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Glucocorticoid sensitivity of alveolar macrophages and modulation by p38 mitogen activated protein kinases in chronic obstructive pulmonary disease

Rationale It had been reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) display glucocorticoid resistance. Previous studies have only investigated limited numbers of inflammatory mediators. Objectives To compare the Gc sensitivity of a range of inflammatory mediators produced by LPS stimulated alveolar macrophages from capo patients compared to smokers (S) and healthy non-smokers (HNS). Methods and measurements LPS stimulated alveolar macrophages from 15 capo patients, 9 Sand 9 HNS were stimulated with LPS with or without dexamethasone (100 and 1000 nM). Luminex and ELISA were used to measure 23 inflammatory mediators. Combination treatment with dexamethasone and p38 MAP K inhibitors was also analysed. Main Results After LPS stimulation there were lower levels of inflammatory mediators in COPD patients and S compared to HNS, reaching statistical significance (p<0.05) for GROa, IL-8 and GM-CSF. Neither dexamethasone concentration inhibited GM-CSF or G-CSF production in any of the 3 groups. There was significant (p<0.05) inhibition ofGRO-a, IL-8, MIPla, IL-6, TNF-a, IL-lO, Rantes and MCP-l production in all 3 subject groups. There was no difference between groups for the effects of dexamethasone at either concentration (p>0.05 for all comparisons). TNF-a, IL-6 and GRO-a displayed the most sensitivity to dexamethasone in CO PO patients, while IL-8, GMCSF and GCSF were the least sensitive. Treatment with p38 MAP K inhibitors maximised inhibition of Gc insensitive mediators. Conclusions COPD macrophages have a reduced response to LPS. Glucocorticoid sensitivity was similar in capo macrophages compared to controls. Some glucocorticoid insensitive cytokines were identified, including GM-CSF, G-CSF and lL-8 that may be involved in the progression of airway inflammation in patients treated with glucocorticoids. Inhibition was maximised using combination treatment with p38 MAPK inhibitors.
Date January 2009
CreatorsArmstrong, Jane Alice
PublisherUniversity of Manchester
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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