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

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 3

Topical application of disulfiram decreases ocular surface inflammation of mice with ovalbumin-induced conjunctivitis and protects them from conjunctival fibrosis in vivo.

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Topical application of disulfiram decreases ocular surface inflammation ...
(A) Expression of ALDH1 in mouse conjunctiva. (B) Ocular surface inflammatory score in ovalbumin-treated (OVA-treated) mice (n = 5) treated daily with topical eye drops containing disulfiram or vehicle for a 7-day antigen challenge period. Naive mice (n = 5) without OVA challenge were also monitored in the same manner throughout the challenge period. (C) Representative histological staining for collagen (MSB, dark blue) and inflammatory infiltrate (H&E) of whole eye sections from naive mice (n = 5) and OVA-challenged mice (n = 5) treated with either disulfiram (300 μM) or vehicle. Arrows and lines indicate differences in collagen accumulation in the MSB panel and visual changes in cellular infiltrate in the H&E panel. (D) Quantitation of fibrosis for naive, OVA + vehicle, and OVA + disulfiram groups (n = 5). The histology images were scored on a scale of 0–5 for each tissue section from these tissue samples, with 5 being highest intensity of MSB staining. (E) Primary conjunctival fibroblasts (n = 5 mouse cultures) were explanted from naive mice and OVA-challenged mice treated with disulfiram or vehicle. Fibroblasts were assessed for contractility (left panel) and proliferation (right panel). Scale bars: 100 μm. Error bars represent mean ±SEM. *P < 0.05, ***P < 0.0005, ****P < 0.00005 as calculated using one-way ANOVA with Bonferroni correction.