Siglec-E对脓毒性心肌病的调节作用及机制研究

Sepsis induced cardiomyopathy (SIC), as a major participant of septic shock in sepsis, has an ambiguous pathogenesis until now. Siglec-E is a molecular mostly expressed on the surface of macrophage, and our previous study showed that Siglec-E on macrophages in sepsis was up-regulated, and the survival of septic mice decreased when the expression of Siglec-E was inhibited. From those phenomena, we suppose that Siglec-E is involved in the pathogenesis of SIC. Siglec-E knock out mice was employed, and the models of sepsis was prepared by cecal ligation and puncture (CLP). Bone-Marrow Stromal Cells from WT mice was adoptive transferred to animals in vein. After that, echocardiogram, accumulation of Neutrophils and Macrophages in heart tissue, and the apoptosis of cardiomyocyte were tested to confirm the function of Siglec-E. NF-κB inhibitor were used to verify the involvement of NF-κB signal pathway. The purpose of this project is to elucidate that Siglec-E regulates the pathogenesis of SIC through NF-κB signal pathway, which provides a new direction in the treatment of sepsis.

脓毒性心肌病是脓毒性休克发生的主要原因之一，但其分子机制尚不明确。Siglec-E多表达于单核巨噬细胞表面，我们前期研究显示，脓毒症小鼠巨噬细胞表面Siglec-E升高，且体内干扰Siglec-E后，脓毒症小鼠死亡率明显升高。我们推测Siglec-E参与了脓毒性心肌病的发病过程。课题采用Siglec-E基因敲除小鼠，以盲肠结扎穿孔术制备脓毒症模型，并结合骨髓基质细胞过继性植入，通过超声心动、心肌组织炎症浸润以及心肌细胞凋亡等方面证实Siglec-E对脓毒性心肌病的发病影响；进一步采用NF-κB特异性抑制剂来证实Siglec-E发挥作用受到NF-κB通路的调控。本课题旨在证实Siglec-E通过NF-κB通路调节脓毒性心肌病的发生发展，也证实NF-κB是Siglec-E发挥免疫调节的重要分子通路，为脓毒症治疗提供新方向。

脓毒性心肌病（Sepsis-induced cardiomyopathy, SIC）是脓毒症的严重并发症，加剧脓毒性休克的循环衰竭，增加脓毒症病死率。我们研究发现Siglec-9/E在单核巨噬细胞以及效应记忆性T细胞表面均有表达，应用Siglec-E阻断剂阻断Siglec-E的保护作用后，脓毒症小鼠心肌病加重，死亡率增加；在脓毒症患者中同样观察到脓毒症早期Siglec-9在单核巨噬细胞、NK细胞以及T细胞的表达与脓毒症患者预后负相关，证实了Siglec-9/E对脓毒症的潜在保护作用。项目进一步在肾素血管紧张素醛固酮系统（renin angiotensin aldosterone system, RAAS）与SIC发病机制之间的作用开展研究。课题组在临床中发现SIC患者早期外周血浆血管紧张素II（Angiotensin II, Ang II）和Ang-(1-7)水平及外周血单核细胞血管紧张素受体（Angiotensin II type 1 receptor, AT1R）的表达异于健康对照者，且其与心肌损伤程度具有相关性。氯沙坦作为AT1R的特异性阻滞剂能够通过TLR4/NF-κB/MAPK通路调节巨噬细胞极化，从而缓解SIC诱导的心肌损伤（Pharmacol Res, 2022）；Ang-(1-7)/MasR作为血管紧张素II的关键转化通路，发挥改善脓毒症心肌病的作用（J Transl Med, 2023）；综合以上，证实RAAS在SIC的发病中扮演关键角色，也成为干预SIC的潜在靶点，为脓毒症及SIC的靶向干预带来了新方向。项目组还在SIC的营养素预防方面开展了研究。研究发现预防性应用芦丁可以改善脓毒症小鼠心肌细胞线粒体障碍，减少心肌细胞凋亡，改善SIC及预后（Front Physiol, 2022）；使用富Omega-3不饱和脂肪酸饮食喂养小鼠，同样可以改善其发生脓毒症后SIC心肌细胞凋亡情况，改善脓毒症小鼠预后（Nutrition, 2023），为脓毒症及SIC预防提供了新的思路。