神经源性肺水肿（NPE）经常作为蛛网膜下腔出血（SAH）后的并发症出现。通常形成S100A8和S100A9的异二聚体，从而通过细胞表面的受体结合引发炎症反应。 Paquinimod 是 S100A9 的特异性抑制剂。本研究的目的是评估帕喹莫德给药和 S100A9 敲除对 SAH 后 NPE 的影响。在本研究中，通过血管内穿孔建立 C57BL/6J 野生型 (WT) 和 S100A9 敲除小鼠 SAH 模型。然后将这些模型分为几个组，包括WT-sham组、S100A9-KO-sham组、WT-SAH组、WT-SAH Paquinimod组和S100A9-KO-SAH组。 SAH诱导24小时后，使用肺湿干重法和苏木精和伊红（HE）染色评估肺水肿。此外，各种蛋白质的表达水平，如白细胞介素-1β (IL-1β)、肿瘤坏死因子 α (TNF-α)、occludin、claudin-3、Bax、Bcl-2、TLR4、MYD88 和 pNF-κB使用蛋白质印迹和免疫荧光染色分析肺组织中的 。通过TUNEL染色检测肺组织凋亡。首先，我们的研究结果表明S100A9的敲除对蛛网膜下腔出血（SAH）后的早期脑损伤具有保护作用。此外，SAH后脑损伤的减少也可以缓解神经源性肺水肿（NPE）。免疫荧光染色和蛋白质印迹分析显示，与野生型S100A9表达的SAH小鼠（WT-SAH）相比，S100A9敲除SAH小鼠（S100A9-KO-SAH）和帕喹莫德治疗小鼠的肺部炎症分子水平降低。 IL-1β 和 TNF-α）和紧密连接蛋白水平增加。此外，S100A9的敲除导致凋亡相关蛋白Bax的表达上调和Bcl-2的表达下调。此外，在 S100A9-KO-SAH 和 Paquinimod 治疗的小鼠中发现 TLR4、MYD88 和磷酸化 pNF-κB 减少，表明 TLR4/MYD88/NF-κB 信号通路可能参与抑制 S100A9-KO-SAH 的保护作用。 S100A9 对 SAH 后 NPE 的影响。敲除 S100A9 不仅可以改善蛛网膜下腔出血 (SAH) 后的初始脑损伤，还可以减轻 SAH 相关的神经源性肺水肿 (NPE)。此外，帕喹莫德被发现可以减少 NPE。这些发现暗示中枢神经系统和周围器官之间存在相关性，凸显了保护大脑以减轻对周围器官伤害的潜力。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Neurogenic pulmonary edema (NPE) frequently arises as a complication subsequent to subarachnoid hemorrhage (SAH). Heterodimers of S100A8 and S100A9 are commonly formed, thereby initiating an inflammatory reaction through receptor binding on the cell surface. Paquinimod serves as a specific inhibitor of S100A9. The objective of this investigation is to assess the impact of Paquinimod administration and S100A9 knockout on NPE following SAH.In this study, SAH models of C57BL/6J wild-type (WT) and S100A9 knockout mice were established through intravascular perforation. These models were then divided into several groups, including the WT-sham group, S100A9-KO-sham group, WT-SAH group, WT-SAH + Paquinimod group, and S100A9-KO-SAH group. After 24 h of SAH induction, pulmonary edema was assessed using the lung wet-dry weight method and Hematoxylin and eosin (HE) staining. Additionally, the expression levels of various proteins, such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), occludin, claudin-3, Bax, Bcl-2, TLR4, MYD88, and pNF-κB, in lung tissue were analyzed using western blot and immunofluorescence staining. Lung tissue apoptosis was detected by TUNEL staining.Firstly, our findings indicate that the knockout of S100A9 has a protective effect on early brain injury following subarachnoid hemorrhage (SAH). Additionally, the reduction of brain injury after SAH can also alleviate neurogenic pulmonary edema (NPE). Immunofluorescence staining and western blot analysis revealed that compared to SAH mice with wild-type S100A9 expression (WT-SAH), the lungs of S100A9 knockout SAH mice (S100A9-KO-SAH) and mice treated with Paquinimod exhibited decreased levels of inflammatory molecules (IL-1β and TNF-α) and increased levels of tight junction proteins. Furthermore, the knockout of S100A9 resulted in upregulated expression of the apoptotic-associated protein Bax and down-regulated expression of Bcl-2. Furthermore, a decrease in TLR4, MYD88, and phosphorylated pNF-κB was noted in S100A9-KO-SAH and Paquinimod treated mice, indicating the potential involvement of the TLR4/MYD88/NF-κB signaling pathway in the inhibition of the protective effect of S100A9 on NPE following SAH.The knockout of S100A9 not only ameliorated initial cerebral injury following subarachnoid hemorrhage (SAH), but also mitigated SAH-associated neurogenic pulmonary edema (NPE). Additionally, Paquinimod was found to diminish NPE. These findings imply a correlation between the central nervous system and peripheral organs, highlighting the potential of safeguarding the brain to mitigate harm to peripheral organs.Copyright © 2023 Elsevier Inc. All rights reserved.