Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.705812
Title: The role of adipokines in obesity-associated asthma
Author: Gibeon, David
ISNI:       0000 0004 6061 6050
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Abstract:
Obesity is a risk factor for the development of asthma and plays a role in disease control, severity and airway inflammation. The relationship between asthma and adiposity is multifactorial and incorporates in-utero conditions, genetic factors, comorbidities and inflammation secondary to excess adipose tissue. Adipocytes produce cytokines, termed adipokines, which play an important role in systemic inflammation and have been correlated to the development of asthma and disease severity. Retrospective analysis of trials using inhaled corticosteroids and an in vitro study using alveolar macrophages has associated obesity with corticosteroid insensitivity in asthma. The first part of this study looked at data taken from a large cohort of well-characterised severe asthmatics and compared patient demographics, disease characteristics, healthcare utilisation and medication according to body mass index (BMI). Lipid laden macrophages (LLMs) in bronchoalveolar lavage fluid (BALF) and perilipin as a marker of lipid droplets in endobronchial biopsies were analysed according to asthma severity and BMI. Finally, peripheral blood mononuclear cells (PBMCs) were used to study the effect of BMI on steroid sensitivity in patients with asthma using an in vitro model and the effects of adipokines (leptin, resistin and adiponectin) on the release of pro-inflammatory cytokines and corticosteroid response were assessed. Severe asthmatics are often overweight (29.3%) or obese (48.3%). Increasing BMI was associated with increasing medication use in terms of short-acting β2-agonist (SABA) use per day, nebulisers and oral corticosteroid requirements (both maintenance and short burst therapy). In addition, obese severe asthmatics reported greater gastro-oesophageal reflux disease (GORD) and were less likely to be in full time employment due to their asthma. LLMs are more prevalent in subjects with GORD which may explain the higher lipid laden macrophage index (LLMI) score seen in severe compared to mild/moderate asthmatics. Perilipin was expressed in the airway epithelium and submucosa in approximately half the study population. Greater expression was seen in the submucosa of asthmatic subjects compared to healthy controls. However, no significant correlations were noted in terms of asthma severity or BMI. Leptin, resistin and adiponectin were pro-inflammatory, in terms of CXCL8 release from PBMCs taken from asthmatics and healthy controls. PBMCs taken from severe asthmatics were less responsive to steroid suppression. Adiponectin induced IL-6, IL-10, CCL2, CCL3 and TNF-α release from PBMCs taken from asthmatics and healthy controls and IFN-γ, IL-1RA, CCL2, CCL3 and TNF-α release was suppressed by dexamethasone. Adiponectin induced CCL2 release and demonstrated relative corticosteroid insensitivity at dexamethasone 10-7 M in the severe asthma group. In conclusion, obesity related severe asthma is associated with more symptoms, a significant societal impact and patients are at risk of the many deleterious side effects of corticosteroid use. Leptin, resistin and adiponectin are pro-inflammatory and adiponectin may play an important role in modulating corticosteroid sensitivity.
Supervisor: Bhavsar, Pankaj ; Chung, Fan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.705812  DOI: Not available
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