Smoking-related airway inflammation and corticosteroid responsiveness in smoking-related COPD
Creators: name: Wen, Yudong
Publisher: name: University Of Tasmania
Year: 2023

description: Chronic obstructive pulmonary disease (COPD) is the internationally preferred term encompassing chronic bronchitis, chronic bronchiolitis (small or peripheral airways disease), and emphysema. It is defined as a chronic, slowly progressive disorder characterised by airflow obstruction (FEVl &lt;80% predicted and FEVl/VC ratio&lt;70%) which does not change markedly over several months. The impairment of lung function is largely fixed but it may be partially reversible by bronchodilator therapy. Although the underlying pathogenesis is not yet fully understood, the main proposed mechanism is airway inflammation and secondary airway remodelling. Traditionally, airway neutrophilia is regard as predominant in COPD, while recently evidence has shown that airway eosinophilia may also feature in COPD. This may present an overlap phenotype with chronic asthma, and has raised an active debate on whether chronic asthma and COPD should be regard as. one entity. Corticosteroid therapy plays a pivotal role in the management of asthma and is increasingly used in COPD. However, the precise role and mechanism(s) of action of corticosteroid in COPD is poorly understood. Published findings, for example, the large ISOLDE and EUROSCOPE studies have suggested that inhaled corticosteroids (ICS) might have a positive disease-modifying effect on \stable\" smoking-related COPD in terms of preventing exacerbations and future deterioration in quality of life (QOL). However Reid/Walters in a letter to Editor NEJM (2001; 344:1554-6) pointed out that those studies have been flawed by their selective criteria. In fact little data exist using full pathological analysis of airway samples (combination of sputum BAL and biopsy) or in the entire population of COPD. In particular patients with increased BDR have generally been excluded from studies. There are no certain predictors for steroid responsiveness although bronchodilator response (BDR) and or eosinophilia in COPD have been suggested: i.e. are the effects of corticosteroids in COPD due exclusively to inhibition of the \"asthma-like\" features of the inflammatory response in COPD. Since cigarette smoke is the overwhelming factor in aetiology of COPD whether it serves as both an irritant and allergen in pathogenesis is another issue of increasing research interest. In this thesis I have addressed a number of these issues. I investigated clinical physiological and pathological indices in my studies. Clinical: symptoms including cough sputum production dyspnoea reliever use of Ventolin and quality of life (QOL) assessed by St. George Respiratory Questionnaire (SGRQ); physiological: full lung function including lung volume and gas transfer factor was measured; pathological: conventional cytology and histology methods were employed for sputum BAL and biopsy pan-inflammatory cell staining and quantification. A well-developed chemiluminescence ELISA method was used to¬¨‚àë measure three important cytokines: IL- 5 eotaxin and IL-8 involved in chemotactic activity and regulation of eosinophils and neutrophils. The ELISA method was also employed in a purely methodological experiment for the potential that dithiothreitol (DTT) used in the processing of sputum may distort the data obtained. In Chapter 3 - I studied the possible destructive effect of DTT used in sputum processing on cytokine protein. I found definite but between - cytokine variable effects on cytokine levels in subsequent ELISA assays. These results have major implications for interpretation of previous research as well as the possible future application of sputum analysis into clinical practice. In Chapter 4 - A smoking effect study: a cross-sectional analysis of cellular indices and cytokines in sputum addressed the impact of cigarette smoke on airway pathology in \"healthy\" smokers and in COPD. The influence of smoking cessation was also studied. It was shown that cigarette smoke lead to airway inflammation in both \"healthy\" smokers and in those with established COPD but the involvement of individual cell types was different. A polymorphic inflammation appeared in COPD compared to \"healthy\" smokers with involvement of both innate and adaptive immune cells. Smoking cessation alters but does not reverse the airway inflammation to normal in either healthy or COPD smokers. In Chapter 5 - a baseline comparison between COPD and non-smoker normals: the features of airway inflammation in a diversed COPD population were described. Using sputum BAL and biopsy specimens we were able to provide both lumenal and airway wall signals. Multiple inflammatory cells are involved in the development of COPD including macrophages neutrophils lymphocytes eosinophils and mast cells. The discrepancy between lumenal and airway wall data reflect the different activity and location of inflammatory cells. The lack of correlation between sputum BAL and biopsy cell counts suggested that the three measurements are complementary to each other and one is not a surrogate for another. A novel finding in COPD of increased mast cells consistent appeared in sputum BAL and biopsy implying an aetiological role in COPD which requires further detailed study. In Chapter 6 - a primary longitudinal intervention study: high-dose ICS (Fluticasone dipropionate) was given to eligible COPD patients in a randomised double blinded placebo controlled manner. BDR was not an exclusion criterion making this an unique study. Positive effects of ICS on COPD were confirmed. We found strong evidence for lung function (FEVl and FVC) improvement after ICS but only a small improvement in the symptom domain of the quality of life assessment. The change in airway pathology predominantly occurred in airway biopsies and BAL but not in sputum. The involvement of neutrophils lymphocytes and mast cells in the ICS treatment effect could be a very important finding for COPD management as it implies that ICS can regulate both innate and adaptive immune responses. In Chapter 7 - a within and between group comparison from the ICS intervention study attempted to answer the most controversial question: is there a \"hidden asthma\" ICS responsive phenotype in COPD. We confirmed the existence of a subgroup with higher BDR and airway eosinophils but these changes were not related to each other and there was little to differentiate clinically between BDR+ve or BDR-ve or eosinophil +ve or -ve subgroups. ICS effect was not dependent upon the presence of either BDR or eosinophilia which were not predictors for the outcomes of using ICS. Nor did we find any other predictors of ICS effect. In conclusion we have described specific smoking and specific COPD inflammatory patterns in airway samples. ICS serves to suppress the airway inflammation in COPD but its role is not dependent on a specific \"hidden asthma\" phenotype but the effects of ICS are generalised across the profile of disease. The development of COPD involves not only innate immune responses but also adaptive immure responses. This novel finding for understanding COPD pathogenesis is potentially important as it offers evidence for cooperation of the whole immune system and provides direction for further research."