IL-17A 促进肺纤维化小鼠模型中 HSV1 感染诱导的急性肺损伤。
IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.
机构信息
Department of Respiratory Medicine, School of Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
Department of Respiratory Medicine, School of Medicine, Shanghai Pulmonary Hospital, Soochow University, Suzhou, China.
出版信息
J Cell Mol Med. 2019 Feb;23(2):908-919. doi: 10.1111/jcmm.13992. Epub 2018 Oct 30.
BACKGROUND
Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold.
AIMS
To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF.
METHODS
Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A ) mice 21 days after intratracheal administration of bleomycin (BLM).
RESULTS
HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response.
CONCLUSIONS
HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.
背景
特发性肺纤维化（IPF）患者在普通感冒后常经历急性加重（AE）。
目的
建立病毒感染诱导的 AE-IPF 小鼠模型，并探讨 AE-IPF 的发病机制。
方法
在气管内给予博来霉素（BLM） 21 天后，通过鼻腔接种单纯疱疹病毒 1（HSV1）感染野生型（WT）和白细胞介素 17A 基因敲除（IL-17A）小鼠。
结果
HSV1 感染导致 BLM 诱导纤维化的小鼠急性加重。与 BLM+生理盐水组小鼠相比，BLM+HSV1 组小鼠的急性肺损伤（ALI）评分显著更高（P<0.0001），存活率更低（100%比 21.4%，P<0.0001），肺功能更差，支气管肺泡灌洗液（BALF）中的炎症反应更强烈，炎症细胞总数增加（P=0.0323），外周血 Th17 细胞比例增加（P=0.0004），BALF 中的炎症因子水平升高。此外，HSV1 感染增加了 BLM 诱导纤维化小鼠内质网应激（ERS）相关蛋白的表达。熊去氧胆酸（TUDCA，一种 ERS 抑制剂）抑制 ERS 可显著降低 BLM+HSV1 小鼠 BALF 中的 IL-17A 水平（P=0.0140）和外周血中的 TH17 细胞数（P=0.0084），表明抑制 ERS 可能减少 AE-IPF 小鼠中的 TH17 反应。与 BLM+HSV1 的 WT 小鼠相比，BLM+HSV1 的 IL-17A 小鼠的 ALI 评分更低（P=0.0119），存活率更高（78.6%比 21.4%，P=0.004），肺功能改善，炎症反应更轻。
结论
除 BLM 诱导的 IPF 外，HSV1 感染还可成功在小鼠中建立 AE-IPF。IL-17A 和 ERS 促进 AE-IPF 发展中的肺炎症。
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