Characteristics of the airway-systemic innate inflammation axis in COPD and severe asthma

Chronic obstructive pulmonary disease (COPD) and severe asthma are common chronic inflammatory airway diseases with increased burden and mortality worldwide. Clinical presentation is heterogeneous and complex with differing clinical and inflammatory phenotypes and endotypes, making precise assessment and treatment difficult. Therefore, the discovery and validation of novel biomarkers that can identify phenotypes and endotypes is critical to advance COPD and severe asthma towards a precision medicine approach. Improved understanding of pathophysiological mechanisms that underlie disease, can also identify novel molecular drug targets for future trials. In this Thesis, I highlight the importance of inflammation in COPD and severe asthma by investigating and validating multiple inflammatory markers, in serum and sputum, for diagnosis and phenotyping/endotyping. I investigate and validate a previously described panel of serum-based acute phase protein biomarkers in COPD, mild, moderate and severe asthma participants and non-respiratory disease controls. I demonstrate a single biomarker, hemopexin, can distinguish COPD from asthma patients with superior predictive ability. I also hypothesise an innate-anti-inflammatory-axis between the airways and the systemic circulation, involving hemopexin as a novel anti-inflammatory component. In my studies, I use a sputum qPCR-based mast cell (MC)/basophil gene signature to demonstrate MCs and basophils are dysregulated in severe asthma and COPD compared to controls. Additionally, measures of MC/basophil-related genes related to airway and systemic eosinophilic inflammation and important clinical features of decreased lung function and exacerbation risk in severe asthma and decreased lung function in COPD. The findings of this Thesis have extended our understanding of inflammation in chronic airway disease. In particular, the hypothesised innate-anti-inflammatory axis involving hemopexin, as well as the importance of MCs and basophils and their relationship to clinical and inflammatory features of disease. Clinically these findings, offer novel inflammatory biomarkers that may be used in diagnosis and phenotyping/endotyping and should be further investigated in clinical trials.