Non-inflammatory mechanisms in asthma : a thesis with publications presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Public Health, Massey University, Wellington, New Zealand

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Massey University
Thesis will be uploaded upon the expiry of the journal embargo on Chapter 5 in June 2024.
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Until relatively recently asthma was considered to be an allergic disease characterised by airway inflammation. However, emerging evidence suggests that approximately 50% of asthmatics have no overt signs of inflammation. The pathophysiological mechanisms underlying disease in this group - non-eosinophilic asthma (NEA) - remain poorly understood. In 130 young-adults with generally well-controlled asthma and 79 non-asthmatics (aged 14-21 years), various non-invasive approaches were used to assess both inflammatory and non-inflammatory mechanisms in eosinophilic asthma (EA) and NEA. Studies focussed on: (i) neural mechanisms (including autonomic nervous system (ANS) activity, sensory nerve activity, and levels of neural mediators in induced sputum); and (ii) airway remodelling (measuring induced sputum levels of airway remodelling mediators), in different asthma phenotypes, whilst also taking into account clinical and inflammatory characteristics. In addition, the response to short acting β-agonist (SABA) and short acting muscarinic-antagonist (SAMA) treatment was compared between asthma phenotypes. Differences in some aspects of neural regulation were observed between EA, NEA, and non-asthmatics. In particular, airway sensory nerve reactivity was enhanced in NEA compared with non-asthmatics (p<0.05). Sensory nerve reactivity was also higher in NEA compared to EA, but this did not reach statistical significance (p=0.07). There was no evidence of an imbalance in ANS activity when comparing asthmatics and non-asthmatics, or EA and NEA. Increased levels of nociceptin were found in asthmatics and EA compared with non-asthmatics (P<0.05); nociceptin was positively associated with sputum eosinophils. Several inflammatory and remodelling mediators (including IL-1β, ECP, periostin, and VEGF-A) were elevated in EA but not NEA. There was no evidence of a differential response to SAMA between EA and NEA; however, a small subgroup of asthmatics responded better to SAMA. In conclusion, the studies described in this thesis suggest that sensory nerve reactivity may play an important role in the pathophysiology of NEA, but not EA, and may potentially represent a novel phenotype-specific treatable trait. Autonomic dysregulation does not appear to play a role in well-controlled asthma or specific asthma phenotypes. Findings suggest a potential involvement of nociceptin in asthma pathology, particularly in relation to airway eosinophilia. Finally, the identification of a small group of asthmatics who responded better to SAMA than SABA challenges current asthma treatment guidelines and suggests a need for a more personalised treatment approach. Further investigation of non-inflammatory mechanisms is warranted to improve understanding of other mechanisms underlying different asthma phenotypes, which will contribute to the identification of more specific treatable traits.
Asthma, Pathophysiology, Treatment, Asthmatics, non-inflammatory mechanisms