2020BagadoodRMPhD.pdf (15.7 MB)
Impact of obesity on lung inflammation and response to corticosteroids in allergic asthma
thesisposted on 2020-07-23, 09:41 authored by Rehab Bagadood
Obesity is both a risk factor and a disease modifier of asthma. Compared to lean patients, obese asthmatic patients suffer from severe symptoms, frequent exacerbations, and poor quality of life. The relationship between asthma and obesity remains unclear. Clinical studies have shown that obese asthmatics are characterized by neutrophilic, eosinophilic or mixed inflammation in the airways. Irrespective of the type of inflammation, obese asthmatic patients have decreased responses to corticosteroid therapy via mechanisms that are still unknown. Preclinical studies performed in mouse models of allergic asthma fed with high fat diet (HFD) have provided different conclusions regarding the mechanisms by which obesity contributes to asthma pathogenesis/worsening and inconsistent results with regard to the impact of obesity on allergic airway eosinophilia. I hypothesized that obesity may contribute to asthma pathogenesis by altering corticosteroid responses in immune cells. I used high fat diet (HFD)-induced obesity in female C57BL/6 mice sensitized and challenged to ovalbumin to determine the impact of obesity on allergen-induced airway inflammation and splenocyte in vitro responses (cell proliferation and cytokine production) to different stimuli with the presence or absence of dexamethasone. The current study showed that proliferation of immune cells as well as production of different inflammatory cytokines TNF-! (~1.5fold), IL-6 (~3fold), IL-13 (~2.5fold) and IL-17 (~3fold) in response to allergen stimulation were augmented in obese sensitised animals. Surprisingly, the anti-inflammatory effect of dexamethasone on the production of IL-6 (completely) and IL-17 (partially) from ovalbumin-treated splenocytes was impaired in obese animals (p<0.0001). Moreover, allergen increased airway inflammation in both perivascular and bronchial areas which was found to be greater in obese sensitised animals compared to corresponding lean group (p<0.01). Obesity also significantly enhanced the percentage of neutrophil infiltration in the airways of allergen exposed animals (p<0.05) while infiltration of eosinophils, macrophages, CD4+ and CD8+ T cells remained unaffected by the diet regime. In conclusion, allergen challenge differentially regulates the sensitivity of cultured splenocytes to corticosteroids in both lean and obese asthmatic mice. Obese allergic mice had also a marked increase in lung neutrophilic inflammation and levels of IL-6, IL-17 and TNF-!. These data support the hypothesis that obesity may play a role in asthma exacerbation/progression by augmenting lung neutrophilic inflammation and impairing the function and sensitivity of immune cells to corticosteroid therapy.
Supervisor(s)Yassine Amrani; Cordula Stover
Date of award2020-07-02
Author affiliationDepartment of Respiratory Sciences
Awarding institutionUniversity of Leicester