Liu Meixuan, Lu Jingjing, Zhang Qian, Zhang Yunxuan, Guo Zhongliang
Shanghai East Clinical Medical College, Nanjing Medical University, Shanghai, 200123, China.
Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
Mol Med. 2021 Feb 4;27(1):11. doi: 10.1186/s10020-021-00277-4.
House dust mite (HDM) inhalation can cause airway epithelial damage which is implicated in the process of airway inflammation in asthma. High mobility group box 1 (HMGB1) is critically required for cellular damage and apoptosis as an important endogenous danger signal. Recently, Clara cell 16KDa protein (CC16) has been identified to exert anti-inflammatory and immunomodulatory influence in various injury-related diseases model. However, little is known about its ability to protect against airway epithelial injury in allergic asthma. This study was aimed to clarify the protective roles of CC16 on airway epithelia in HDM-induced asthma and the regulation of HMGB1 by CC16.
Mice were sensitized and challenged by HDM extract and administrated intranasally with CC16 (5 μg/g or 10 μg/g) or saline in the challenged period. The BEAS-2B human airway epithelial cell line were cultured with CC16 or the control vehicle and then exposed to HDM. Knockdown or overexpression of HMGB1 was induced by cell transfection or intratracheal injection of recombinant adenovirus.
CC16 treatment decreased airway inflammation and histological damage of airway epithelium dose-dependently in HDM-induced asthma model. Airway epithelia apoptosis upon HDM stimulation was noticeably abrogated by CC16 in vivo and in vitro. In addition, upregulation of HMGB1 expression and its related signaling were also detected under HDM conditions, while silencing HMGB1 significantly inhibited the apoptosis of BEAS-2B cells. Furthermore, the activity of HMGB1-mediated signaling was restrained after CC16 treatment whereas HMGB1 overexpression abolished the protective effect of CC16 on HDM-induced airway epithelia apoptosis.
Our data confirm that CC16 attenuates HDM-mediated airway inflammation and damage via suppressing airway epithelial cell apoptosis in a HMGB1-dependent manner, suggesting the role of CC16 as a potential protective option for HDM-induced asthma.
吸入屋尘螨（HDM）可导致气道上皮损伤，这与哮喘气道炎症的发生过程有关。高迁移率族蛋白B1（HMGB1）作为一种重要的内源性危险信号，在细胞损伤和凋亡过程中至关重要。最近，已证实 Clara 细胞 16KDa 蛋白（CC16）在各种损伤相关疾病模型中发挥抗炎和免疫调节作用。然而，关于其在过敏性哮喘中预防气道上皮损伤的能力知之甚少。本研究旨在阐明 CC16 在 HDM 诱导的哮喘中对气道上皮的保护作用以及 CC16 对 HMGB1 的调节作用。
用 HDM 提取物对小鼠进行致敏和激发，并在激发期经鼻给予 CC16（5μg/g 或 10μg/g）或生理盐水。将 BEAS-2B 人气道上皮细胞系用 CC16 或对照载体培养，然后暴露于 HDM。通过细胞转染或气管内注射重组腺病毒诱导 HMGB1 的敲低或过表达。
在 HDM 诱导的哮喘模型中，CC16 治疗剂量依赖性地减轻了气道炎症和气道上皮的组织学损伤。CC16 在体内和体外均显著消除了 HDM 刺激后气道上皮细胞的凋亡。此外，在 HDM 条件下还检测到 HMGB1 表达及其相关信号的上调，而沉默 HMGB1 显著抑制了 BEAS-2B 细胞的凋亡。此外，CC16 治疗后 HMGB1 介导的信号活性受到抑制，而 HMGB1 过表达消除了 CC16 对 HDM 诱导的气道上皮细胞凋亡的保护作用。
我们的数据证实，CC16 通过以 HMGB1 依赖的方式抑制气道上皮细胞凋亡来减轻 HDM 介导的气道炎症和损伤，提示 CC16 作为 HDM 诱导哮喘的潜在保护选择的作用。
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