Bonfield Tracey L, Farver Carol F, Barna Barbara P, Malur Anagha, Abraham Susamma, Raychaudhuri Baisakhi, Kavuru Mani S, Thomassen Mary Jane
Department of Pulmonary and Critical Care Medicine, 9500 Euclid Avenue, Cleveland Clinic Foundation, Desk A90, Cleveland, OH 44195-5038.
Am J Respir Cell Mol Biol. 2003 Dec;29(6):677-82. doi: 10.1165/rcmb.2003-0148OC. Epub 2003 Jun 12.
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. GM-CSF 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.
过氧化物酶体增殖物激活受体γ（PPAR-γ）是一种配体激活的核转录因子，可调节参与脂质和葡萄糖代谢、炎症及其他信号通路的基因。造血生长因子粒细胞巨噬细胞集落刺激因子（GM-CSF）对肺内环境稳定至关重要，被认为可调节表面活性物质清除，但具体机制尚不清楚。据报道，GM-CSF可刺激PPAR-γ，但人肺泡巨噬细胞中PPAR-γ的激活状态尚未明确。在罕见的间质性肺疾病肺泡蛋白沉积症（PAP）中，表面活性物质在肺泡腔中积聚，驻留巨噬细胞充满脂蛋白样物质，GM-CSF缺乏与发病机制密切相关。在此我们发现，PPAR-γ mRNA和蛋白在健康对照者的肺泡巨噬细胞中高表达，但在PAP患者中以细胞特异性方式严重缺乏。此外，我们还发现PPAR-γ调节的脂质清道夫受体CD36在PAP中也缺乏。PPAR-γ和CD36缺乏并非PAP肺泡巨噬细胞所固有，但可通过GM-CSF治疗上调。而且，GM-CSF治疗PAP患者可使PPAR-γ完全恢复至健康对照水平。基于这些新发现，我们推测GM-CSF通过PPAR-γ依赖途径调节肺内环境稳定。
