Guo Yu, Gao Zhenqiang, Zhang Ruoyang, Long Huanyu, Zhang Muzhi, Liu Lin, An Zhe, Shi Yuezhe, Cui Ye, Jia Yufeng, Wang Lei, Sun Ying, Liu Jie, Wang Wei
Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Department of Respiratory Medicine, Capital Medical University, Beijing, 100069, China.
Adv Sci (Weinh). 2025 Aug;12(31):e04397. doi: 10.1002/advs.202504397. Epub 2025 Jun 10.
Pulmonary hypertension (PH) is a severe disease characterized by pulmonary vascular remodeling in which various immune cells play a critical role in vascular remodeling, although the details are still vague. Furthermore, current clinical treatments primarily focus on pulmonary vasodilation, but do not fundamentally address vascular remodeling itself. Here, first significant changes in neutrophils during the development of PH are demonstrated and show that neutrophil depletion can effectively attenuate disease progression. Moreover, the data show that neutrophil-derived S100A9 is the key mediator to promote vascular remodeling, while both knockout and inhibition of S100A9 can prevent PH. In a co-culture system of neutrophils and endothelial cells (ECs), hypoxic stimulation leads to increased S100A9 secretion by neutrophils, which activates the RAGE/PI3K/AKT pathway and causes dysfunction of ECs. These findings suggest that neutrophil-derived S100A9 mediated neutrophil-EC crosstalk plays an important role in pulmonary vascular remodeling, providing a promising strategy for treatment of PH.
肺动脉高压（PH）是一种严重疾病，其特征为肺血管重塑，尽管具体细节仍不明确，但多种免疫细胞在血管重塑中发挥关键作用。此外，目前的临床治疗主要集中在肺血管舒张上，并未从根本上解决血管重塑本身的问题。在此，首次证明了PH发展过程中中性粒细胞的显著变化，并表明中性粒细胞减少可有效减缓疾病进展。此外，数据显示中性粒细胞衍生的S100A9是促进血管重塑的关键介质，而敲除和抑制S100A9均可预防PH。在中性粒细胞与内皮细胞（ECs）的共培养系统中，缺氧刺激导致中性粒细胞分泌的S100A9增加，激活RAGE/PI3K/AKT通路并导致ECs功能障碍。这些发现表明，中性粒细胞衍生的S100A9介导的中性粒细胞与ECs的相互作用在肺血管重塑中起重要作用，为PH的治疗提供了一种有前景的策略。
