Tanosaki Takae, Mikami Yu, Shindou Hideo, Suzuki Tomoyuki, Hashidate-Yoshida Tomomi, Hosoki Keisuke, Kagawa Shizuko, Miyata Jun, Kabata Hiroki, Masaki Katsunori, Hamamoto Ryuji, Kage Hidenori, Miyashita Naoya, Makita Kosuke, Matsuzaki Hirotaka, Suzuki Yusuke, Mitani Akihisa, Nagase Takahide, Shimizu Takao, Fukunaga Koichi
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Inflammation. 2022 Aug;45(4):1765-1779. doi: 10.1007/s10753-022-01659-4. Epub 2022 Mar 26.
Chronic obstructive pulmonary disease (COPD) is primarily caused by inhalation of cigarette smoke and is the third leading cause of death worldwide. Pulmonary surfactant, a complex of phospholipids and proteins, plays an essential role in respiration by reducing the surface tension in the alveoli. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is an enzyme that catalyzes the biosynthesis of surfactant lipids and is expressed in type 2 alveolar epithelial cells. Its dysfunction is suggested to be involved in various lung diseases; however, the relationship between LPCAT1 and COPD remains unclear. To investigate the role of LPCAT1 in the pathology of COPD, we analyzed an elastase-induced emphysema model using Lpcat1 knockout (KO) mice. In Lpcat1 KO mice, elastase-induced emphysema was significantly exacerbated with increased apoptotic cells, which was not ameliorated by supplementation with dipalmitoylphosphatidylcholine, which is a major component of the surfactant synthesized by LPCAT1. We subsequently evaluated the effects of cigarette smoking on primary human type 2 alveolar epithelial cells (hAEC2s) and found that cigarette smoke extract (CSE) downregulated the expression of Lpcat1. Furthermore, RNA sequencing analysis revealed that the apoptosis pathway was significantly enriched in CSE-treated primary hAEC2s. Finally, we downregulated the expression of Lpcat1 using small interfering RNA, which resulted in enhanced CSE-induced apoptosis in A549 cells. Taken together, cigarette smoke-induced downregulation of LPCAT1 can promote the exacerbation of pulmonary emphysema by increasing the susceptibility of alveolar epithelial cells to apoptosis, thereby suggesting that Lpcat1 is a novel therapeutic target for irreversible emphysema.
慢性阻塞性肺疾病（COPD）主要由吸入香烟烟雾引起，是全球第三大死因。肺表面活性物质是一种磷脂和蛋白质的复合物，通过降低肺泡表面张力在呼吸中起重要作用。溶血磷脂酰胆碱酰基转移酶1（LPCAT1）是一种催化表面活性物质脂质生物合成的酶，在2型肺泡上皮细胞中表达。其功能障碍被认为与多种肺部疾病有关；然而，LPCAT1与COPD之间的关系仍不清楚。为了研究LPCAT1在COPD病理中的作用，我们使用Lpcat1基因敲除（KO）小鼠分析了弹性蛋白酶诱导的肺气肿模型。在Lpcat1 KO小鼠中，弹性蛋白酶诱导的肺气肿明显加重，凋亡细胞增加，补充二棕榈酰磷脂酰胆碱（LPCAT1合成的表面活性物质的主要成分）并不能改善这种情况。我们随后评估了吸烟对原代人2型肺泡上皮细胞（hAEC2s）的影响，发现香烟烟雾提取物（CSE）下调了Lpcat1的表达。此外，RNA测序分析显示，凋亡途径在CSE处理的原代hAEC2s中显著富集。最后，我们使用小干扰RNA下调Lpcat1的表达，这导致A549细胞中CSE诱导的凋亡增强。综上所述，香烟烟雾诱导的LPCAT1下调可通过增加肺泡上皮细胞对凋亡的易感性促进肺气肿的加重，从而表明Lpcat1是不可逆肺气肿的一个新的治疗靶点。
