Veterans Health Administration, Veterans Affairs Western New York Healthcare System at Buffalo, Division of Pulmonary, Critical Care and Sleep Medicine, Buffalo, New York, United States of America.
University at Buffalo, State University of New York, Jacobs School of Medicine and Biomedical Sciences, Division of Pulmonary, Critical Care and Sleep Medicine, Buffalo, New York, United States of America.
PLoS One. 2019 Jan 24;14(1):e0207675. doi: 10.1371/journal.pone.0207675. eCollection 2019.
RATIONALE: Patients with COPD have an increased risk for community-acquired pneumonia, which is further increased by inhaled corticosteroids. OBJECTIVE: To assess effects of the corticosteroids, budesonide and fluticasone propionate, on macrophage bacterial responses in COPD. METHODS: Monocyte-derived macrophages (MDMs) generated from blood monocytes from 10 non-smoker controls (NoS), 20 smokers without COPD (Sm), and 40 subjects with moderate to severe COPD (21 ex-smokers (COPD-ES) and 19 current smokers (COPD-S)) were pre-treated with budesonide or fluticasone (10 nM-1 μM) and challenged with live non-typeable Haemophilus influenzae (NTHI) or Streptococcus pneumoniae (SP). Cell surface bacterial recognition receptor expression (flow cytometry) and cytokine release (bead array) were analyzed. RESULTS: NTHI and SP reduced bacterial recognition receptor expression on MDMs from COPD and Sm, but not NoS (except TLR4). SR-AI and MARCO were reduced by both NTHI and SP, whereas other receptors by either NTHI or SP. Among COPD subjects, COPD-ES demonstrated a greater number of reductions as compared to COPD-S. NTHI reduced SR-AI, MARCO, CD11b, CD35 and CD206 in COPD-ES while only SR-AI and CD11b in COPD-S. SP reduced SRA-1, CD1d, TLR2 and TLR4 in both COPD-ES and COPD-S, and reduced MARCO and CD93 only in COPD-ES. All receptors reduced in COPD by NTHI and most by SP, were also reduced in Sm. Budesonide counteracted the receptor reductions induced by both NTHI (CD206 p = 0.03, MARCO p = 0.08) and SP (SR-AI p = 0.02) in COPD-ES. Fluticasone counteracted only SP-induced reductions in TLR2 (p = 0.008 COPD-ES and p = 0.04 COPD-S) and TLR4 (p = 0.02 COPD-ES). Cytokine release was equivalently reduced by both corticosteroids. CONCLUSIONS: Reduction in macrophage bacterial recognition receptors during bacterial exposure could provide a mechanism for the increased pneumonia risk in COPD. Differential effects of budesonide and fluticasone propionate on macrophage bacterial recognition receptor expression may contribute to the higher pneumonia incidence reported with fluticasone propionate.
背景：慢性阻塞性肺疾病（COPD）患者罹患社区获得性肺炎的风险增加，而吸入性皮质类固醇会进一步增加这种风险。
目的：评估皮质类固醇布地奈德和丙酸氟替卡松对 COPD 患者巨噬细胞细菌反应的影响。
方法：从 10 名非吸烟者对照（NoS）、20 名无 COPD 的吸烟者（Sm）和 40 名中度至重度 COPD 患者（21 名戒烟者（COPD-ES）和 19 名当前吸烟者（COPD-S））的血液单核细胞中生成单核细胞衍生的巨噬细胞（MDM），用布地奈德或丙酸氟替卡松（10 nM-1 μM）预处理，然后用非定型流感嗜血杆菌（NTHI）或肺炎链球菌（SP）进行挑战。通过流式细胞术分析细胞表面细菌识别受体的表达（流式细胞术）和细胞因子释放（珠阵列）。
结果：NTHI 和 SP 降低了 COPD 和 Sm 患者的 MDM 表面细菌识别受体的表达，但非吸烟者（TLR4 除外）没有。NTHI 和 SP 均可降低 SR-AI 和 MARCO，而其他受体则由 NTHI 或 SP 降低。在 COPD 患者中，与 COPD-S 相比，COPD-ES 表现出更多的减少。NTHI 降低了 COPD-ES 中的 SR-AI、MARCO、CD11b、CD35 和 CD206，而 COPD-S 中仅降低了 SR-AI 和 CD11b。SP 降低了 COPD-ES 和 COPD-S 中的 SRA-1、CD1d、TLR2 和 TLR4，仅降低了 COPD-ES 中的 MARCO 和 CD93。NTHI 和 SP 降低的所有受体在 COPD 中均降低，在 Sm 中也降低。布地奈德拮抗了 NTHI 诱导的（CD206 p = 0.03，MARCO p = 0.08）和 SP 诱导的（SR-AI p = 0.02）COPD-ES 中所有受体的减少。氟替卡松仅拮抗了 SP 诱导的 TLR2（p = 0.008 COPD-ES 和 p = 0.04 COPD-S）和 TLR4（p = 0.02 COPD-ES）的减少。两种皮质类固醇均可同等降低细胞因子的释放。
结论：细菌暴露期间巨噬细胞细菌识别受体的减少可能为 COPD 中肺炎风险增加提供了一种机制。布地奈德和丙酸氟替卡松对巨噬细胞细菌识别受体表达的不同影响可能导致氟替卡松丙酸酯报告的肺炎发病率更高。
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