Overview
Excessive scarring (fibrosis) is a major part of conditions including liver cirrhosis, lung fibrosis, and scleroderma. The biological pathways that control scarring are being studied and have led to developing treatment to reduce scarring that are already in clinical trials for some of these conditions.
The conjunctiva is a membrane that lines the eyelid and covers the white of the eye. Conjunctival scarring is a major part of some eye conditions including trachoma, chemical injuries and mucous membrane pemphigoid (MMP). But scar control, and potential for changing scarring, has hardly been studied in these eye conditions.
This project comes from the research team’s previous studies on MMP, which is a useful condition for investigating both inflammation and how scars form in conjunctival scarring. MMP is an ‘autoimmune’ condition (like rheumatoid arthritis) which means it is due to the body’s defence against infection turning on its own body. It affects the lining tissues (mucous membranes) of the eyes and mouth. It starts aged 30-90 and lasts for life from then on.
MMP causes inflammation, ulcers and scarring. It is debilitating, painful and leads to in blindness in about 1 in 3 people affected. The team’s earlier studies have shown that scars keep developing despite good medical control of inflammation. And they have found a molecule (called IL-6) that’s important for scars to develop in the conjunctiva of people who are having this treatment.
These findings have led to this project. The aim is to identify the key molecules controlling the scarring process, in order to choose those that are promising targets. The goal is to develop eye drops or eyelid injections to control scarring in eye conditions that can be used as well as anti-inflammatory treatment.
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Publications
- Ahadome, S. D. et al. Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. JCI Insight 1, (2016).
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Research update
The team has identified a gene that drives scarring, together with a potential therapy to treat it.
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Scientific summary
Signal transduction pathways promoting conjunctival fibrosis: therapeutic implications of selective inhibition
Fibroproliferative diseases including liver cirrhosis, pulmonary fibrosis, and scleroderma are leading causes of mortality. However there are no approved treatments that directly target the mechanisms of tissue fibrosis, although pro-fibrogenic signalling pathways are currently therapeutic targets for these diseases.
Conjunctival scarring is a blinding component of a number of diseases including trachoma and mucous membrane pemphigoid (MMP), but the control of fibrosis has not been studied in these disorders. This project stems from the research team’s interest in MMP, from both the clinical perspective, and as a model disease for investigating the role and control of inflammation and fibrogenesis in conjunctival scarring.
Their previous studies have shown that clinical control of inflammation in MMP does not prevent the progression of scarring and that one pro-fibrotic cytokine (IL-13), that is intensely expressed in inflamed tissue, remains elevated in clinically uninflamed conjunctiva and may be a key driver of progressive fibrosis. However the effects of IL-13 may be enhanced by synergism with other T cell-secreted products and pro-fibrotic signal transduction pathways.
This study tests the hypothesis that "pro-fibrogenic signalling pathways are differentially expressed in different MMP disease states and represent novel targets for therapy"; inhibition strategies may need to be different for inflamed versus non-inflamed conjunctiva. Having identified potential pro-fibrogenic signalling pathways in conjunctival fibroblasts the team will confirm which are activated in vivo in conjunctival tissue and responsible for scarring. Finally they will assess the potential therapeutic benefit of molecular manipulation of these signalling pathways using functional in vitro fibrogenic assays.