Tanshinone increases Hemopexin expression in lung cells and macrophages to protect against cigarette smoke-induced COPD and enhance antiviral responses

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease, while respiratory infections can elicit exacerbations in COPD patients to mediate increased mortality. Administration of Tanshinones (TS) derivatives has been demonstrated to protect against cigarette smoking (CS) and lipopolysaccharide (LPS)-induced COPD progression. However, the underlying molecular mechanisms and the roles of TS in mitigating the severity of viral-mediated exacerbations of COPD have not been elucidated. Here, we found that TS treatments significantly attenuated lung function decline, inflammatory responses and oxidative stress in CS and LPS-induced COPD mice. Subsequent RNA-seq analysis revealed significantly upregulated Hemopexin expression and enriched interferons (IFNs) signaling pathways in lung tissues of COPD mice upon TS treatments. Moreover, TS administration demonstrated Hemopexin-dependent beneficial roles in BEAS-2B lung cells and RAW264.7 macrophages, which was associated with the suppression of oxidative stress and ERK, NF-κB, and NLRP3 inflammasome signaling pathways-mediated inflammation. Furthermore, TS promoted IFN signaling and rescued impaired antiviral responses in CS and LPS-exposed lung cells that were infected by influenza virus. Notably, hemopexin over-expression in lung cells and macrophages recapitulated the pharmacological activities of TS. Taken together, these results indicate that TS administration is a promising and potential therapeutic strategy for treating COPD and preventing COPD exacerbations.

慢性阻塞性肺疾病（COPD）是一种慢性炎症性疾病，呼吸道感染可诱发慢阻肺患者病情急性加重，进而升高死亡率。已有研究证实，丹参酮类（TS）衍生物可减轻香烟烟雾（CS）与脂多糖（LPS）诱导的慢阻肺疾病进展，但丹参酮类在缓解病毒介导的慢阻肺急性加重中的具体分子机制及其作用尚未阐明。本研究发现，丹参酮类处理可显著减轻香烟烟雾与脂多糖诱导的慢阻肺小鼠的肺功能下降、炎症反应与氧化应激；后续RNA测序（RNA-seq）分析显示，经丹参酮类处理的慢阻肺小鼠肺组织中，血红素结合蛋白（Hemopexin）的表达显著上调，且干扰素（IFNs）信号通路显著富集。此外，在BEAS-2B人支气管上皮细胞与RAW264.7小鼠单核巨噬细胞中，丹参酮类处理展现出依赖血红素结合蛋白的保护作用，该作用与抑制氧化应激及细胞外信号调节激酶（ERK）、核因子κB（NF-κB）、NLRP3炎症小体（NLRP3 inflammasome）信号通路介导的炎症反应密切相关；进一步研究表明，丹参酮类可激活干扰素信号通路，并修复经香烟烟雾与脂多糖处理后感染流感病毒的肺细胞受损的抗病毒应答。值得注意的是，在肺细胞与巨噬细胞中过表达血红素结合蛋白，可重现丹参酮类的药理学活性。综上，本研究结果表明，丹参酮类给药是一种极具潜力的慢阻肺治疗及慢阻肺急性加重预防策略。