A Pneumocyte–Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis

炎症 肺泡巨噬细胞 生物 医学 特发性肺纤维化 支气管肺泡灌洗 细胞生物学
作者
Freddy Romero,Dilip Shah,Michelle Duong,Raymond B. Penn,Michael B. Fessler,Jennifer H. Madenspacher,William Stafstrom,Mani S. Kavuru,Bo Lu,Caleb B. Kallen,Kenneth Walsh,Ross Summer
出处
期刊:American Journal of Respiratory Cell and Molecular Biology [American Thoracic Society]
卷期号:53 (1): 74-86 被引量:72
标识
DOI:10.1165/rcmb.2014-0343oc
摘要

Lipid-laden macrophages, or 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-β1. 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.
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