Exploration of the protective effect of aprotinin on liver injury in septic rats based on Toll-like receptor 4/nuclear factor κB axis_West China Medical Journal

Authors：

YAN Yufen , MIAO Shaoyi , ZHANG Yurong , ZHENG Jiahui , ZHANG Xinyue ,  LI Peiwu

Department of Emergency Center, Lanzhou University Second Hospital (Second Clinical Medical College), LanZhou, Gansu 730000, P. R. China;

Corresponding?author：

LI Peiwu, Email: lipeiw@lzu.edu.cn

Keywords：

Aprotinin; sepsis; liver injury; Toll-like receptor 4; nuclear factor κB

DOI：

10.7507/1002-0179.202510099

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the protective effect of aprotinin on liver injury in septic rats and its mechanism. Methods Thirty male SPF rats were randomly divided into sham operation group, cecum ligation and puncture (CLP) group and aprotinin intervention group (10 rats in each group). The sham operation group was treated with cecal exploration, CLP group and aprotinin group were treated with CLP method to establish sepsis rat model. The rats in each group were sacrificed 24 hours after operation, and the morphological changes of liver tissue in rats were observed, the serum liver function indicators and inflammatory cytokines levels were detected, and the protein expression of Toll-like receptor (TLR4)/nuclear factor κB (NF-κB) signaling pathway in liver tissue was detected. Results In the CLP group, septic rats exhibited significant inflammatory cell infiltration in hepatic tissue and disordered hepatocyte morphology. Compared with the CLP group, the aprotinin group exhibited nearly normal hepatocyte morphology with significant improvement in vacuolar degeneration. Compared with the sham operation group, the serum aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor-α, interleukin-6 were increased, and the expression of TLR4 and p-NF-κB protein in liver tissue was up-regulated in the CLP group (P<0.05). Compared with the CLP group, serum aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor-α, interleukin-6 were decreased, and the expression of TLR4 and p-NF-κB protein in liver tissue was decreased in the aprotinin group (P<0.05). Conclusion Aprotinin may play a protective role against sepsis related liver injury by inhibiting TLR4 / NF-κB signaling axis, reducing the production of inflammatory factors and alleviating inflammatory reactions.

Citation： YAN Yufen, MIAO Shaoyi, ZHANG Yurong, ZHENG Jiahui, ZHANG Xinyue, LI Peiwu. Exploration of the protective effect of aprotinin on liver injury in septic rats based on Toll-like receptor 4/nuclear factor κB axis. West China Medical Journal, 2025, 40(11): 1766-1770. doi: 10.7507/1002-0179.202510099 Copy

1.	Fleischmann-Struzek C, Mellhammar L, Rose N, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med, 2020, 46(8): 1552-1562.
2.	Srzi? I, Nesek Adam V, Tunji? Pejak D. Sepsis definition: what’s new ?in the treatment guidelines. Acta Clin Croat, 2022, 61(Suppl 1): 67-72.
3.	Moreira J. Severe sepsis and septic shock. N Engl J Med, 2013, 369(21): 2063.
4.	Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther, 2012, 10(6): 701-706.
5.	Patel JJ, Taneja A, Niccum D, et al. The association of serum bilirubin levels on the outcomes of severe sepsis. J Intensive Care Med, 2015, 30(1): 23-29.
6.	Cui L, Bao J, Yu C, et al. Development of a nomogram for predicting 90-day mortality in patients with sepsis-associated liver injury. Sci Rep, 2023, 13(1): 3662.
7.	Guo Q, Jin Y, Chen X, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther, 2024, 9(1): 53.
8.	Ivachtchenko AV, Ivashchenko AA, Shkil DO, et al. Aprotinin-drug against respiratory diseases. Int J Mol Sci, 2023, 24(13): 11173.
9.	Sakr AG, Kafl HE, El-Kashef DH. Rupatadine modulates TLR4/MYD88/NF-κB and AKT/PI3K signaling pathways, attenuating sepsis-induced liver injury in mice. Eur J Pharmacol, 2025, 1002: 177873.
10.	Pruefer D, Buerke U, Khalil M, et al. Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart. J Thorac Cardiovasc Surg, 2002, 124(5): 942-949.
11.	Redondo-Calvo FJ, Padín JF, Mu?oz-Rodríguez JR, et al. Aprotinin treatment against SARS-CoV-2: a randomized phase III study to evaluate the safety and efficacy of a pan-protease inhibitor for moderate COVID-19. Eur J Clin Invest, 2022, 52(6): e13776.
12.	Atasever AG, Eerens M, Van den Eynde R, et al. Efficacy and safety of aprotinin in paediatric cardiac surgery: a systematic review and meta-analysis. Eur J Anaesthesiol, 2022, 39(4): 352-367.
13.	Padín JF, Pérez-Ortiz JM, Redondo-Calvo FJ. Aprotinin (I): understanding the role of host proteases in COVID-19 and the importance of pharmacologically regulating their function. Int J Mol Sci, 2024, 25(14): 7553.
14.	Padín JF, Pérez-Ortiz JM, Redondo-Calvo FJ. Aprotinin (II): inhalational administration for the treatment of COVID-19 and other viral conditions. Int J Mol Sci, 2024, 25(13): 7209.
15.	王麗君, 郝建, 趙建, 等. 抑肽酶對全氟異丁烯誘導大鼠急性肺損傷的影響及其機制. 安徽醫科大學學報, 2014, 49(11): 1600-1604.
16.	Rittirsch D, Huber-Lang MS, Flierl MA, et al. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc, 2009, 4(1): 31-36.
17.	王麗君, 郝建, 趙建, 等. 抑肽酶對全氟異丁烯致大鼠急性肺損傷的作用. 中國急救醫學, 2014, 34(6): 533-537, 后插 2.
18.	Wang H, Ma T, Bao Q, et al. Knockdown of protein interacting with C α kinase 1 aggravates sepsis-induced acute liver injury by regulating the TLR4/NF-κB pathway. Sci Rep, 2023, 13(1): 11913.
19.	Zhang X, Yuan S, Fan H, et al. Liensinine alleviates sepsis-induced acute liver injury by inhibiting the NF-κB and MAPK pathways in an Nrf2-dependent manner. Chem Biol Interact, 2024, 396: 111030.
20.	Wang M, Cai XF, Zhang SM, et al. Alprostadil alleviates liver injury in septic rats via TLR4/NF-κB pathway. Eur Rev Med Pharmacol Sci, 2021, 25(3): 1592-1599.
21.	Sun S, Wang L, Wang J, et al. Maresin1 prevents sepsis-induced acute liver injury by suppressing NF-κB/Stat3/MAPK pathways, mitigating inflammation. Heliyon, 2023, 9(11): e21883.
22.	Song Y, Miao S, Li Y, et al. Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model. J Cell Biochem, 2019, 120(1): 417-424.
23.	Wenying S, Jing H, Ying L, et al. The role of TLR4/MyD88/NF-κB in the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis. BMC Anesthesiol, 2023, 23(1): 414.
24.	Hill GE, Pohorecki R, Alonso A, et al. Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass. Anesth Analg, 1996, 83(4): 696-700.
25.	Zhang X, Zhu Z, Jiao W, et al. Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials. BMC Pulm Med, 2019, 19(1): 196.
26.	王育凱, 陳軍賢, 施小偉, 等. 連續性腎臟替代治療聯合烏司他丁對嚴重膿毒癥患者臨床療效的 Meta 分析. 中華危重癥醫學雜志(電子版), 2021, 14(4): 297-307.

1. Fleischmann-Struzek C, Mellhammar L, Rose N, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med, 2020, 46(8): 1552-1562.
2. Srzi? I, Nesek Adam V, Tunji? Pejak D. Sepsis definition: what’s new ?in the treatment guidelines. Acta Clin Croat, 2022, 61(Suppl 1): 67-72.
3. Moreira J. Severe sepsis and septic shock. N Engl J Med, 2013, 369(21): 2063.
4. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther, 2012, 10(6): 701-706.
5. Patel JJ, Taneja A, Niccum D, et al. The association of serum bilirubin levels on the outcomes of severe sepsis. J Intensive Care Med, 2015, 30(1): 23-29.
6. Cui L, Bao J, Yu C, et al. Development of a nomogram for predicting 90-day mortality in patients with sepsis-associated liver injury. Sci Rep, 2023, 13(1): 3662.
7. Guo Q, Jin Y, Chen X, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther, 2024, 9(1): 53.
8. Ivachtchenko AV, Ivashchenko AA, Shkil DO, et al. Aprotinin-drug against respiratory diseases. Int J Mol Sci, 2023, 24(13): 11173.
9. Sakr AG, Kafl HE, El-Kashef DH. Rupatadine modulates TLR4/MYD88/NF-κB and AKT/PI3K signaling pathways, attenuating sepsis-induced liver injury in mice. Eur J Pharmacol, 2025, 1002: 177873.
10. Pruefer D, Buerke U, Khalil M, et al. Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart. J Thorac Cardiovasc Surg, 2002, 124(5): 942-949.
11. Redondo-Calvo FJ, Padín JF, Mu?oz-Rodríguez JR, et al. Aprotinin treatment against SARS-CoV-2: a randomized phase III study to evaluate the safety and efficacy of a pan-protease inhibitor for moderate COVID-19. Eur J Clin Invest, 2022, 52(6): e13776.
12. Atasever AG, Eerens M, Van den Eynde R, et al. Efficacy and safety of aprotinin in paediatric cardiac surgery: a systematic review and meta-analysis. Eur J Anaesthesiol, 2022, 39(4): 352-367.
13. Padín JF, Pérez-Ortiz JM, Redondo-Calvo FJ. Aprotinin (I): understanding the role of host proteases in COVID-19 and the importance of pharmacologically regulating their function. Int J Mol Sci, 2024, 25(14): 7553.
14. Padín JF, Pérez-Ortiz JM, Redondo-Calvo FJ. Aprotinin (II): inhalational administration for the treatment of COVID-19 and other viral conditions. Int J Mol Sci, 2024, 25(13): 7209.
15. 王麗君, 郝建, 趙建, 等. 抑肽酶對全氟異丁烯誘導大鼠急性肺損傷的影響及其機制. 安徽醫科大學學報, 2014, 49(11): 1600-1604.
16. Rittirsch D, Huber-Lang MS, Flierl MA, et al. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc, 2009, 4(1): 31-36.
17. 王麗君, 郝建, 趙建, 等. 抑肽酶對全氟異丁烯致大鼠急性肺損傷的作用. 中國急救醫學, 2014, 34(6): 533-537, 后插 2.
18. Wang H, Ma T, Bao Q, et al. Knockdown of protein interacting with C α kinase 1 aggravates sepsis-induced acute liver injury by regulating the TLR4/NF-κB pathway. Sci Rep, 2023, 13(1): 11913.
19. Zhang X, Yuan S, Fan H, et al. Liensinine alleviates sepsis-induced acute liver injury by inhibiting the NF-κB and MAPK pathways in an Nrf2-dependent manner. Chem Biol Interact, 2024, 396: 111030.
20. Wang M, Cai XF, Zhang SM, et al. Alprostadil alleviates liver injury in septic rats via TLR4/NF-κB pathway. Eur Rev Med Pharmacol Sci, 2021, 25(3): 1592-1599.
21. Sun S, Wang L, Wang J, et al. Maresin1 prevents sepsis-induced acute liver injury by suppressing NF-κB/Stat3/MAPK pathways, mitigating inflammation. Heliyon, 2023, 9(11): e21883.
22. Song Y, Miao S, Li Y, et al. Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model. J Cell Biochem, 2019, 120(1): 417-424.
23. Wenying S, Jing H, Ying L, et al. The role of TLR4/MyD88/NF-κB in the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis. BMC Anesthesiol, 2023, 23(1): 414.
24. Hill GE, Pohorecki R, Alonso A, et al. Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass. Anesth Analg, 1996, 83(4): 696-700.
25. Zhang X, Zhu Z, Jiao W, et al. Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials. BMC Pulm Med, 2019, 19(1): 196.
26. 王育凱, 陳軍賢, 施小偉, 等. 連續性腎臟替代治療聯合烏司他丁對嚴重膿毒癥患者臨床療效的 Meta 分析. 中華危重癥醫學雜志(電子版), 2021, 14(4): 297-307.

West China Medical Journal

Exploration of the protective effect of aprotinin on liver injury in septic rats based on Toll-like receptor 4/nuclear factor κB axis

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content