Nasal mucus: friend or foe? The effect of mucus on mucosal barrier dysfunction in chronic rhinosinusitis

Abstract

Chronic rhinosinusitis (CRS) is a complex and heterogenous disease characterised by nasal obstruction, facial pressure, rhinorrhoea, postnasal drip and reduction in smell. The pathophysiology of CRS is multifaceted with an interplay between host, environmental and microbial factors. Numerous hypothesise have been proposed to elucidate this complicated disease process, however, the jury is still out. Recently, the dysfunction in the mucosal barrier with associated pathogen invasion is described as a potential basis for the development of CRS. Studies have identified the overactivation of inflammatory cells with superfluous secretion of proinflammatory proteases and cytokines associated with the chronic inflammatory environment observed in CRS. Therefore, it is vital to understand the interactions between the host immunity with the mucosal barrier. Nasal mucus overproduction is a hallmark symptom of CRS and thus it is paramount to investigate its interaction with the mucosal barrier function in both healthy and CRS patients. Classically, nasal mucus from CRS patients are more viscous and contain increased levels of inflammatory cytokines. Previous research has found Pseudomonas aeruginosa elastase, an exoprotein, present in CRS nasal mucus associated with increased barrier dysfunction and worse symptom-scores. Furthermore, neutrophil infiltration is observed in CRS mucosa secondary to the persistent inflammation and bacterial activation. The collateral damage to host tissues secondary to the release of neutrophil-associated proteases against infections must be elucidated. Advances in mass spectrometry techniques allow for detailed analysis of differentially expressed proteins in nasal mucus. A systemic review of the nasal proteome will be conducted to determine the current progress and deficiencies within the literature. Based on these findings, the direct comparison of healthy and CRS mucus proteomes will be performed. By analysing the different proteins and cellular processes present in nasal mucus may assist in understanding the downstream manifestations of CRS. This thesis examines the interaction of nasal mucus with the nasal mucosal barrier function. Secondly, to ascertain the effects of neutrophil serine proteases on the mucosa barrier function. Lastly, to investigate and understand the differing mucus composition between healthy and CRS patients. Ultimately, through understanding the pathophysiology and various endotypes of CRS, we aim to direct future research to develop treatment regimens for numerous patients.