PDF(Pubmed)
Abstract：
Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.
摘要：
肺泡上皮II型（AEC2）细胞严格调节脂质代谢以维持表面活性剂的合成。AEC2细胞功能的丧失和表面活性剂的产生与吸烟相关的肺疾病慢性阻塞性肺疾病（COPD）的发病机理有关。吸烟是否会改变AEC2细胞的脂质合成，以及改变AEC2细胞的脂质代谢是否有助于COPD的发展尚不清楚。在这项研究中,高通量脂质组学分析显示，从长期暴露于香烟烟雾（CS）的小鼠中分离出的AEC2细胞中脂质生物合成增加。具有从头脂肪生成酶的靶向缺失的小鼠，脂肪酸合成酶（FASN），暴露于CS的AEC2细胞（FasniΔAEC2）表现出更高的支气管肺泡灌洗液（BALF）中性粒细胞，较高的BALF蛋白，和更严重的空域扩大。暴露于CS的FasniΔAEC2小鼠的关键表面活性剂磷脂水平较低，但BALF醚磷脂水平较高，鞘磷脂,和含多不饱和脂肪酸的磷脂，以及增加BALF表面张力。暴露于CS的FasniΔAEC2小鼠在肺中也具有较高水平的保护性铁凋亡标志物。这些数据表明AEC2细胞FASN通过调节表面活性剂磷脂体的组成来调节肺对烟雾的反应。
