长链酰基辅酶A合成酶4在脓毒症炎症反应中的作用

The role of Acyl-CoA synthetase long-chain family member 4 in the inflammatory response of sepsis

摘要

目的 探讨长链酰基辅酶A合成酶4（ACSL4）在脓毒症中的作用及潜在机制，为脓毒症的临床治疗提供新的靶点。方法 采用盲肠结扎穿刺术（CLP）建立小鼠脓毒症模型，设置对照组、CLP模型及ACSL4特异性抑制剂PRGL493干预组（0.125、0.25、1 mg/kg）；连续观察7ｄ小鼠生存状况及体质量变化，检测外周血ACSL4表达水平，通过临床评分评估小鼠一般状态，采用ＨＥ染色观察肺、肝、肾、脾脏病理损伤，Elisa检测生化功能和炎症因子水平。结果 CLP脓毒症模型组小鼠外周血ACSL4水平较对照组显著升高。与CLP组相比，0.125、0.25mg/kg PRGL493组小鼠7ｄ生存率显著提高（P<0.05），其中0.25mg/kg组保护作用最显著。PRGL493干预可降低脓毒症小鼠外周血ACSL4表达，改善小鼠一般状态及临床评分，减轻肺、肝、肾、脾脏的病理损伤，显著降低血清肌酐、尿素氮、乳酸脱氢酶、丙氨酸转氨酶、天冬氨酸转氨酶水平，同时降低促炎细胞因子ＴＮＦ-α水平、升高抗炎因子IL-10水平。结论 ACSL4在脓毒症小鼠外周血中高表达，其特异性抑制剂PRGL493可通过抑制ACSL4活性，减轻脓毒症小鼠的炎症反应及多器官损伤，提高生存率，提示ACSL4可作为脓毒症治疗的潜在靶点。

Abstract

Objective To investigate the role of Acyl-CoA synthetase long chain family member 4 (ACSL4) in sepsis and to explore its potential as a therapeutic target for clinical intervention. Methods A sepsis mouse model was established by cecal ligation and puncture (CLP). Mice were randomly assigned to a sham group, a CLP group, and PRGL493 treatment groups receiving an ACSL4-specific inhibitor at doses of 0.125, 0.25, or 1 mg/kg. Survival and body weight were monitored for 7 consecutive days. ACSL4 expression in peripheral blood was measured. General condition was assessed using a clinical scoring system. Histopathological changes in the lung, liver, kidney, and spleen were evaluated by hematoxylin and eosin staining. Serum biochemical parameters and inflammatory cytokines were determined by ELISA. Results Compared with the control group, ACSL4 expression in peripheral blood was significantly increased in septic mice in the CLP group. Compared with the CLP group, the 7-day survival rate was significantly improved in the PRGL493-treated groups at 0.125 mg/kg and 0.25 mg/kg (P<0.05), with the most pronounced protective effect observed at 0.25 mg/kg. PRGL493 treatment reduced the expression of ACSL4 in peripheral blood of septic mice, improved their general condition and clinical scores, alleviated pathological damage to the lung, liver, kidney and spleen. In addition, PRGL493 significantly reduced serum levels of creatinine (Crea), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), decreased the pro-inflammatory cytokine TNF-α, and increased the anti-inflammatory cytokine IL-10. Conclusion ACSL4 is highly expressed in the peripheral blood of septic mice. Pharmacological inhibition of ACSL4 with PRGL493 alleviates systemic inflammation and multiple organ injury and improves survival, suggesting that ACSL4 may serve as a promising therapeutic target for sepsis.

关键词

脓毒症 / 长链酰基辅酶A合成酶4 / 多器官损伤 / 炎症反应

Key words

sepsis / Acyl-CoA synthetase long chain family member 4 / multiple organ injury / inflammatory response

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基金资助

国家临床重点专科建设项目(xm040212)

贵州省教育厅高等学校自然科学研究项目(黔教技(2024)141)

贵州省急诊医学临床医学研究中心(黔科合平LCZX(2025)004)