TY - JOUR T1 - S71 Sustained impairment of neutrophil migration following acute exacerbations of chronic obstructive pulmonary disease JF - Thorax JO - Thorax SP - A47 LP - A47 DO - 10.1136/thorax-2019-BTSabstracts2019.77 VL - 74 IS - Suppl 2 AU - WJ McIver AU - M Hughes AU - GM Walton AU - RA Stockley AU - E Sapey Y1 - 2019/12/01 UR - http://thorax.bmj.com/content/74/Suppl_2/A47.1.abstract N2 - Introduction/objectives In stable COPD (sCOPD), peripheral blood neutrophils migrate with greater speed but less accuracy, potentially reducing the efficiency of bacterial clearance and increasing the potential for tissue damage. These defects can be normalised in-vitro by Phosphoinositide 3-kinase (PI3K) inhibition.1 Acute exacerbations of COPD (AECOPD) are often associated with bacterial infections. Neutrophil migration during AECOPD has not been characterised. Given the repetitive nature of and poor outcomes from AECOPD, we hypothesised that neutrophil functions would be similarly impaired.Methods Peripheral neutrophils were isolated from 33 hospitalised patients on day 0 and day 56 (recovery) of an AECOPD, and 33 sCOPD patients, matched by age and FEV1% predicted. An Insall chamber and time-lapse microscopy assessed neutrophil migration towards Interleukin-8 (IL8) and formyl-Methionyl-Leucyl-Phenylalanine (fMLP) following pre-incubating with PI3K inhibitors or vehicle controls. Expression of the key receptor for IL8, C-X-C motif chemokine receptor 2 (CXCR2), and 3 markers of activation (CD11b, CD66b, CD62L) were assessed by flow cytometry.Results Neutrophils from patients on day 0 of AECOPD migrated towards IL8 and fMLP with lower speed and velocity compared with sCOPD (table 1). Day 0 velocity towards IL8 inversely related to Day 0 serum C-reactive protein concentration (r= -0.37, p=0.037). 56 days later (when clinically stable), migration had not improved and remained lower than sCOPD patients.Unlike sCOPD, incubation with PI3Kδ or γ inhibitors did not improve migration compared to vehicle control.CXCR2 was expressed at a lower level on AECOPD neutrophils compared to sCOPD [Median MFI (IQR): 2739 (2469–3496) vs 3891 (3216–4229), (p=0.006)]. Expression of CD11b was higher in AECOPD compared to sCOPD [Median MFI (IQR): 2559 (1315–2647) vs 1301 (1001–2061); p=0.015].Conclusions AECOPD are associated with a sustained reduction in neutrophil migratory accuracy, with the degree of impairment related to the systemic inflammatory burden at onset and seeming to reflect a primed state. Unlike sCOPD, inhibition of PI3K δ or γ was unable to normalise migration during AECOPD. Moreover, expression of CXCR2 was reduced in AECOPD compared to sCOPD, offering a putative mechanism for the observed migratory defects.ReferenceSapey, et al. AJRCCM, https://doi.org/10.1164/rccm.201008-1285OCView this table:Abstract S71 Table 2 neutrophil migration on day 0 of AECOPD compared to stable COPD ER -