Evidence suggests that psychosocial factors are important in severe asthma. Wider research and theory highlight complex, bi-directional pathways by which interactions may occur. This thesis took a psychological perspective to investigating these. A systematic review including 17 interventions targetting psychosocial factors in adults with severe asthma highlighted that most do not explicitly consider the multiple pathways by which psychosocial factors and asthma interact. This may explain their limited effectiveness and suggests scope for their improvement, informed by further research. Such research requires adequate measures of important constructs. This thesis therefore identified, compiled and, where necessary, developed suitable measures of clinical outcomes, self-management behaviours, and key emotional and cognitive factors (perceived control, readiness to change). These were used, and in the case of a measure of readiness to change self-management also subjected to detailed testing, in an observational study of 132 adults with severe asthma. This investigated cross-sectional and longitudinal relationships between psychological factors and outcomes (asthma control, asthma-specific quality of life and severe attacks).

Asthma is one of the most prevalent chronic conditions that presents amongst adolescents. Untreated asthma can be debilitating. Hence, for many adolescents the successful management of asthma relies on taking medicines. It has been observed that non-adherence to asthma medicines is widely reported during adolescence. The unique challenges inherent to the adolescent developmental phase have been implicated in this observation. A more comprehensive understanding of the reasons influencing adherence to medicines is needed before interventions to facilitate adherence can be implemented. This thesis aimed to explore what factors influenced medicines adherence in adolescents with asthma through a systematic review of 17 adherence enhancing interventions (AEls) in adolescents taking long-term medicines; 30 in-depth semi-structured interviews with adolescents aged 13 to 19 years old, of which 13 were photo-interviews; and a quantitative analysis of 248 online surveys completed by university students with asthma aged 18 or 19 years old. The systematic review identified focussing interventions on a narrow age range, involving parent/family support for complex medicines regimens and improving access to care, as factors impacting positively on adherence. The qualitative inquiry found that forgetting, having concerns about medicines, perceiving that asthma medicines were not necessary, unwillingness to respond to asthma symptoms and being ill-equipped as an asthma self- manager, negatively impacted adherence. Adolescents also reported a variety of strategies they used to facilitate medicines-taking. Hierarchical regression analysis modelling revealed that higher medicines concerns, lower belief in the necessity for medicines, binge drinking and not usually carrying inhalers were associated with low self-reported adherence by the 8- item Morisky Medication Adherence Scale (MMAS-8). The knowledge gleaned from this thesis provides policy makers, health care practitioners, researchers, and others responsible for caring for adolescents with asthma, with new evidence to consider when engaging efforts to understand and facilitate medicines-taking in this patient group.

Asthma is a disease that still causes a significant amount of morbidity and mortality in the UK. Airway smooth muscle hypertrophy and hyperplasia, with a corresponding infiltration by mast cells, are key features of the inflammatory process that results in airway remodelling and fixed airflow obstruction. A 3 dimensional collagen I model was developed to examine differences in airway smooth muscle cell morphology, phenotype and MMP 2 expression, when cultured in a 30 environment in comparison to a 20 monolayer. Using :: this technique, airway smooth muscle cells and HMC-1s, a mast cell line, ,; were co-cultured to assess the effects of cell to cell interaction on airway I smooth muscle proliferation rates and MMP2 production. A novel method for assessing HMC-1 migration towards airway smooth cells was also established. To further study mast cell migration in asthma, a new technique of patient recruitment and endobronchial biopsying of individuals had to be established. Airway smooth muscle cells when cultured in 30 were observed to adopt a spindle like morphology. They also appeared to express lower levels of a smooth muscle actin and vimentin. In the model, basal rates of airway smooth muscle cell proliferation, when examined using Ki67, are reduced by over 50% compared to the 20 controls (p<0.05). Rates of airway smooth muscle cell proliferation were significantly increased in the model when they were co-cultured with the HMC-1s, and activated HMC-1s; the rate doubling in the latter from sole culture alone (p<0.05). 6 --. ---------- - Culturing airway smooth muscle cells in 3D also resulted in increased and sustained MMP2 production with a further increase when co-cultured with HMC-1s. This also resulted in increased expression of the activated form. Co-culturing of the cells resulted in increased rates of gel contraction, by 22%. This contraction could be reduced by using a broad spectrum MMP inhibitor, 1I0mastat. HMC-1 migration towards airway smooth muscle is partially MMP dependent. The rate of HMC-1 s migrating when treated with 1I0mastat was reduced by 45% (p<O.05). Initial studies of migration of HMC-1s to asthma derived airway smooth muscle cells showed up to 66% increase in migration compared to non-asthmatic controls, and that there is a trend towards increased proliferation in this group. Asthma airway smooth muscle cells also promoted gel contraction. 7

Asthma and COPD are complex diseases with both genetic and environmental factors interacting with each other to determine disease expression. Identifying genes which contribute to these diseases should lead to advances in the diagnosis and treatment of asthma and COPD.

Asthma is a chronic disease characterised by airway inflammation and remodelling. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy, and yet many asthmatics remain symptomatic, some with severe manifestations of the disease. The bronchial epithelium produces coagulation factors locally in the absence of plasma exudation. There is evidence in asthma that there is upregulation and stimulation of the external coagulation cascade in the airways, and locally derived factors may be involved.

An acute asthmatic episode can occur following exercise and is termed exercise induced asthma (EIA). The purpose of this thesis was to investigate the prevalence, diagnosis, and treatment of EIA in elite British athletes. The addition of objective pulmonary function assessment to the criteria an athlete must submit to use inhaled 02-agonists at Olympic Games may result in a change in the prevalence of asthma within elite athletes. The purpose of study 1 was to compare the prevalence of asthma at the 2000 and 2004 Olympic Games in the Great British Olympic team (Team GB). The asthma prevalence of Team GB reported in 2000 (21.2%) was similar to the asthma prevalence reported in 2004 (20.7%). 13 out of 62 (21.0%) athletes, from 2004 Team GB with a previous diagnosis of asthma failed to present evidence of EIA. The overall asthma prevalence of Team GB remained unchanged between 2000 and 2004. Mid-expiratory airflow measurements may improve the diagnosis of EIA in elite athletes. Study 2 investigated the response of Forced Expiratory Flow at 50% vital capacity (FEFso) following eucapnic voluntary hyperpnoea (EVH) and exercise challenge, in elite athletes, as an adjunct to Forced Expiratory Volume in one second (FEVI). 66 male and 50 female athletes were tested for EIA. Sixty athletes demonstrated a fall in FEVI >10% leading to the diagnosis of EIA. Using the FEF50 criteria (1FEF50 >-26%) led to 21 (35%) asthmatic athletes receiving false negative diagnosis. The addition of FEF50 failed to enhance the diagnosis of EIA in elite athletes. It is unclear, between exercise and EVH challenges as to which one provides the greatest sensitivity and most suitable method of EIA diagnosis in elite athletes. Study 3 investigated the response of elite winter athletes to EVH and two exercise challenges (laboratory-based [LB] and sport-specific [SS]). 14 athletes from the British Short-track Speed Skating and Biathlon teams volunteered for the study. Ten athletes presented with a positive response to EVH (71%); of these, only 3 (21%) had a positive response to the SS challenge. No athletes had a positive test to the LB challenge. Our results suggest that the EVH challenge is more sensitive, compared with either LB or SS exercise challenge, to diagnose EIA in elite winter athletes. A limited number of studies exist examining the optimal pharmacotherapy for elite athletes with EIA. The purpose of study 4 was to examine the effects of fluticasone propionate and salmeterol in the control of EIA in athletes. Eight athletes were prescribed 200mcg fluticasone propionate (FLU), 50mcg Salmeterol (SAL), 250mcg fluticasone propionate and salmeterol in combination (FXS) or placebo (PLA), in a randomised double blind design. No significant (p=0.07) differences were observed in the FEV1 change (zFEV1) following EVH challenge between the 4 treatments. Baseline eNO for both FXS (20.3 +/- 8.2ppb) and FLU (19.7 +/- 9.2 ppb) were significantly (p=0.02) lower than SAL (39.3 +/- 26.7ppb) or PLA (46.3 +/- 26.8ppb). Four athletes were prescribed FLU, 2 athletes were prescribed FXS and 2 athletes were prescribed SAL. The results of this study demonstrate the heterogeneity of response in elite athletes with EIA to the three medication regimes employed. Therefore, suggesting differences in the pathogenesis of EIA in this population. This thesis is the first to investigate EIA within elite British athletes. The prevalence of asthma within elite athletes is greater than that of the British general population. Optimal EIA diagnostic methods should include EVH challenges using FEV1 as the criterion measurement. Treatment for athletes with EIA should be taken on an individual basis due to the heterogeneity of response to medications that attenuate EIA in elite athletes.

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