Dispersion and utilization of lipid droplets mediates respiratory syncytial virus-induced airway hyperresponsiveness
Dispersion and utilization of lipid droplets mediates respiratory syncytial virus-induced airway hyperresponsiveness
复制标题
脂滴的分散和利用介导呼吸道合胞病毒诱导的气道高反应性
DOI：
10.1111/pai.13651
复制
发表时间：
2021-08-27
影响因子：
4.4
通讯作者：
Tan, Yurong
中科院分区：
文献类型：
--
作者：
Dai, Pei;Tang, Zhongxiang;Tan, Yurong
背景呼吸道病毒感染(RSV)可引起急性哮喘发作，从而破坏肺功能，加速疾病的发展。然而，哮喘稳定期的药物对病毒感染引起的急性发作往往无效。我们旨在通过脂肪酸代谢来阐明病毒感染诱发哮喘的可能机制。方法与结果呼吸道合胞病毒感染动物模型急性期(7d)和慢性期(28d)的气道阻力、炎症损伤和氧化应激均显著高于对照组。此外，使用非靶向代谢组学方法，28d时肺组织中长链脂肪酸的浓度显著增加，包括14：0(肉豆蔻酸)、16：0(棕榈酸)、18：1(油酸)和18：2(亚油酸)。呼吸道上皮细胞经RSV处理后，FSP27、RAB8A和PLIN5表达降低，脂滴(LD)融合生长，LD分散基因Perilipin 2表达增加；PPARγ表达降低，脂肪酸分解基因PPARα表达增加，导致脂质氧化、游离脂肪酸释放，IL-1、IL-2、IL-4和IL-6表达升高，GPR40抑制剂可抑制上述作用。用C18脂肪酸处理的小鼠或上皮细胞显示出抑制上皮细胞增殖、增加炎症和氧化损伤的作用。结论RSV促进了脂质的分散和利用，导致氧化损伤的扩大和促炎细胞因子的升高，从而导致气道高反应性(AHR)的进展。
Background Respiratory viral infections (RSV) can induce acute asthma attacks, thereby destroying lung function and accelerating the progression of the disease. However, medications in the stable phase of asthma are often not effective for acute attacks induced by viral infections. We aimed to clarify the possible mechanism of viral infection-induced asthma through fatty acid metabolism. Methods and Results The airway resistances, inflammatory injuries, and oxidative stress in the RSV-induced animal models were significantly higher than those in the control group at acute phase (7 days) and chronic phase (28 days). Moreover, the concentrations of the medium- and long-chain fatty acids in lung tissue at (28 days) were significantly increased, including 14:0 (myristic acid), 16:0 (palmitic acid, PA), 18:1 (oleic acid, OA), and 18:2 (linoleic acid, LA) using non-targeted metabonomics. Airway epithelial cells treated with RSV showed the reduced expression of FSP27, RAB8A, and PLIN5, which caused the fusion and growth of lipid droplet (LD), and increased expression of the LD dispersion gene perilipin 2. There was also a decrease in PPAR gamma expression and an increase in the fatty acid catabolism gene PPAR alpha, causing lipid oxidation, free fatty acid releases, and an upsurge in IL-1, IL-2, IL-4, and IL-6 expression, which could be abrogated by GPR40 inhibitor. Treated mice or epithelial cells with C18 fatty acid exhibited inhibition of epithelial proliferation, increases of inflammation, and oxidative damage. Conclusions RSV promoted lipid dispersion and utilization, causing enlarged oxidative injuries and an upsurge in the pro-inflammatory cytokines, leading to the progression of airway hyperresponsiveness (AHR).