PMID- 27680884
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220131
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 9
DP  - 2016
TI  - Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial 
      Phagocytosis and Efferocytosis by Macrophages in COPD.
PG  - e0163139
LID - 10.1371/journal.pone.0163139 [doi]
LID - e0163139
AB  - 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 alpha 
      (NVS-P13K-2), delta (NVS-P13K-3) or gamma (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.
FAU - Bewley, Martin A
AU  - Bewley MA
AD  - Department of Infection, Immunity and Cardiovascular Disease and The Florey 
      Institute for Host-Pathogen Interactions, University of Sheffield Medical School, 
      Sheffield, United Kingdom.
FAU - Belchamber, Kylie B R
AU  - Belchamber KB
AD  - Airway Disease National Heart and Lung Institute, Imperial College London, 
      London, United Kingdom.
FAU - Chana, Kirandeep K
AU  - Chana KK
AD  - Airway Disease National Heart and Lung Institute, Imperial College London, 
      London, United Kingdom.
FAU - Budd, Richard C
AU  - Budd RC
AD  - Department of Infection, Immunity and Cardiovascular Disease and The Florey 
      Institute for Host-Pathogen Interactions, University of Sheffield Medical School, 
      Sheffield, United Kingdom.
AD  - Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.
AD  - 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.
FAU - Donaldson, Gavin
AU  - Donaldson G
AD  - Airway Disease National Heart and Lung Institute, Imperial College London, 
      London, United Kingdom.
FAU - Wedzicha, Jadwiga A
AU  - Wedzicha JA
AD  - Airway Disease National Heart and Lung Institute, Imperial College London, 
      London, United Kingdom.
FAU - Brightling, Christopher E
AU  - Brightling CE
AD  - Institute for Lung Heath, University of Leicester, Leicester, United Kingdom.
FAU - Kilty, Iain
AU  - Kilty I
AD  - Pfizer Inc, Cambridge, Massachusetts, United States of America.
FAU - Donnelly, Louise E
AU  - Donnelly LE
AD  - Airway Disease National Heart and Lung Institute, Imperial College London, 
      London, United Kingdom.
FAU - Barnes, Peter J
AU  - Barnes PJ
AD  - Airway Disease National Heart and Lung Institute, Imperial College London, 
      London, United Kingdom.
FAU - Singh, Dave
AU  - Singh D
AD  - 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.
FAU - Whyte, Moira K B
AU  - Whyte MK
AD  - Department of Respiratory Medicine and MRC Centre for Inflammation Research, 
      University of Edinburgh, Edinburgh, United Kingdom.
FAU - Dockrell, David H
AU  - Dockrell DH
AD  - Department of Infection, Immunity and Cardiovascular Disease and The Florey 
      Institute for Host-Pathogen Interactions, University of Sheffield Medical School, 
      Sheffield, United Kingdom.
AD  - Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.
CN  - COPDMAP
LA  - eng
GR  - G0800570/MRC_/Medical Research Council/United Kingdom
GR  - G0901697/MRC_/Medical Research Council/United Kingdom
GR  - G1001372/MRC_/Medical Research Council/United Kingdom
GR  - G1001365/MRC_/Medical Research Council/United Kingdom
GR  - RP-PG-0109-10056/DH_/Department of Health/United Kingdom
PT  - Journal Article
DEP - 20160928
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
PMC - PMC5040258
COIS- IK is an employee of Pfizer. This does not alter our adherence to PLOS ONE 
      policies on sharing data and materials. All other authors have declared that no 
      competing interests exist.
EDAT- 2016/09/30 06:00
MHDA- 2016/09/30 06:01
PMCR- 2016/09/28
CRDT- 2016/09/30 06:00
PHST- 2015/12/16 00:00 [received]
PHST- 2016/09/02 00:00 [accepted]
PHST- 2016/09/30 06:00 [entrez]
PHST- 2016/09/30 06:00 [pubmed]
PHST- 2016/09/30 06:01 [medline]
PHST- 2016/09/28 00:00 [pmc-release]
AID - PONE-D-15-54547 [pii]
AID - 10.1371/journal.pone.0163139 [doi]
PST - epublish
SO  - PLoS One. 2016 Sep 28;11(9):e0163139. doi: 10.1371/journal.pone.0163139. 
      eCollection 2016.