Necroptosis Inhibition Preserves Diaphragm Function in Experimental Sepsis

作者：Xin Fu, Lietao Wang, Qian Xu, Hua Yao, Xiao-Xiao Xia, Yucong Wang, Tao Li, Zhiwei Yao, Ji Luo, Guopeng Liang, Jing Yang, Qin Wu · 发表于：American Journal Of Pathology · 年份：2025 · DOI：10.1016/j.ajpath.2025.08.013 · 被引用次数：1 · 研究领域：Cell death mechanisms and regulation、Immune Response and Inflammation、Sepsis Diagnosis and Treatment

Diaphragm dysfunction in sepsis remains a critical challenge in intensive care, yet its underlying mechanisms are poorly understood. This study investigates the role of necroptosis, a recently recognized form of programmed cell death, in sepsis-induced diaphragm dysfunction. A cecal ligation and puncture model in C57BL/6 mice was employed to induce sepsis. Diaphragm function was assessed through ultrasound imaging and pulmonary function testing. Necroptosis markers [receptor-interacting protein kinase (Ripk)-1, Ripk3, and mixed-lineage kinase domain-like protein (Mlkl)] and inflammatory cytokines [Il-6, tumor necrosis factor (Tnf)-α] were quantified using real-time quantitative RT-PCR, Western blot analysis, and enzyme-linked immunosorbent assay. The effect of the necroptosis inhibitor necrostatin-1 (Nec-1) was evaluated in vivo and in vitro. Septic mice exhibited significant diaphragm dysfunction correlated with an elevated expression of necroptosis markers and inflammatory cytokines in diaphragm tissue. Nec-1 treatment not only suppressed necroptosis but also markedly improved diaphragm function and respiratory parameters. In vitro, peritoneal lavage fluid from septic mice induced necroptosis in C2C12 myotubes, an effect mitigated by Nec-1. The findings unveil necroptosis as a key player in sepsis-induced diaphragm dysfunction. A novel mechanism is proposed in which Tnf-α, produced by activated peritoneal macrophages, triggers diaphragm necroptosis. This study not only adva...