Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases
Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases
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非抗生素类大环内酯类药物可恢复气道巨噬细胞的吞噬功能，并对慢性肺部疾病具有潜在的抗炎作用。
DOI：
10.1152/ajplung.00518.2016
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发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
Wilbert, Sibylle
中科院分区：
文献类型：
--
作者：
Hodge, Sandra;Tran, Hai B.;Wilbert, Sibylle
我们报道了慢性肺病（包括慢性阻塞性肺病、严重哮喘和儿童支气管扩张）中与吸烟和/或气道炎症相关的缺陷性红细胞增多症。我们还发现，在这些疾病中，下呼吸道常见的定植者--无法分型的流感嗜血杆菌（NTHi）的吞噬作用存在缺陷。这些缺陷可以用低剂量阿奇霉素基本克服，但是，长期使用可能会诱导细菌耐药性。因此，本研究的目的是研究两种新的大环内酯类化合物--2 '-脱氧-9-（S）-红霉素胺（GS-459755）和阿奇霉素基2'-脱氧分子（GS-560660）--对金黄色葡萄球菌、肺炎链球菌、卡他莫拉菌和H.流感。我们测试了它们对细胞吞噬作用、NTHi吞噬作用、细胞活力、参与识别凋亡细胞和/或NTHi的受体的影响（流式细胞术），分泌和裂解的细胞内IL-1 β（细胞计数珠阵列，免疫荧光/共聚焦显微镜），和使用原代肺泡巨噬细胞和THP-1巨噬细胞+/-10%的核苷酸结合寡聚化结构域样受体家族含吡啉结构域3（NLRP 3）香烟烟雾提取物剂量反应实验表明，与我们对阿奇霉素的研究结果相比，GS-459755和GS-560660在0.5-1 μ g/ml浓度下具有最佳的原噬细胞作用。两种大环内酯类均显著改善了凋亡细胞和NTHi的吞噬作用（例如，NTHi的吞噬作用和吞噬作用增加：GS-459755，分别为23%和22.5%，P = 0.043; GS-560660，分别为23.5%和22%，P = 0.043）。在暴露于浓度高达20 μ g/ml的任一大环内酯24小时后，巨噬细胞存活率保持>85%。两种大环内酯类药物均降低了分泌和细胞内裂解的IL-1 β，但识别分子c-mer原癌基因酪氨酸激酶、清道夫受体A类成员1、Toll样受体2/4或CD 36无显著变化。NLRP 3炎性小体的颗粒细胞质免疫荧光也显著降低。我们得出结论，GS-459755和GS-560660可能有助于减少慢性肺部疾病的气道炎症，而不会诱导细菌耐药性。
We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with lowdose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides-2'-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2'-desoxy molecule (GS-560660)-with significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and H. influenzae. We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1 beta (cytometric bead array, immunofluorescence/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages +/- 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5-1 mu g/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, P = 0.043; GS-560660, 23.5 and 22%, P = 0.043, respectively). Macrophage viability remained >85% following 24 h exposure to either macrolide at concentrations up to 20 mu g/ml. Secreted and intracellular-cleaved IL-1 beta was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member 1; Toll-like receptor 2/4; or CD36. Particulate cytoplasmic immunofluorescence of NLRP3 inflammasome was also reduced significantly. We conclude that GS-459755 and GS-560660 may be useful for reducing airway inflammation in chronic lung diseases without inducing bacterial resistance.