Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD.
Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD.
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DOI：
10.1371/journal.pone.0163139
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
COPDMAP
中科院分区：
文献类型：
--
作者：
Bewley MA;Belchamber KB;Chana KK;Budd RC;Donaldson G;Wedzicha JA;Brightling CE;Kilty I;Donnelly LE;Barnes PJ;Singh D;Whyte MK;Dockrell DH;COPDMAP
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。巨噬细胞吞噬细菌和凋亡细胞的缺陷导致COPD表型。对p38丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶（PI 3 K）和Rho激酶（ROCK）具有抗炎活性的小分子抑制剂正在被研究作为COPD的新型治疗剂。然而，人们对脱靶效应感到关切。我们研究了p38 MAPK抑制剂（VX 745和SCIO 469）、PI 3 K α（NVS-P13 K-2）、δ（NVS-P13 K-3）或γ（NVS-P13 K-5）的特异性抑制剂和ROCK抑制剂PF 4950834对巨噬细胞吞噬作用、细菌的早期细胞内杀伤和凋亡中性粒细胞的吞噬作用的影响。研究了从充分表征的临床队列（MRC COPD-MAP联盟）或从健康的前吸烟者对照招募的COPD患者（GOLD II/III期）的支气管肺泡灌洗（BAL）或单核细胞衍生的巨噬细胞（MDM）获得的肺泡巨噬细胞（AM）。COPD AM和MDM的细菌吞噬作用（使用肺炎链球菌和不可分型的流感嗜血杆菌）和嗜酸性粒细胞增多症水平均低于健康对照组。这些抑制剂都没有改变AM或MDM中的细菌内化或早期细胞内细菌杀伤。相反，PF 4950834，而不是其他抑制剂，增强COPD AM和MDM中的红细胞增多。这些结果表明，这些抑制剂都不可能加剧COPD中吞噬相关的缺陷，同时证实ROCK抑制剂可以增强COPD中的吞噬作用。
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.
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DOI：
10.1084/jem.20031237
发表时间：
2004-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Doyle SE;O'Connell RM;Miranda GA;Vaidya SA;Chow EK;Liu PT;Suzuki S;Suzuki N;Modlin RL;Yeh WC;Lane TF;Cheng G
通讯作者：
Cheng G
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
9.6
作者：
Dockrell, David H.;Whyte, Moira K. B.;Mitchell, Timothy J.
通讯作者：
Mitchell, Timothy J.
影响因子：
6.4
作者：
Ali, F;Lee, ME;Dockrell, DH
通讯作者：
Dockrell, DH
影响因子：
3.1
作者：
Bogaert, D;van der Valk, P;Hermans, PWM
通讯作者：
Hermans, PWM