COPD is a condition characterised by chronic inflammation in which macrophages arethought to play a central role. Corticosteroids are the most widely used antiinflammatoryagents to treat COPD. There is a subset of inflammatory mediatorswhich are corticosteroid insensitive and so there is a need for novel anti-inflammatorytherapies to treat COPD. One such target is the liver X receptor (LXR), a cholesterolsensing nuclear hormone receptor with anti-inflammatory properties. Before investigating the anti-inflammatory potential of LXR, I aimed to validate thealveolar macrophage in vitro culture model. I investigated the effect of differentculture times on unstimulated and stimulated cytokine release, dexamethasoneinhibition of cytokine release, and transcription factor phosphorylation in alveolarmacrophages from COPD patients and controls. I found that freshly isolatedmacrophages release higher levels of cytokines, are less responsive to dexamethasoneand have increased levels of phosphorylated p38 MAPK.I next investigated LXR gene and protein expression levels in alveolar macrophages andwhole lung tissue from COPD patients and controls, the effect of LXR activation on thesuppression of inflammatory mediators from LPS stimulated COPD alveolarmacrophages, and the effect of LXR activation on the induction of genes associatedwith alternative macrophage polarisation. The levels of LXR mRNA were significantlyincreased in whole lung tissue extracts in COPD patients and smokers compared tonever smokers. The expression of LXR protein was significantly increased in smallairway epithelium and alveolar epithelium in COPD patients compared to controls. Nodifferences in LXR mRNA and protein levels were observed in alveolar macrophagesbetween patient groups. The LXR agonist GW3965 significantly induced the expressionof the LXR dependent genes ABCA1 and ABCG1 in alveolar macrophage cultures. InLPS stimulated alveolar macrophages, GW3965 suppressed the production of CXCL10and CCL5, whilst stimulating IL-10 production. GW3965 did not significantly suppressthe production of TNFα, IL-1β, or CXCL8. The major finding is that LXR activation hasanti-inflammatory effects on CXC10, CCL5 and IL-10 production from alveolarmacrophages. Finally, I investigated whether dysfunctional lipid homeostasis is a feature of COPDalveolar macrophages. I found that alveolar macrophages from current smokers withand without COPD had increased levels of neutral lipids compared to never smokersand ex-smokers with and without COPD. Dysfunctional lipid homeostasis may play arole in COPD.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:603284 |
| Date | January 2014 |
| Creators | Higham, Andrew James |
| Contributors | Singh, Sukh |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-the-liver-x-receptor-in-chronic-obstructive-pulmonary-disease(b1916ddb-6514-4407-b657-0dede8d7fa28).html |
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