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Title: The 'smoking endotype' of asthma : studies on cigarette smoke-induced, IL-17A dependent neutrophilic inflammation in the bronchial mucosa of asthmatics who smoke
Author: Siew, Leonard Quok Chean
ISNI:       0000 0004 5369 1335
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2015
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Introduction: Many asthmatics smoke, and this has a detrimental effect on the course and control of the disease. The pathophysiological mechanisms through which smoking exerts these effects remain ill defined. The main aims of the studies described in this thesis are to investigate the effects of cigarette smoke on airways structural cells, in particular how it influences the expression of pro-inflammatory and pro-remodelling cytokines, and thereby to understand the role that structural cells may play in the development of Th17/IL-17A mediated neutrophilic inflammation in asthmatics who smoke. A further aim is to show that there is increased vascular remodelling in the airways of asthmatic smokers. Methods: The neutrophilic and angiogenesis hypotheses were addressed by investigating the effects of cigarette smoke extract (CSE) and IL-17A on human tracheal epithelial cells (HTEpC) and primary bronchial fibroblasts cells in vitro, and also by measuring the expression of these mediators and remodelling changes in bronchial mucosal biopsies from smoking and non-smoking asthmatics in vivo. Results: There was elevated expression of IL-17A in the bronchial mucosa of asthmatic smokers compared to non-smokers. This was accompanied by elevated expression of IL-6 and IL-8 as well as elevated numbers of neutrophils. In the smoking asthmatics, the expression of IL-17A correlated both with that of IL-8 and with the numbers of neutrophils. Interestingly, the numbers of bronchial mucosal eosinophils also correlated with the expression of IL-8, IL-17A and the numbers of neutrophils. In these mild asthmatic patients there was no difference in the extent of vascular remodelling or numbers of mucosal eosinophils in smokers compared to nonsmokers. Exposure of HTEpC cells to both CSE and IL-17A resulted in increased expression of IL-6 and IL-8 synergistically. The data further suggested that the synergistic interaction between CSE and IL-17A in HTEpC cells may be mediated by reactive oxygen species (ROS). Co-stimulation of HTEpC cells with CSE, IL-17A and allergens lacking intrinsic protease activity (cat dander and Timothy grass pollen) also increased IL-6 and IL-8 production synergistically. Stimulation of primary human airways fibroblasts with both CSE and IL-17A also resulted in increased expression of IL-6 and VEGF, again with a suggestion of synergy in the effects. CSE exposure induced HTEpC cells to express VEGF in a concentration-dependent manner. This induction was dependent on MAPK signalling (p38 MAPK, Erk and JNK) and, upstream from this, PI3 kinase-dependent Akt phosphorylation. CSE also induced expression of IL-6, TGF-β1 and VEGF in primary bronchial fibroblasts in a concentration-dependent manner. The induction of IL-6 and VEGF by CSE was found to be dependent on p38 MAPK and ERK signalling, while the induction of TGF-β1 was dependent on ERK and JNK signalling. When primary bronchial fibroblasts were co-stimulated with either Poly I:C or LTA and CSE, there was a synergistic increase in the expression of VEGF. When HTEpC cells were stimulated with Poly I:C the expression of TSLP was inhibited by CSE, while there was no effect on the expression of IL-6. Conclusion: Asthmatic smokers have IL-17A mediated neutrophilic inflammation of the airways, which is supported by the effects of CSE interacting with other environmental stimuli (allergens, viruses) on airways epithelial cells and fibroblasts. This evidence supports the categorisation of asthmatic smokers as a specific endotype of asthma.
Supervisor: Lee, Tak Hong; Corrigan, Christopher John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available