Journal Article

Neutrophil–Endothelium Interaction Mediated by S100A9 Promotes Pulmonary Vascular Remodeling During Pulmonary Hypertension

Sun, Ying, Zhang, Muzhi, Guo, Yu, Wang, Wei, Gao, Zhenqiang, Jia, Yufeng, Liu, Lin, An, Zhe, Liu, Jie, Long, Huanyu, Cui, Ye, Wang, Lei, Zhang, Ruoyang, Shi, Yuezhe

2025

Overview

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. This study investigates the critical mechanisms underlying pulmonary hypertension progression, with a focus on the novel role of neutrophil‐derived S100A9 in endothelial dysfunction‐mediated pulmonary vascular remodeling. By integrating human lung samples, multi‐omics analyses, animal models, and mechanistic in vitro studies, it is revealed that how neutrophil–endothelial interactions mediated through the S100A9‐RAGE‐PI3K‐AKT signaling pathway contribute to endothelial dysfunction and vascular remodeling in PH.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / Calgranulin B - genetics / Calgranulin B - metabolism / Chronic obstructive pulmonary disease / Coculture Techniques / Endothelial Cells - metabolism / endothelial dysfunction / Endothelium / Endothelium, Vascular - metabolism / Humans / Hypertension, Pulmonary - metabolism / Hypertension, Pulmonary - pathology / Hypertension, Pulmonary - physiopathology / Inflammation / Lung / Lungs / Male / Mice / Mice, Inbred C57BL / Neutrophils / Neutrophils - metabolism / Pathogenesis / Proteins / Pulmonary arteries / Pulmonary hypertension / pulmonary vascular remodeling / S100A9 / Signal Transduction / Vascular Remodeling - physiology