S115 The effects of hypoxia on neutrophil-mediated tissue damage in the lung

Abstract

have shown neutrophil migratory accuracy to be reduced in COPD. This is thought to contribute to the destruction of lung parenchyma and the poor responses seen in infective exacerbations. We aimed to characterise neutrophil migration in COPD and assess whether physiologically relevant concentrations of simvastatin altered neutrophil migration. Methods Neutrophils were isolated from COPD patients and healthy smoking age-matched controls (age > 60yrs, n = 13 per group) and incubated with 1nM -1µM Simvastatin or with a carrier control before migratory dynamics were assessed towards IL8 and fMLP using time-lapse photography. Data is expressed as means with standard deviation in parentheses. Results COPD neutrophils displayed reduced chemotaxis (directional speed of migration) and reduced chemotactic accuracy (Chemotactic Index -a vector analysis of migratory tracks) compared to cells from healthy age-matched controls (HC) in the presence of IL-8 and f-MLP, replicating previous work. For example, Chemotactic Index: IL8; HC, 0.42CU (0.03), COPD 0.22CU (0.05), p = 0.002: fMLP; HC, 0.34CU (0.05), COPD, 0.18CU (0.03) p = 0.014).Treatment with Simvastatin significantly improved the chemotactic ability of COPD neutrophils in a dose response with greatest improvement seen at the highest concentration (e.g. Chemotaxis to IL8, Carrier control 0.8um/min (0.2), 1nM Simvastatin 1.3um/min (0.2), p = 0.04; 1uM Simvastatin 1.4um/min (0.2), p = 0.004). A similar improvement was seen in Chemotactic Accuracy (e.g. Chemotactic Index to fMLP, Carrier control 0.17CU (0.03), 1nM Simvastatin 0.26CU (0.02), p = 0.018; 1uM Simvastatin 0.31CU (0.03), p = 0.002). Conclusions Migratory accuracy of circulating neutrophils is reduced in COPD patients compared with healthy, smoking, agematched controls but can be restored by treatment with therapeutic concentrations of Simvastatin in vitro. Our data suggest statin therapy might be an adjuvant intervention in COPD, modulating neutrophil responses.