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Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring
Sarah D Ahadome1, David J Abraham2, Suryanarayana Rayapureddi3
1Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom.
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.
Insights
Aldehyde dehydrogenase 1 (ALDH1) drives scarring in ocular mucous membrane pemphigoid (OMMP). Inhibiting ALDH1 with disulfiram shows potential as an antifibrotic therapy for OMMP, preventing blindness.
Area of Science:
- Ophthalmology
- Fibrosis Research
- Drug Discovery
Background:
- Mucous membrane pemphigoid (MMP) is a scarring disease affecting mucous membranes, often leading to blindness.
- Current treatments lack antifibrotic options for ocular MMP (OMMP).
- Aldehyde dehydrogenase family 1 (ALDH1) is implicated in fibrotic processes.
Purpose of the Study:
- Investigate the role of ALDH1 in OMMP pathogenesis.
- Evaluate ALDH inhibitors as a potential antifibrotic therapy for OMMP.
Main Methods:
- Examined ALDH1 expression in OMMP conjunctiva and fibroblasts.
- Treated normal and OMMP fibroblasts with retinoic acid (RA) and ALDH inhibitors (disulfiram).
- Utilized a mouse model of allergic eye disease (AED) as a surrogate for OMMP, testing topical disulfiram.
Main Results:
- ALDH1 was upregulated in OMMP conjunctiva and fibroblasts.
- RA induced a fibrotic phenotype in normal conjunctival fibroblasts.
- Disulfiram restored normal function to OMMP fibroblasts in vitro.
- Disulfiram reduced fibrosis in the mouse model of scarring allergic eye disease.
Conclusions:
- Progressive scarring in OMMP may stem from ALDH/RA fibroblast autoregulation.
- ALDH1 plays a key role in immune-mediated ocular mucosal scarring.
- Disulfiram represents a promising, translatable antifibrotic therapy for OMMP.
