Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD.
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.
Department of Infection, Immunity and Cardiovascular Disease and The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom.
Martin A
MA
Bewley
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Kylie B R
KB
Belchamber
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Kirandeep K
KK
Chana
Department of Infection, Immunity and Cardiovascular Disease and The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom.|Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.|Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
Richard C
RC
Budd
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Gavin
G
Donaldson
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Jadwiga A
JA
Wedzicha
Institute for Lung Heath, University of Leicester, Leicester, United Kingdom.
Christopher E
CE
Brightling
Pfizer Inc, Cambridge, Massachusetts, United States of America.
Iain
I
Kilty
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Louise E
LE
Donnelly
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Peter J
PJ
Barnes
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
Dave
D
Singh
Department of Respiratory Medicine and MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
Moira K B
MK
Whyte
Department of Infection, Immunity and Cardiovascular Disease and The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom.|Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.
David H
DH
Dockrell
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