Peroxisome proliferator-activated receptor-γ is deficient in alveolar macrophages from patients with alveolar proteinosis
Peroxisome proliferator-activated receptor-γ is deficient in alveolar macrophages from patients with alveolar proteinosis
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DOI：
10.1165/rcmb.2003-0148oc
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发表时间：
2003-12-01
影响因子：
6.4
通讯作者：
Thomassen, MJ
中科院分区：
文献类型：
--
作者：
Bonfield, TL;Farver, CF;Thomassen, MJ
过氧化物酶体增殖物激活受体-γ(PPAR-Gamma)是一种配体激活的核转录因子，调节与脂肪和葡萄糖代谢、炎症等途径有关的基因。粒细胞巨噬细胞集落刺激因子(GM-CSF)是一种造血生长因子，对肺内环境的稳定至关重要，被认为可以调节肺表面活性物质的清除，但其作用机制尚不清楚。据报道，GMCSF可以刺激PPAR-γ，但PPAR-γ在人肺泡巨噬细胞中的激活状态尚未确定。肺泡蛋白沉积症(PAP)是一种罕见的间质性肺疾病，肺泡内表面活性物质积聚，滞留巨噬细胞充盈脂蛋白物质，GM-CSF缺乏与发病密切相关。在这里，我们发现PPAR-Gamma的mRNA和蛋白在健康对照组的肺泡巨噬细胞中高度表达，但在PAP中以细胞特异性的方式严重缺乏。此外，我们发现PPAR-伽马调节的脂质清道夫受体CD36在PAP中也是缺乏的。PPAR-γ和CD36缺乏并非PAP肺泡巨噬细胞所特有，但可被GM-CSF治疗上调。此外，对PAP患者进行GM-CSF治疗后，PPAR-Gamma完全恢复到健康对照水平。基于这些新的发现，我们假设GM-CSF通过PPAR-γ依赖的途径调节肺内稳态。
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated, nuclear transcription factor that regulates genes involved in lipid and glucose metabolism, inflammation, and other pathways. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is essential for lung homeostasis and is thought to regulate surfactant clearance, but mechanisms involved are unknown. GMCSF is reported to stimulate PPAR-gamma, but the activation status of PPAR-gamma in human alveolar macrophages has not been defined. In pulmonary alveolar proteinosis (PAP), a rare interstitial lung disease, surfactant accumulates in alveolar airspaces, resident macrophages become engorged with lipoproteinaceous material, and GM-CSF deficiency is strongly implicated in pathogenesis. Here we show that PPAR-gamma mRNA and protein are highly expressed in alveolar macrophages of healthy control subjects but severely deficient in PAP in a cell-specific manner. Further, we show that the PPAR-gamma-regulated lipid scavenger receptor, CD36, is also deficient in PAP. PPAR-gamma and CD36 deficiency are not intrinsic to PAP alveolar macrophages, but can be upregulated by GM-CSF therapy. Moreover, GM-CSF treatment of patients with PAP fully restores PPAR-gamma to healthy control levels. Based upon these novel findings, we hypothesize that GM-CSF regulates lung homeostasis via PPAR-gamma-dependent pathways.