Lysophosphatidylcholine Acyltransferase 1 Deficiency Promotes Pulmonary Emphysema via Apoptosis of Alveolar Epithelial Cells
Lysophosphatidylcholine Acyltransferase 1 Deficiency Promotes Pulmonary Emphysema via Apoptosis of Alveolar Epithelial Cells
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DOI：
10.1007/s10753-022-01659-4
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发表时间：
2022-03
期刊：
影响因子：
5.1
通讯作者：
Takae Tanosaki;Yu Mikami;H. Shindou;Tomoyuki Suzuki;T. Hashidate‐Yoshida;Keisuke Hosoki;Shizuko Kagawa;J. Miyata;H. Kabata;K. Masaki;Ryuji Hamamoto;H. Kage;Naoya Miyashita;Kosuke Makita;H. Matsuzaki;Yusuke Suzuki;A. Mitani;T. Nagase;Takao Shimizu;K. Fukunaga
中科院分区：
文献类型：
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作者：
Takae Tanosaki;Yu Mikami;H. Shindou;Tomoyuki Suzuki;T. Hashidate‐Yoshida;Keisuke Hosoki;Shizuko Kagawa;J. Miyata;H. Kabata;K. Masaki;Ryuji Hamamoto;H. Kage;Naoya Miyashita;Kosuke Makita;H. Matsuzaki;Yusuke Suzuki;A. Mitani;T. Nagase;Takao Shimizu;K. Fukunaga
慢性阻塞性肺疾病（COPD）主要由吸入香烟烟雾引起，是全球第三大死亡原因。肺表面活性物质是磷脂和蛋白质的复合物，通过降低肺泡中的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（LPCAT 1）是一种催化表面活性剂脂质生物合成的酶，在2型肺泡上皮细胞中表达。它的功能障碍被认为与各种肺部疾病有关;然而，LPCAT 1与COPD之间的关系尚不清楚。为了研究LPCAT 1在COPD病理学中的作用，我们使用Lpcat 1敲除（KO）小鼠分析弹性蛋白酶诱导的肺气肿模型。在Lpcat 1 KO小鼠中，弹性蛋白酶诱导的肺气肿随着凋亡细胞的增加而显著加重，补充二棕榈酰磷脂酰胆碱（LPCAT 1合成的表面活性剂的主要成分）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（hAEC 2）的影响，发现香烟烟雾提取物（CSE）下调Lpcat 1的表达。此外，RNA测序分析显示，细胞凋亡途径在CSE处理的原代hAEC 2中显著富集。最后，我们使用小干扰RNA下调Lpcat 1的表达，这导致CSE诱导的A549细胞凋亡增强。总之，香烟烟雾诱导的LPCAT 1下调可通过增加肺泡上皮细胞对凋亡的敏感性来促进肺气肿的恶化，从而表明Lpcat 1是不可逆性肺气肿的新的治疗靶点。
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 usingLpcat1knockout (KO) mice. InLpcat1KO 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 ofLpcat1. Furthermore, RNA sequencing analysis revealed that the apoptosis pathway was significantly enriched in CSE-treated primary hAEC2s. Finally, we downregulated the expression ofLpcat1using 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 thatLpcat1is a novel therapeutic target for irreversible emphysema.