniels, John K. Dart

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Figure 2

Aldehyde dehydrogenase (ALDH) is upregulated in the conjunctiva of OMMP patients compared with control patients.

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Aldehyde dehydrogenase (ALDH) is upregulated in the conjunctiva of OMMP ...
(A) ALDH1A3 mRNA expression in conjunctival biopsies from control patients (Cont., n = 5), inflamed OMMP patients (PemI, n = 5), or noninflamed (after immunosuppressive treatment) OMMP patients (PemU, n = 5). (B and C) ALDH1A3 mRNA expression in primary conjunctival fibroblasts obtained from Cont. (primary cultured fibroblasts from controls [F-C], n = 4) compared with fibroblasts from pemphigoid inflamed (F-PemI, n = 4) or pemphigoid uninflamed (F-PemU, n = 4) from the microarray and qPCR. The microarray was carried out in duplicate and the qPCR in triplicate. (D) Representative immunohistochemical staining for ALDH1A3 in Cont. (n = 3), PemI (n = 3), and PemU (n = 3). Arrows indicate positive staining for ALDH1A3. ALDH1A3-positive staining was scored on a scale of 0–5 for each tissue section from these tissue samples, with 5 being highest level of ALDH1A3-positive staining. 40× magnification. (E) Flow cytometry analysis of mean fluorescence intensity (MFI) of ALDEFLOUR (an ALDH1 substrate that only fluoresces once it has been metabolized by ALDH) in F-C (n = 3), F-PemI (n = 3), or F-PemU (n = 3) fibroblasts. (F) MFI of ALDH activity of F-PemI (n = 3) and F-PemU (n = 3) fibroblasts treated with diethylaminobenzaldehyde (DEAB) or F-C (n = 3) fibroblasts treated with retinoic acid. Error bars represent mean ±SEM. *P < 0.05 and ****P < 0.00005 as calculated using one-way ANOVA with Bonferronni correction

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