Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis.
Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis.
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DOI：
10.1038/s41467-018-05491-z
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发表时间：
2018-08-07
影响因子：
16.6
通讯作者：
Trapnell BC
中科院分区：
文献类型：
--
作者：
McCarthy C;Lee E;Bridges JP;Sallese A;Suzuki T;Woods JC;Bartholmai BJ;Wang T;Chalk C;Carey BC;Arumugam P;Shima K;Tarling EJ;Trapnell BC
肺泡蛋白沉积症（PAP）是一种由巨噬细胞介导的GM-CSF依赖性表面活性物质清除减少、肺泡巨噬细胞功能障碍、肺泡表面活性物质积聚和低氧性呼吸衰竭引起的综合征，其发病机制尚不清楚。在这里，我们研究了脂质积聚在肺泡巨噬细胞和表面活性剂，以确定PAP的发病机制，并评估一种新的药理学方法。在PAP患者中，肺泡巨噬细胞胆固醇显著增加，但磷脂仅轻微增加，肺表面活性物质胆固醇与磷脂的比例增加。口服他汀类药物治疗与自身免疫性PAP患者的临床、生理和放射学改善相关，体外他汀类药物治疗可降低肺泡巨噬细胞中的胆固醇水平。在Csf 2 rb −/−小鼠中，他汀类药物治疗可减少肺泡巨噬细胞中的胆固醇蓄积并改善PAP，离体他汀类药物治疗可增加巨噬细胞的胆固醇流出。这些结果支持了他汀类药物作为一种新的基于PAP发病机制的药物治疗的可行性。肺泡蛋白沉积症（PAP）与巨噬细胞表面活性物质清除缺陷有关。在这里，作者表明，PAP患者的表面活性剂中胆固醇与磷脂的比例发生了改变，更重要的是，他汀类药物治疗和减少巨噬细胞中的胆固醇积累可以改善人类和小鼠的PAP。
Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb−/− mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP. Pulmonary alveolar proteinosis (PAP) is associated with defective macrophage clearance of surfactant. Here, the authors show that patients with PAP have altered cholesterol-to-phospholipid ratio in their surfactant, and that more importantly, statin therapy and reduction of cholesterol accumulation in macrophages can ameliorate PAP in both humans and mice.
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影响因子：
4.6
作者：
Sallese A;Suzuki T;McCarthy C;Bridges J;Filuta A;Arumugam P;Shima K;Ma Y;Wessendarp M;Black D;Chalk C;Carey B;Trapnell BC
通讯作者：
Trapnell BC
DOI：
10.1084/jem.20080759
发表时间：
2008-11-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Martinez-Moczygemba M;Doan ML;Elidemir O;Fan LL;Cheung SW;Lei JT;Moore JP;Tavana G;Lewis LR;Zhu Y;Muzny DM;Gibbs RA;Huston DP
通讯作者：
Huston DP
影响因子：
32.4
作者：
Shibata, Y;Berclaz, PY;Trapnell, BC
通讯作者：
Trapnell, BC
影响因子：
6.5
作者：
Baker, Anna D.;Malur, Anagha;Thomassen, Mary Jane
通讯作者：
Thomassen, Mary Jane
影响因子：
9.6
作者：
Miyata, Ryohei;Bai, Ni;Van Eeden, Stephan F.
通讯作者：
Van Eeden, Stephan F.