RT Journal Article SR Electronic T1 LSC 2013 abstract - Abnormal neutrophil migration is a feature of early COPD, present across disease phenotypes and causally related to increased phosphoinositide-3-kinase signalling JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP PP125 VO 42 IS Suppl 57 A1 Georgia Walton A1 James Stockley A1 Adam Usher A1 Robert Stockley A1 Elizabeth Sapey YR 2013 UL http://erj.ersjournals.com/content/42/Suppl_57/PP125.abstract AB All COPD clinical phenotypes have airway neutrophilia & neutrophil(PMN)-related damage. COPD PMNs are less accurate when migrating, however it is unclear if this is specific to COPD or a general feature of inflammation. Phosphoinositide-3-kinase (PI3K) has been shown to be important in migration, the mechanism involved is unclear. We aim to assess the role of PI3K in migration of PMNs from COPD patients.Method: PMNs from 60 patients with COPD (GOLD stages I-IV, emphysema, frequent exacerbators), chronic severe asthma, Bronchiectasis, A1ATD & Healthy Smokers(HS) migrated towards CXCL8, CXCL1, LTB4 & fMLP after incubation with Class 1 isoform selective PI3K inhibitors(α,β,δ,γ), SHIP inhibitors or carrier control. PI3K, AKT & phosphatase activity was assessed.Results: COPD PMNs initiated migration faster(COPD 48s ± 13, HS 68s±19, p=0.001) with increased random movement but reduced accuracy towards stimuli(p≤0.01 for all) in all COPD stages & phenotypes, but not in other inflammatory conditions. COPD PMNs had constitutive PI3K & AKT activity compared with HS. PI3K blocking strategies(specifically PI3K γ & δ) restored accuracy. SHIP inhibition worsened chemotaxis in COPD & HS PMNs. There was no difference in phosphatase activity(COPD 150MFI(51-203), HS122(43-192)).Conclusion: COPD PMNs show increased random migration, but are less accurate. This is an early disease phenomenon & may contribute to increased damage. Inaccurate migration is causally related to PI3K activity, a potential target for disease modification.