Li Yingying, Jiang Huimin, Li Xinyi, Zhu Hui, Dai Yue, Zhang Jie, Sun Yueyue, Chu Xiang, Ju Wen, Xu Mengdi, Li Zhenyu, Zeng Lingyu, Xu Kailin, Qiao Jianlin
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, China. Blood Diseases Institute, Xuzhou Medical University, China. Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China.
Arterioscler Thromb Vasc Biol. 2025 Jan;45(1):136-143. doi: 10.1161/ATVBAHA.124.322029. Epub 2024 Dec 5.
Sepsis is featured as a systemic inflammation and thrombosis induced by infection. TGF-β (transforming growth factor-β) 1 is mainly secreted from platelets and plays a role in immune response and inflammation. Whether platelet-derived TGF-β1 participates in sepsis remains unclear. This study intends to investigate its role in sepsis in mice.
Platelet-specific TGF-β1 knockout mice received cecal ligation and puncture surgery to induce sepsis followed by the analysis of survival time, platelets number, pathology changes of lung and liver, liver function, the recruitment of platelets, neutrophils and monocytes, and neutrophil extracellular traps' formation. In addition, adoptive transfer of wild-type platelets into platelet-specific TGF-β1 knockout mice was performed to further evaluate the role of TGF-β1 in the pathogenesis of sepsis.
TGF-β1 level was gradually increased in the lung during the progress of sepsis, and platelets are the major source of the elevated TGF-β1 level in the lung after sepsis. Deficiency of platelet-derived TGF-β1 prolonged the survival of sepsis mice, inhibited the drop of platelet number and bacterial growth, impaired the thrombus formation in the lung and liver, and improved liver function. In addition, platelet TGF-β1 deficiency also decreased the recruitment of neutrophils and monocytes to the lung and impaired neutrophil extracellular trap formation. However, the adoptive transfer of normal platelets to platelet-specific TGF-β1 knockout mice significantly reduced the number of circulating platelets, increased thrombosis in the lung and liver, and promoted the neutrophil extracellular trap formation.
Deficiency of platelet-derived TGF-β1 inhibits septic thrombosis and prolongs survival time, indicating that it might be a novel therapeutic target for the treatment of sepsis.
脓毒症的特征是由感染引起的全身炎症和血栓形成。转化生长因子-β（TGF-β）1主要由血小板分泌，在免疫反应和炎症中起作用。血小板源性TGF-β1是否参与脓毒症仍不清楚。本研究旨在探讨其在小鼠脓毒症中的作用。
血小板特异性TGF-β1基因敲除小鼠接受盲肠结扎和穿刺手术以诱导脓毒症，随后分析生存时间、血小板数量、肺和肝脏的病理变化、肝功能、血小板、中性粒细胞和单核细胞的募集以及中性粒细胞胞外陷阱的形成。此外，将野生型血小板过继转移到血小板特异性TGF-β1基因敲除小鼠中，以进一步评估TGF-β1在脓毒症发病机制中的作用。
在脓毒症进展过程中，肺组织中TGF-β1水平逐渐升高，且血小板是脓毒症后肺组织中TGF-β1水平升高的主要来源。血小板源性TGF-β1缺乏可延长脓毒症小鼠的生存期，抑制血小板数量下降和细菌生长，损害肺和肝脏中的血栓形成，并改善肝功能。此外，血小板TGF-β1缺乏还可减少中性粒细胞和单核细胞向肺组织的募集，并损害中性粒细胞胞外陷阱的形成。然而，将正常血小板过继转移到血小板特异性TGF-β1基因敲除小鼠中可显著减少循环血小板数量，增加肺和肝脏中的血栓形成，并促进中性粒细胞胞外陷阱的形成。
血小板源性TGF-β1缺乏可抑制脓毒症血栓形成并延长生存时间，表明其可能是治疗脓毒症的新治疗靶点。
