Bewley Martin A, Belchamber Kylie B R, Chana Kirandeep K, Budd Richard C, Donaldson Gavin, Wedzicha Jadwiga A, Brightling Christopher E, Kilty Iain, Donnelly Louise E, Barnes Peter J, Singh Dave, Whyte Moira K B, Dockrell David H
Department of Infection, Immunity and Cardiovascular Disease and The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom.
Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
PLoS One. 2016 Sep 28;11(9):e0163139. doi: 10.1371/journal.pone.0163139. eCollection 2016.
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.
肺部炎症和细菌定植是慢性阻塞性肺疾病（COPD）发病机制的核心。巨噬细胞对细菌和凋亡细胞的吞噬缺陷导致了COPD的表型。具有抗炎活性的小分子抑制剂，如针对p38丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶（PI3K）和Rho激酶（ROCK）的抑制剂，正在作为COPD的新型治疗药物进行研究。然而，人们担心其脱靶效应。我们研究了p38 MAPK抑制剂（VX745和SCIO469）、PI3K α（NVS-P13K-2）、δ（NVS-P13K-3）或γ（NVS-P13K-5）的特异性抑制剂以及ROCK抑制剂PF4950834对巨噬细胞吞噬作用、细菌早期细胞内杀伤和凋亡中性粒细胞的胞葬作用的影响。研究对象为从一个特征明确的临床队列（MRC COPD-MAP联盟）招募的COPD患者（GOLD II/III期）或健康前吸烟者对照的支气管肺泡灌洗（BAL）获得的肺泡巨噬细胞（AM）或单核细胞衍生巨噬细胞（MDM）。与健康对照相比，COPD的AM和MDM均表现出较低水平的细菌吞噬作用（使用肺炎链球菌和不可分型流感嗜血杆菌）和胞葬作用。这些抑制剂均未改变AM或MDM中的细菌内化或早期细胞内细菌杀伤。相反，PF4950834而非其他抑制剂增强了COPD的AM和MDM中的胞葬作用。这些结果表明，这些抑制剂均不太可能加剧COPD中与吞噬作用相关的缺陷，同时证实ROCK抑制剂可增强COPD中的胞葬作用。
