A Pneumocyte-Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis
A Pneumocyte-Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis
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DOI：
10.1165/rcmb.2014-0343oc
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发表时间：
2015-07-01
影响因子：
6.4
通讯作者：
Summer, Ross
中科院分区：
文献类型：
--
作者：
Romero, Freddy;Shah, Dilip;Summer, Ross
在纤维化肺病患者的肺中观察到载脂巨噬细胞或“泡沫细胞”，但其对疾病发病机制的贡献仍未探索。在这里，我们证明了博莱霉素，硅尘，或胸部放射诱导的纤维化促进早期和持续的泡沫细胞在肺中的积累。在博莱霉素模型中，我们发现泡沫细胞来自相邻的肺泡上皮II型细胞，其通过将脂质倾倒到肺的远端气隙中来响应损伤。我们证明了氧化磷脂在博莱霉素损伤后肺泡巨噬细胞（AM）内积累，并且用氧化磷脂酰胆碱（oxPc）处理的小鼠和人AM沿着M2表型极化，并显示转化生长因子-β 1的产生增强。将oxPc直接滴注到小鼠肺中诱导泡沫细胞形成并引发严重的纤维化反应。此外，我们发现，通过靶向删除脂质外排转运蛋白ATP结合盒亚家族G成员1来减少肺脂质清除，增加了博来霉素治疗后的泡沫细胞形成和肺纤维化。相反，我们发现，治疗与粒细胞-巨噬细胞集落刺激因子减弱纤维化反应，至少部分通过其能力，以减少AM脂质积累。总之，这项工作描述了一种导致小鼠肺中泡沫细胞形成的新机制，并表明旨在阻断泡沫细胞形成的策略可能对治疗纤维化肺疾病有效。
Lipid-laden macrophages, or "foam cells," are observed in the lungs of patients with fibrotic lung disease, but their contribution to disease pathogenesis remains unexplored. Here, we demonstrate that fibrosis induced by bleomycin, silica dust, or thoracic radiation promotes early and sustained accumulation of foam cells in the lung. In the bleomycin model, we show that foam cells arise from neighboring alveolar epithelial type II cells, which respond to injury by dumping lipids into the distal airspaces of the lungs. We demonstrate that oxidized phospholipids accumulate within alveolar macrophages (AMs) after bleomycin injury and that murine and human AMs treated with oxidized phosphatidylcholine (oxPc) become polarized along an M2 phenotype and display enhanced production of transforming growth factor-beta 1. The direct instillation of oxPc into the mouse lung induces foam cell formation and triggers a severe fibrotic reaction. Further, we show that reducing pulmonary lipid clearance by targeted deletion of the lipid efflux transporter ATP-binding cassette subfamily G member 1 increases foam cell formation and worsens lung fibrosis after bleomycin. Conversely, we found that treatment with granulocyte-macrophage colony-stimulating factor attenuates fibrotic responses, at least in part through its ability to decrease AM lipid accumulation. In summary, this work describes a novel mechanism leading to foam cell formation in the mouse lung and suggests that strategies aimed at blocking foam cell formation might be effective for treating fibrotic lung disorders.