Mechanical ventilation (MV) has the potential to induce extra-pulmonary organ damage by adversely affecting the lungs and promoting the secretion of inflammatory cytokines. High-mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury (VILI), but its effect on MV-associated liver injury and the mechanisms are poorly understood. In the present study, mice were subjected to high-volume MV (20 ml/kg) to induce VILI. MV-induced HMGB1 prompted neutrophil extracellular traps (NETs) formation and PANoptosis within the liver. Inhibiting NETs formation by DNase I or PAD4 inhibitor, or by HMGB1 neutralizing ameliorated the liver injury. HMGB1 activated neutrophils to form NETs through TLR4/MyD88/TRAF6 pathway. Importantly, Importin7 siRNA nanoparticles inhibited HMGB1 release and protected against MV-associated liver injury. These data provide evidence of MV-induced HMGB1 prompted NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway. HMGB1 is a potential therapeutic target for MV-associated liver injury.

中文翻译：

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Imp7 siRNA 纳米颗粒通过抑制 HMGB1 产生和 NET 形成来防止机械通气相关的肝损伤

机械通气（MV）有可能通过对肺部产生不利影响并促进炎症细胞因子的分泌而诱发肺外器官损伤。高迁移率族蛋白 1 (HMGB1) 是呼吸机所致肺损伤 (VILI) 中的促炎介质，但其对 MV 相关肝损伤的影响及其机制尚不清楚。在本研究中，对小鼠进行高容量 MV (20 ml/kg) 诱导 VILI。MV 诱导的 HMGB1 促进中性粒细胞胞外陷阱 (NET) 形成和肝脏内 PAN 凋亡。通过 DNase I 或 PAD4 抑制剂或通过 HMGB1 中和抑制 NET 形成可改善肝损伤。HMGB1通过TLR4/MyD88/TRAF6通路激活中性粒细胞形成NET。重要的是，Importin7 siRNA 纳米颗粒抑制 HMGB1 释放并防止 MV 相关的肝损伤。这些数据提供了 MV 诱导的 HMGB1 通过 TLR4/MyD88/TRAF6 途径促进肝脏中 NET 形成和 PAN 凋亡的证据。HMGB1 是 MV 相关肝损伤的潜在治疗靶点。