Dale, S; (2014) Aldehyde dehydrogenase as a novel and potential therapy for conjunctival fibrosis. Doctoral thesis , UCL (University College London).

Abstract

Fibroproliferative diseases including pulmonary fibrosis and scleroderma are leading causes of mortality. Mucous membrane pemphigoid (MMP) is a systemic autoimmune disease characterised by inflammation and variable blistering and scarring of one or more of the mucous membranes and the skin. MMP affecting the conjunctiva was formally termed Ocular Cicatricial Pemphigoid (OCP). Ocular MMP (OcMMP) will be used in this thesis to describe studies carried out on MMP patients having ocular involvement as a major component of their disease. Therefore OcMMP is synonymous with the term OCP used in previous studies. OcMMP affects the readily accessible conjunctiva; providing a model disease for investigating the role and control of inflammation and fibrosis. Current immunosuppressive therapy fails to halt the aggressive and visually devastating scarring. This study aimed to identify novel pro-fibrotic genes and to use functional surrogate scarring assays to assess the gene products for their therapeutic potential. OcMMP fibroblasts maintained their phenotype in-vitro and exhibited increased collagen production and secretion, decreased matrix reorganisation and reduced rates of proliferation and myofibroblast differentiation. Gene expression profiling revealed that Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) is up regulated in OcMMP. Elevated expression of ALDH1A3 was confirmed by qPCR and protein levels assessed by western blot. Addition of disulfiram, a selective aldehyde dehydrogenase inhibitor restored phenotype and function of OcMMP fibroblasts to control cell levels. Conversely, aldehyde dehydrogenase activation using retinoic acid added to control conjunctival fibroblasts cultures promoted OcMMP-like phenotype in the scarring assays. Protein phosphorylation profiling also uncovered potential ALDH1A3 signalling pathways and that ALDH1A3 may be mediating the fibrotic response in OcMMP by orchestrating impaired fibroblast/dendritic cell interactions and metabolic stress. These significant findings not only show that ALDH1A3 is a novel anti-scarring target in OcMMP but also that ALDH inhibition may be a novel therapeutic approach to fibrosis with application in OcMMP and one that should be evaluated in other scarring disorders.

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