COPD is a disease of global importance and its primary cause airway inflammation as a consequence of cigarette smoking is well described. However, there remains a lack ofeffective therapies for this important condition. Animal models of disease are limited in their predictive utility and therefore creation of a complex, human disease modelis an important step for testing new therapeutic interventions. We therefore established a tissue model of oxidative and inflammatory responses to relevant triggers—cigarette smoke and LPS and determined the impact of interventions in the optimised system.
Methods Human lung tissueexplants from the resected lobes of six consented patients undergoing lobectomy were used. Uniform tissue explants were established on a novel culture system and then treated with CSE and LPS before the supernatants were collected optimal dosing was determined. Treatments and control experiments were performed with the anti-oxidant Vitamin C and fluticasone. Inflammatory readouts were measured by ELISA; TNFa, IL-8 and MMP-9.
Results Lung tissue treated with CSE showed a dose-dependent increase in IL-8 and MMP-9 secretion across a range 0.6250%–20% CSE. IL-8 response to 20% CSE was 71592.21 pg/mg/ml ±4680.7 SE compared to non-stimulated tissue 14 177 pg/mg/ml ±1088 SE (n=6, p<0.001), MMP-9 response to 20% CSE 206 pg/mg/ml ±30.55SE vs control 104 pg/mg/ml ±4.49 SE (n=6, p<0.001).However no demonstrable rise in TNF-α secretion from tissue treatedwith CSE was detectable. With LPS stimulation both TNF-α and IL-8 responses demonstrated adose-dependent increase within the range 0.01–100 ng/ml (n=5, p=0.0003).
Treatment effects Stimulated IL-8 and MMP-9 secretion was significantly reduced in tissue treated with 0.1% vitamin C. 25% reduction in IL8 (n=3, p=0.065) and 32% reduction in MMP9 (n=3, p=0.0133). Fluticasone treatment reduced LPS induced TNF-α and IL-8 in a dose dependent manner (n=4, p=0.03).
Conclusions A human lung tissue model of smoke and LPS induced inflammation demonstrates the importance of selecting appropriate readouts for a given stimulus or treatment and hence a potential utility in selecting trial endpoints. Furthermore it demonstrates that vitamin C and corticosteroids can reduce oxidative stress and inflammation in a complex tissue system- their combined effects warrant investigation in COPD.
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