Interleukin-6 neutralizing antibody attenuates the hypersecretion of airway mucus via inducing the nuclear translocation of Nrf2 in chronic obstructive pulmonary disease.
Interleukin-6 neutralizing antibody attenuates the hypersecretion of airway mucus via inducing the nuclear translocation of Nrf2 in chronic obstructive pulmonary disease.
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DOI：
10.1016/j.biopha.2022.113244
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
Yuan-Yuan Wei-Yuan;Dawei Zhang;Jing-jing Ye;Qingyu Lan;S. Ji;Li Sun;Fang Li;G. Fei
中科院分区：
文献类型：
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作者：
Yuan-Yuan Wei-Yuan;Dawei Zhang;Jing-jing Ye;Qingyu Lan;S. Ji;Li Sun;Fang Li;G. Fei
气道粘液高分泌是慢性阻塞性肺疾病（COPD）患者的重要病理生理特征，是COPD治疗策略的关键。为探讨白细胞介素6中和抗体（IL-6 Ab）减轻COPD气道粘液高分泌的作用机制，从COPD患者和小鼠分离人和小鼠原代支气管上皮细胞，建立人气管类器官模型，并用IL-6和/或IL-6 Ab治疗。通过转录组的高通量测序，确定Muc 5ac和Nrf 2在pDHBE中与pNHBE细胞相比的差异表达。COPD患者血清中Muc 5ac浓度显著升高，与IL-6呈正相关; HE、AB-PAS和IHC染色显示COPD患者气管内粘液分泌过多。在体外和使用qRT-PCR、WB和IF的类器官模型中，Muc 5ac的水平在IL-6处理组中显著升高，并且随着IL-6 Ab处理而降低。转染IL-6小干扰RNA（siRNA-IL-6）的细胞中Muc 5ac蛋白的表达水平显著降低，而转染Nrf 2短发夹RNA（shRNA-Nrf 2）的细胞中Muc 5ac蛋白的表达水平显著降低，IL-6 Ab的保护作用也受到抑制。IL-6 Ab可通过诱导Nrf 2核转位减轻COPD气道黏液高分泌。这些结果表明，IL-6 Ab可能通过改善COPD患者的气流限制而成为治疗IL-6诱导的气道粘液高分泌的新药物。
Airway mucus hypersecretion is a vital pathophysiologic feature in chronic obstructive pulmonary disease (COPD) patients in which airflow limitation result, and it is key to strategizing in the management of COPD. To investigate the mechanisms underlying the action of interleukin-6 neutralizing antibody (IL-6 Ab) in attenuating airway mucus hypersecretion in COPD, human and mouse primary bronchial epithelial cells from COPD patients and mice were isolated, human organoid model of trachea was established and all treated with IL-6 and/or IL-6 Ab. The differential expression of Muc5ac and Nrf2 were determined in pDHBE compared to pNHBE cells via high-throughput sequencing of transcriptome. The serum concentration of Muc5ac was significantly elevated and positively correlated with IL-6 in COPD patients using ELISA, and the excessive mucus secretion was observed in the trachea of COPD patients using HE, AB-PAS and IHC staining. The levels of Muc5ac were significantly elevated in the IL-6-treated group, and diminished with IL-6 Ab treatment, both in vitro and in the organoid model using qRT-PCR, WB and IF. The expression levels of protein Muc5ac were significantly reduced in cells transfected with the IL-6 small interfering RNA (siRNA-IL-6), which was in contrast to the levels of protein Nrf2, and the protective effects of IL-6 Ab were inhibited in cells transfected with Nrf2 short hairpin RNA (shRNA-Nrf2). IL-6 Ab significantly attenuated hypersecretion of airway mucus by inducing nuclear translocation of Nrf2 in COPD. These findings indicated that IL-6 Ab may constitute a novel therapeutic agent for IL-6-induced airway mucus hypersecretion by improving airflow limitation in COPD patients.