A Delicate Balance: Modulation of Reactive Oxygen Species after Sinus Surgery to Improve the Healing Process

Abstract

The purpose of this thesis is to examine the role of reactive oxygen species in wound healing, with respect to the paranasal sinuses and in the dual context of chronic inflammation and surgery. It goes on to explore emerging therapies that modulate reactive oxygen species and act as wound healing adjuncts. The work describes a body of translational research, utilising both in vitro and in vivo experiments aimed at improving postoperative outcomes. Focus was given to the prevention of postoperative infections and sinonasal adhesions, as these are significant issues in the realm of ENT surgery. The thesis itself is composed of six chapters, each dealing with a different aspect of reactive oxygen species, as well as various established and novel therapies that interact with them in the postoperative period. Chapter 1 serves as an introductory chapter and briefly explores the core concepts that underpin the subsequent chapters. It is subdivided into three sections. The first deals with chronic rhinosinusitis diagnosis and management (including sinus surgery), the second describes the stages and mechanisms involved in wound healing and the third explains the role of reactive oxygen species in this process. Chapter 2 is a peer-reviewed publication, examining the modulation of reactive oxygen species by antibiotics given peri and post-operatively in ENT surgery, and the implications this may have for wound healing quality. Chapter 3 is a manuscript describing the suppression of Staphylococcus aureus biofilms from the upper respiratory tract using a pair of novel mitochondrially-targeted antioxidants (MTAs). Chapter 4 is a manuscript investigating the direct effect of these same antioxidants on fibroblast migration into freshly wounded cell monolayers, and the utility this has for limiting scar formation. Chapter 5 is a manuscript tying these concepts together using an in vivo murine model of infected cutaneous wound healing, to investigate whether these agents concurrently improve wound healing and suppress active staphylococcal biofilm infection. Conclusions and reflections on future directions for this body of research are drawn in Chapter 6. Modulation of reactive oxygen species represents a promising treatment avenue for chronic rhinosinusitis, in unison with existing treatments such as sinus surgery. Mitochondrially-targeted antioxidants have the potential to utilise this mechanism to address multiple factors driving disease persistence at once, providing hope for an elusive definitive treatment.