Elevated counts of alveolar macrophages and attenuated phagocytic capacity are associated with chronic obstructive pulmonary disease (COPD). Factors governing macrophage phagocytosis are poorly understood. In this study we aimed to compare the influence of airway epithelial cell secretions from individuals with COPD and without COPD (non-COPD) on macrophage phagocytic activity, and the role of antimicrobial peptides (AMPs).

Supernatants from non-COPD and COPD small airway epithelial cell (SAEC) cultures exposed to non-typeable Haemophilus influenzae (NTHi) were applied to human monocyte-derived macrophages (MDMs) to assess their influence on phagocytosis. SAECs were analysed for changes in AMP expression by quantitative reverse transcription PCR, and the influence of select AMPs on macrophage phenotype and function was assessed by flow cytometry and metabolic activity assay.

Secretions from the apical and basolateral surface of NTHi-exposed SAECs from non-COPD donors elicited superior phagocytic capacity in MDMs. Moreover, NTHi exposure led to a rapid increase in the expression of a range of AMPs by non-COPD SAECs, but this response was delayed in COPD SAECs. We demonstrate that treatment with AMPs β-defensin 2 and S100 calcium binding protein A8/S100 calcium binding protein A9 (S100A8/A9) improved the phagocytic capacity of MDMs. In-depth analysis of the influence of S100A8/A9 on MDMs revealed a role for this AMP in macrophage phenotype and function. Furthermore, we show that the expression of S100A8 and S100A9 is directly regulated by WNT/β-catenin signalling, a known deregulated pathway in COPD.

In conclusion, for the first time, we demonstrate that airway epithelium from patients with COPD has a reduced capacity to support the phagocytic function of macrophages in response to acute NTHi exposure, and we identify the WNT/β-catenin signalling-modulated and epithelium-derived S100A8/A9 as a potent regulator of macrophage phenotype and function.

肺泡巨噬细胞计数升高和吞噬能力减弱与慢性阻塞性肺病 (COPD) 相关。控制巨噬细胞吞噬作用的因素知之甚少。在这项研究中，我们旨在比较患有 COPD 和没有 COPD（非 COPD）的个体的气道上皮细胞分泌物对巨噬细胞吞噬活性的影响，以及抗菌肽 (AMP) 的作用。

将暴露于不可分型流感嗜血杆菌(NTHi) 的非 COPD 和 COPD 小气道上皮细胞 (SAEC) 培养物的上清液应用于人单核细胞衍生的巨噬细胞 (MDM)，以评估它们对吞噬作用的影响。通过定量逆转录 PCR 分析 SAECs 中 AMP 表达的变化，并通过流式细胞术和代谢活性测定评估选定 AMP 对巨噬细胞表型和功能的影响。

来自非 COPD 供体的 NTHi 暴露的 SAEC 的顶端和基底外侧表面的分泌物在 MDM 中引起了优异的吞噬能力。此外，NTHi 暴露导致非 COPD SAECs 一系列 AMP 表达的快速增加，但这种反应在 COPD SAECs 中被延迟。我们证明用 AMPs β-防御素 2 和 S100 钙结合蛋白 A8/S100 钙结合蛋白 A9 (S100A8/A9) 治疗可提高 MDM 的吞噬能力。深入分析 S100A8/A9 对 MDM 的影响揭示了这种 AMP 在巨噬细胞表型和功能中的作用。此外，我们表明 S100A8 和 S100A9 的表达直接受 WNT/β-连环蛋白信号传导调控，这是 COPD 中已知的失调途径。

总之，我们首次证明来自 COPD 患者的气道上皮细胞支持巨噬细胞吞噬功能的能力降低以应对急性 NTHi 暴露，并且我们确定了 WNT/β-catenin 信号调节和上皮细胞-衍生的 S100A8/A9 作为巨噬细胞表型和功能的有效调节剂。