Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.693890
Title: Effect of cigarette smoke and Toll-like receptor activation on alveolar inflammation
Author: Grandolfo, Davide
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Abstract:
The innate immune system is a first line defence mechanism against infection of the lower respiratory tract by pathogenic microorganisms. Pulmonary alveolar epithelial type 1 (TT1) and type-2 (AT-II) cells and macrophages (AMs) express Toll-like receptors (TLRs), which recognize microbial ligands and initiate the innate immune response by signalling synthesis and release of mediators, including cytokines. We hypothesized that activation of specific TLRs would elicit a unique profile of cytokine release from each cell type which would be enhanced in co-culture of pulmonary alveolar epithelial cells and macrophages. Mono-cultures of each cell type, and co-cultures, were incubated with either Lipopolysaccharide (LPS, TLR-4 ligand), MALP-2 (TLR-2 ligand) or Poly I:C (TLR-3 ligand) for 24 hours. There was, as hypothesised, potentiation of IL-6, IL-8, and IP-10 release from cells in co-culture compared to mono-culture following LPS and Poly I:C. However, there was no additional effect of co-culture on IL-6 and IL-8 release following MALP-2 exposure. Further studies using antibody eutralisation demonstrated that a significant proportion of the potentiation was initiated by soluble factors, released by AMs, acting on the epithelial cells. Furthermore, neutralization of inflammasome -related cytokines, IL-1? and IL-18, significantly inhibited release of IL-8 and IP-10. Although exacerbations due to pathogen infection enhance lung function impairment, cigarette smoking is the major risk factor for COPD. We hypothesized that cigarette smoke e xtract (CSE) would moderate inflammatory response in the cells. 1% CSE caused inhibition of mediator release, suggesting that this may increase risk of infection among smokers. Subsequent studies demonstrated that concentrations < 0.01% were stimulatory and resulted in the release of chemokines involved in the recruitment of dendritic cells. In conclusion, cytokine release at the alveolar interface will be up-regulated by interactions between alveolar epithelial cells and macrophages, via paracellular proces ses involving release of soluble factors by macrophages, including TNF-, IL-1 and IP-10.
Supervisor: Thorley, Andrew ; Tetley, Terry Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.693890  DOI: Not available
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