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Title: Comparison of inflammatory responses in human lung, skin and nasal tissue
Author: Lowings, Kelly Marie
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2010
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Inflammatory responses underpin many diseases in the skin, lung and upper airways. This study aimed to develop an explant model to allow ex vivo study of responses in these different tissues. Human skin (n= 120), lung (n=92) and nasal tissue (n=72) were obtained from surgery with patients' consent. Tissue was chopped into explants and stimulated with inflammatory stimuli, then cytokine release measured. Lung, skin and nasal tissue explants respond to stimulation with lipopolysaccharide (LPS) and anti-IgE by releasing a similar panel of cytokines. Pro-inflammatory cytokine TNF-α appears to be released first and may control release of other cytokines such as IL-1β, IL-6, IL-8 and IL-10. Whilst the kinetics of cytokine release from the different tissues are comparable, the magnitude is much higher from the lung; maximal TNF-α release from the lung is 79±13pg/mg tissue, from nasal tissue it reaches 39±11pg/mg tissue, but only 3.5±0.8pg/mg tissue is released from the skin. We have demonstrated similar numbers of macrophages in lung, skin and nasal tissue but there are significant differences in the numbers of mast cells, eosinophils and neutrophils. Furthermore we have shown that fewer cells migrate out of the skin during culture than the lung or nasal tissue, which may be pivotal in defining the level of responsiveness. We have shown that heat-killed S.aureus can also induce cytokine release from lung, skin and nasal tissue explants, although this response may be mediated by the cell wall component peptidoglycan (PGN), as similar responses to non-pathogenic S.epidermidis were seen in the skin. Staphylococcal enterotoxins (SEs) A and B were also shown to induce cytokine release, although this occurred on a slower timescale and a distinct panel of cytokines were released. Of particular interest, SEB induced release of Th2 cytokines IL-5 and IL-13 from the lung, but only IL-5 from the nasal tissue and skin; this may have implications for the role of the bacteria in allergic priming in different tissues or could indicate prior exposure to S.aureus in some patients. The corticosteroid dexamethasone downregulated LPS-, anti-IgE- and PGN-induced cytokine release from lung and nasal tissue explants, but failed to inhibit PGN-induced cytokine release from the skin, indicating the presence of distinct mechanisms in different tissues. Dexamethasone may increase expression of Toll-like receptor (TLR) 2 in keratinocytes, allowing PGN to continue to induce cytokine release, but this does not appear to occur in the other tissues. Immunosuppressive drugs cyclosporin A and methotrexate failed to downregulate TLR-mediated cytokine release in the skin. However, there appeared to be suppression of the T cell-mediated response, indicating that these drugs have distinct mechanisms of action to the corticosteroids. In summary, we have demonstrated development of an ex vivo model to study inflammatory responses in human lung, skin and nasal tissue and we have demonstrated differences in responses to stimuli and anti-inflammatory drugs in the different tissues.
Supervisor: Warner, Jane ; Wilson, Susan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available