Pan Yilin, Xue Yishu, Fei Xia, Zhao Lei, Han Lei, Su Hang, Lin Yanmei, Zhou Yan, Zhang Yingying, Xie Guogang, Kong Deping, Bao Wuping, Zhang Min
Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
J Inflamm Res. 2025 Mar 25;18:4381-4394. doi: 10.2147/JIR.S501645. eCollection 2025.
Type 2 (T2)-high asthma with neutrophilic inflammation is characterized by airway eosinophilic and neutrophilic infiltration, hyperresponsiveness, remodeling, and insensitivity to steroid treatment. Sphingosine-1-phosphate (S1P), which has a crucial role in the development of asthma, promotes the proliferation and contraction of airway smooth muscle cells (ASMCs), contributing to the pathophysiological processes of asthma. However, the downstream mediator of S1P remains unclear, as does its role in T2-high asthma with neutrophilic inflammation.
Ovalbumin- and ozone-induced murine models were used to replicate T2-high asthma with neutrophilic inflammation and primary ASMCs were applied to explore the underlying effects. Through transcriptomic analysis, PLK1 was identified as a potential key molecule associated with S1P-induced proliferation and contraction. Functional studies were performed both in vitro and in vivo by pharmacological inhibition to validate the role of PLK1 and to evaluate the therapeutic effects of PLK1 inhibition.
S1P level was elevated in the bronchoalveolar lavage fluid (BALF) of T2-high asthma with neutrophilic inflammation model, and promoted ASMCs proliferation and contraction. PLK1 expression increased in S1P-stimulated ASMCs and asthmatic lung tissues. Inhibition of PLK1 blocked S1P-induced ASMCs proliferation and contraction. In vivo, PLK1 inhibition reduced airway inflammation (particularly neutrophilic infiltration), airway remodeling (airway smooth muscle proliferation and collagen deposition), and airway hyperresponsiveness and resistance, improving lung function (of both large and small airways), with superior therapeutic effects to those of dexamethasone. In addition, PLK1 inhibition markedly reduced the BALF levels of IL-17A, IL-21 and IL-6, suggesting that PLK1 might exert its effects mainly through the regulation of Th17 pathway.
PLK1 mediates S1P-induced ASMC proliferation and contraction, and plays an important part in T2-high asthma with neutrophilic inflammation model, making it a potential therapeutic target for treating T2-high asthma with neutrophilic inflammation.
伴有嗜中性粒细胞炎症的2型（T2）高哮喘的特征是气道嗜酸性粒细胞和嗜中性粒细胞浸润、高反应性、重塑以及对类固醇治疗不敏感。鞘氨醇-1-磷酸（S1P）在哮喘发展中起关键作用，可促进气道平滑肌细胞（ASMC）的增殖和收缩，参与哮喘的病理生理过程。然而，S1P的下游介质尚不清楚，其在伴有嗜中性粒细胞炎症的T2高哮喘中的作用也不明确。
采用卵清蛋白和臭氧诱导的小鼠模型复制伴有嗜中性粒细胞炎症的T2高哮喘，并应用原代ASMC来探究潜在影响。通过转录组分析，确定PLK1是与S1P诱导的增殖和收缩相关的潜在关键分子。通过药理学抑制在体外和体内进行功能研究，以验证PLK1的作用并评估PLK1抑制的治疗效果。
在伴有嗜中性粒细胞炎症模型的T2高哮喘的支气管肺泡灌洗液（BALF）中，S1P水平升高，并促进ASMC增殖和收缩。在S1P刺激的ASMC和哮喘肺组织中，PLK1表达增加。抑制PLK1可阻断S1P诱导的ASMC增殖和收缩。在体内，抑制PLK1可减轻气道炎症（尤其是嗜中性粒细胞浸润）、气道重塑（气道平滑肌增殖和胶原沉积）以及气道高反应性和阻力，改善肺功能（包括大气道和小气道），其治疗效果优于地塞米松。此外，抑制PLK1可显著降低BALF中IL-17A、IL-21和IL-6的水平，表明PLK1可能主要通过调节Th17途径发挥作用。
PLK1介导S1P诱导的ASMC增殖和收缩，并在伴有嗜中性粒细胞炎症的T2高哮喘模型中起重要作用，使其成为治疗伴有嗜中性粒细胞炎症的T2高哮喘的潜在治疗靶点。
