German Center for Lung Research, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
Center for Interstitial and Rare Lung Diseases, Department of Pneumology, Ruhrlandklinik University Hospital, Essen, Germany.
Am J Respir Crit Care Med. 2019 Oct 1;200(7):881-887. doi: 10.1164/rccm.201901-0086OC.
Pulmonary alveolar proteinosis (PAP) is characterized by filling of the alveolar spaces by lipoprotein-rich material of ill-defined composition, and is caused by molecularly different and often rare diseases that occur from birth to old age. To perform a quantitative lipidomic analysis of lipids and the surfactant proteins A, B, and C in lavage fluids from patients with proteinosis of different causes in comparison with healthy control subjects. During the last two decades, we have collected BAL samples from patients with PAP due to autoantibodies against granulocyte-macrophage colony-stimulating factor; genetic mutations in CSF2RA (colony-stimulating factor 2 receptor α-subunit), MARS (methionyl aminoacyl-tRNA synthetase), FARSB (phenylalanine-tRNA synthetase, β-subunit), and NPC2 (Niemann-Pick disease type C2); and secondary to myeloid leukemia. Their lipid composition was quantified. Free cholesterol was largely increased by 60-fold and cholesteryl esters were increased by 24-fold. There was an excessive, more than 130-fold increase in ceramide and other sphingolipids. In particular, the long-chain ceramides d18:1/20:0 and d18:1/24:0 were elevated and likely contributed to the proapoptotic environment observed in PAP. Cellular debris lipids such as phosphatidylethanolamine and phosphatidylserine were only moderately increased, by four- to sevenfold. The surfactant lipid class phosphatidylcholine expanded 17-fold, lysophosphatidylcholine expanded 54-fold, and the surfactant proteins A, B, and C expanded 144-, 4-, and 17-fold, respectively. These changes did not differ among the various diseases that cause PAP. This insight into the alveolar lipidome may provide monitoring tools and lead to new therapeutic strategies for PAP.
肺泡蛋白沉积症（PAP）的特征是肺泡腔充满了组成成分不明的富含脂蛋白的物质，由从出生到老年发生的分子上不同且通常罕见的疾病引起。对不同病因导致的蛋白沉积症患者的支气管肺泡灌洗液中的脂质和表面活性剂蛋白 A、B、C 进行定量脂质组学分析，并与健康对照者进行比较。在过去的二十年中，我们收集了由于抗粒细胞-巨噬细胞集落刺激因子自身抗体、CSF2RA（集落刺激因子 2 受体α亚基）、MARS（甲硫氨酸氨酰-tRNA 合成酶）、FARSB（苯丙氨酸-tRNA 合成酶，β亚基）和 NPC2（尼曼-匹克病 C2 型）基因突变，以及继发于骨髓性白血病导致的 PAP 患者的 BAL 样本。对其脂质组成进行了定量分析。游离胆固醇增加了 60 倍，胆固醇酯增加了 24 倍。神经酰胺和其他鞘脂类物质过度增加了 130 倍以上。特别是长链神经酰胺 d18:1/20:0 和 d18:1/24:0 升高，可能导致 PAP 中观察到的促凋亡环境。细胞碎片脂质如磷酸乙醇胺和磷脂酰丝氨酸仅适度增加了 4 到 7 倍。表面活性剂脂质类别磷脂酰胆碱增加了 17 倍，溶血磷脂酰胆碱增加了 54 倍，表面活性剂蛋白 A、B、C 分别增加了 144、4 和 17 倍。这些变化在导致 PAP 的各种疾病中没有差异。对肺泡脂质组学的这种了解可能为 PAP 提供监测工具并导致新的治疗策略。
