| Summary: | Interferons (IFNs) are an integral part of the innate immune response to viral infection. As well as possessing important anti-viral properties, they possess immunomodulatory, cytotoxic and anti-tumoural functions. As a consequence, the IFNs (mainly type I IFN) have been utilised for the treatment of human disease where they represent important therapies, most commonly in the treatment of chronic hepatitis C virus (HCV). However, there is now emerging evidence of an association between type I IFN drug treatment and the development of severe and at times irreversible pulmonary arterial hypertension (PAH). Through the course of this PhD I have investigated potential mechanisms for type I IFN induced PAH and have identified the IFN regulated protein IP10 and the promitogen and vasoconstrictor endothelin (ET)-1 as important candidate mediators. It is well established that autoimmune conditions such as systemic sclerosis, where PAH is a common complication, are typified by chronic activation of type I IFN pathways. I have used the observation that IFN drug treatment may cause PAH, as a platform to hypothesise that endogenous type I IFN production may be important in the pathogenesis of systemic sclerosis associated PAH. Through a comprehensive approach utilising in vitro cell culture models, in vivo animal models of disease and patient samples, I have demonstrated that endogenously produced type I IFN plays an important role in the development of systemic sclerosis associated PAH and also idiopathic PAH. I have also gone on to show that other facets of the immune system appear to have pathogenic relevance in this devastating and still under-characterised disease. I conclude that a dysregulated and chronically active innate immune system plays a pathological role in the development of pulmonary arterial hypertension.
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