Repurposing Mesalazine as a Potential Treatment Option for Chronic Rhinosinusitis

Abstract

The research enclosed in this thesis revolves around investigating the therapeutic viability of repurposing the drug mesalazine into a sinonasal wash for the potential treatment of chronic rhinosinusitis (CRS). This body of work utilises an in vitro and in vivo experiments to evaluate the safety and efficacy of mesalazine as an emerging treatment option. This thesis is comprised of 6 chapters, each chapter representing different aspects of developing potential treatments for CRS. This includes exploring the current understanding and treatment options available in CRS, repurposing mesalazine into an appropriate sinonasal wash, testing it’s safety and efficacy in vitro, developing an appropriate in vivo inflammatory model and finally, establishing the effects of mesalazine on sinonasal inflammation in vivo. Chapter 1 functions as an introductory chapter, exploring the fundamental concepts of CRS that lay the foundational work for the coming chapters. This chapter is broken down into six parts. The first and second section provide a concise overview and epidemiology of CRS, respectively. The third section focuses on the aetiology of CRS. The fourth section delves deeper into the immune system and the cells within it that are associated with CRS. The final sections concentrate on the current treatment options for CRS and lastly propose mesalazine as a potential treatment option for CRS. Chapter 2 is a manuscript examining repurposing mesalazine into a sinus wash, and investigating its safety in vitro on human nasoepithelial cells, whilst still retaining its antiinflammatory function. From this an appropriate dosing range was established which maximised anti-inflammatory effects and minimised cell toxicity. Chapter 3 is rat sinusitis model. This chapter centered around creating a new inflammatory small animal model that is cheap, easily accessible and non-invasive, and mimics the lymphoplasmacytic histopathology seen in a subset of patients with difficult to treat CRS. Chapter 4 is a manuscript that ties the two previous chapter together by investigating the effects of mesalazine on sinonasal inflammation in the established rat model. Mesalazine was also compared to current treatments available for CRS in vivo. The systemic effects were also investigated. Finally, in Chapter 6, conclusions are drawn and future directions of research are reflected upon. Mesalazine presents as a potential therapeutic option for the treatment of CRS through its anti-inflammatory effects. Whilst the work embodies in this thesis looks at the effects of mesalazine in vitro and in vivo, future directions should be aim at investigating its effects in human clinical trials.