沉默凝血因子V基因通过抑制JNK1/2和p38 MAPK信号通路对脓毒症大鼠的保护作用

doi:10.13481/j.1671-587X.20260214

Abstract

Abstract:

Objective To discuss the effect of coagulation factor V （FV） on the immune inflammatory response and the c-Jun N-terminal kinase 1/2 （JNK1/2） and p38 mitogen-activated protein kinase （p38 MAPK） signaling pathways in the septic rats， and to clarify its possible mechanism. Methods A total of 150 rats were divided into sham operation group， model group， sh-NC group， sh-FV group， and anisomycin group， with 30 rats in each group. The sepsis model was established by cecal ligation and puncture （CLP） method. The survival rates of the rats in various groups within 5 d after modeling were observed. Hematoxylin-eosin （HE） staining was used to observe the pathomorphology of lung， kidney， liver， and spleen tissues of the rats in various groups； real-time fluorescence quantitative PCR （RT-qPCR） was used to detect the expression levels of FV mRNA in lung tissue of the rats in various groups； Western blotting method was used to detect the expression levels of FV， JNK1/2， and p38 MAPK signaling pathway-related proteins in lung tissue of the rats in various groups； enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） in serum of the rats in various groups； flow cytometry was used to detect the apoptotic rates of neutrophils and the percentages of T lymphocyte subsets in blood of the rats in various groups. Results Compared with model group and sh-NC group， the survival rate of the rats in sh-FV group was significantly increased （P<0.05）； compared with sh-FV group， the survival rate of the rats in anisomycin group was significantly decreased （P<0.05）. Compared with sham operation group， the expression levels of FV mRNA in lung tissue of the rats in model group and sh-NC group were significantly increased （P<0.05）； compared with model group and sh-NC group， the expression level of FV mRNA in lung tissue of the rats in sh-FV group was significantly decreased （P<0.05）. The Western blotting results showed that compared with sham operation group， the expression levels of FV protein in lung tissue of the rats in model group and sh-NC group were significantly increased （P<0.05）， and the ratios of p-JNK1/2/JNK1/2 and p-p38 MAPK/p38 MAPK were significantly increased （P>0.05）； compared with model group and sh-NC group， the expression level of FV protein and the ratios of p-JNK1/2/JNK1/2 and p-p38 MAPK/p38 MAPK in lung tissue of the rats in sh-FV group were significantly decreased （P<0.05）； compared with sh-FV group， the ratios of p-JNK1/2/JNK1/2 and p-p38 MAPK/p38 MAPK in lung tissue of the rats in anisomycin group were significantly increased （P<0.05）. The ELISA results showed that compared with sham operation group， the serum levels of IL-1β， IL-6， and TNF-α of the rats in model group and sh-NC group were significantly increased （P<0.05）； compared with model group and sh-NC group， the serum levels of IL-1β， IL-6， and TNF-α of the rats in sh-FV group were significantly decreased （P<0.05）； compared with sh-FV group， the serum levels of IL-1β， IL-6， and TNF-α of the rats in anisomycin group were significantly increased （P<0.05）. The flow cytometry results showed that compared with sham operation group， the apoptotic rates of neutrophils， the percentage of CD4⁺ T lymphocytes， and the ratios of CD4⁺/CD8⁺ T lymphocytes of the rats in model group and sh-NC group were significantly decreased （P<0.05）， while the percentages of CD8⁺ T lymphocytes were significantly increased （P<0.05）； compared with model group and sh-NC group， the apoptotic rate of neutrophils， the percentage of CD4⁺ T lymphocytes， and the ratio of CD4⁺/CD8⁺ T lymphocytes of the rats in sh-FV group were significantly increased （P<0.05）， while the percentage of CD8⁺ T lymphocytes was significantly decreased （P<0.05）； compared with sh-FV group， the apoptotic rate of neutrophils， the percentage of CD4⁺ T lymphocytes， and the ratio of CD4⁺/CD8⁺ T lymphocytes of the rats in anisomycin group were significantly decreased （P<0.05）， while the percentage of CD8⁺ cells was significantly increased （P<0.05）. Conclusion Silencing FV gene can alleviate the damage of lung， liver， spleen， and kidney tissues， induce the apoptosis of blood neutrophils， reduce the serum levels of inflammatory factors， and increase the percentage of CD4⁺ T lymphocytes and the ratio of CD4⁺/CD8⁺ T lymphocytes in blood of the septic rats. Its mechanism may be related to the inhibition of JNK1/2 and p38 MAPK signaling pathways.

Key words: Coagulation factor V, c-Jun N-terminal kinase 1/2, p38 mitogen-activated protein kinase, Sepsis, Immune inflammation

CLC Number:

R364.5

Jingyuan WANG,Fang CHEN,Yancun LIU,Shixin LI,Songtao SHOU. Protective effect of silencing coagulation factor V gene on septic rats by inhibiting JNK1/2 and p38 MAPK signaling pathways[J].Journal of Jilin University(Medicine Edition), 2026, 52(2): 418-428.

Figures/Tables 9

Fig. 1

Tab.1

Fig. 2

Fig. 3

Fig. 4

Fig. 5

Fig. 6

Fig. 7

Fig. 8

References 27

[1]	SRZIĆ I， NESEK ADAM V， TUNJIĆ PEJAK D. Sepsis definition： what’s new in the treatment guidelines［J］. Acta Clin Croat， 2022， 61（）： 67-72.
[2]	RUDD K E， JOHNSON S C， AGESA K M， et al. Global， regional， and national sepsis incidence and mortality， 1990-2017： Analysis for the Global Burden of Disease Study［J］. Lancet， 2020， 395（10219）： 200-211.
[3]	WANG B B， ZHU L L， JIA B， et al. Sepsis induces non-classic innate immune memory in granulocytes［J］. Cell Rep， 2023， 42（9）： 113044.
[4]	UNAR A， BERTOLINO L， PATAUNER F， et al. Pathophysiology of disseminated intravascular coagulation in sepsis： A clinically focused overview［J］. Cells， 2023， 12（17）： 2120.
[5]	LIND S M， SLETTEN M， HELLENES M， et al. Coagulation factor V in breast cancer： A p53-regulated tumor suppressor and predictive marker for treatment response to chemotherapy［J］. J Thromb Haemost， 2024， 22（6）： 1569-1582.
[6]	文柯力. 脓毒症合并弥散性血管内凝血的机制及抗凝治疗研究进展［J］. 现代医药卫生， 2019， 35（9）： 1370-1374.
[7]	张铭，雷娇，龚禹，等. 芍药苷通过JNK/NEK7/NLRP3通路缓解脓毒症相关急性肾损伤［J］. 中国病理生理杂志， 2024， 40（9）： 1711-1717.
[8]	ZHANG Y R， CHEN Z R， GUO J Y， et al. Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice［J］. Br J Pharmacol， 2024， 181（19）： 3760-3778.
[9]	沈磊，董林，贺福义，等. 三七总皂苷调节RAGE/MAPK/NF-κB信号通路对糖尿病骨质疏松大鼠骨密度及骨代谢的影响［J］. 中国老年学杂志， 2024， 44（23）： 5768-5772.
[10]	温亚，李燕，白思怡，等. 瑞香素调节STING/TBK1/IRF3信号通路对脓毒症大鼠免疫炎症反应的影响［J］. 西安交通大学学报（医学版）， 2024， 45（5）： 822-827.
[11]	ZENG Y C， CAO G D， LIN L， et al. Resveratrol attenuates sepsis-induced cardiomyopathy in rats through anti-ferroptosis via the Sirt1/Nrf2 pathway［J］. J Invest Surg， 2023， 36（1）： 2157521.
[12]	NEDEVA C. Inflammation and cell death of the innate and adaptive immune system during sepsis［J］. Biomolecules， 2021， 11（7）： 1011.
[13]	CHEN W J， PAN J Y. Anatomical and pathological observation and analysis of SARS and COVID-19： Microthrombosis is the main cause of death［J］. Biol Proced Online， 2021， 23（1）： 4.
[14]	FANG Z D， ZHANG X W， HUANG Y Y， et al. Piperlongumin improves survival in the mouse model of sepsis： Effect on coagulation factors and lung inflammation［J］. Inflammation， 2022， 45（6）： 2513-2528.
[15]	MOHAMMED B M， PELC L A， RAU M J， et al. Cryo-EM structure of coagulation factor V short［J］. Blood， 2023， 141（26）： 3215-3225.
[16]	XUAN W X， WU X， ZHENG L C， et al. Gut microbiota-derived acetic acids promoted sepsis-induced acute respiratory distress syndrome by delaying neutrophil apoptosis through FABP4［J］. Cell Mol Life Sci， 2024， 81（1）： 438.
[17]	罗玉娇，郑小莉，罗波，等. PD-L1通过调控PKC-α-NF-κB信号通路延迟脓毒血症中性粒细胞凋亡［J］. 中国免疫学杂志， 2020， 36（17）： 2049-2052.
[18]	GENDRE B， MARTINEZ-PEREZ A， KLEBER M E， et al. Genome-wide search for nonadditive allele effects identifies PSKH2 as involved in the variability of factor V activity［J］. J Am Heart Assoc， 2024， 13（21）： e034943.
[19]	郑涵雪，张连生，李莉娟. 微移植治疗急性髓系白血病不同预处理方案精细免疫指标的差异性研究［J］. 中国实用内科杂志， 2025， 45（1）： 54-61.
[20]	谢小丽，张予晋，谭瑶，等. JAK/STAT通路介导免疫缺陷大鼠CD4⁺T细胞分化的研究［J］. 湖南中医药大学学报， 2023， 43（7）： 1206-1214.
[21]	DE GROOT A S， ROSENBERG A S， SHAHJAHAN MIAH S M， et al. Identification of a potent regulatory T cell epitope in factor V that modulates CD4⁺ and CD8⁺ memory T cell responses［J］. Clin Immunol， 2021， 224： 108661.
[22]	王静，辛绍斌. 脓毒症亚型的研究进展［J］. 中国实用内科杂志， 2025， 45（9）： 785-792.
[23]	FAWZY M A， MAHER S A， BAKKAR S M， et al. Pantoprazole attenuates MAPK （ERK1/2， JNK， p38）- NF-κB and apoptosis signaling pathways after renal ischemia/reperfusion injury in rats［J］. Int J Mol Sci， 2021， 22（19）： 10669.
[24]	MOHYELDIN R H， ALAAELDIN R， SHARATA E E， et al. LCZ696 attenuates sepsis-induced liver dysfunction in rats； the role of oxidative stress， apoptosis， and JNK1/2-P38 signaling pathways［J］. Life Sci， 2023， 334： 122210.
[25]	ZHANG W， CHEN H Z， XU Z Y， et al. Liensinine pretreatment reduces inflammation， oxidative stress， apoptosis， and autophagy to alleviate sepsis acute kidney injury［J］. Int Immunopharmacol， 2023， 122： 110563.
[26]	CUI Y N， TIAN N， LUO Y H， et al. High-dose Vitamin C injection ameliorates against sepsis-induced myocardial injury by anti-apoptosis， anti-inflammatory and pro-autophagy through regulating MAPK， NF-κB and PI3K/AKT/mTOR signaling pathways in rats［J］. Aging， 2024， 16（8）： 6937-6953.
[27]	ISHIKURA S， OGAWA M， DOI K， et al. Zfat-deficient CD4⁺ CD8⁺ double-positive thymocytes are susceptible to apoptosis with deregulated activation of p38 and JNK［J］. J Cell Biochem， 2015， 116（1）： 149-157.

Group	Survival number
Group	(t/d) 0	1	3	5
Sham operation	10（100.00）	10（100.00）	10（100.00）	10（100.00）
Model	10（100.00）	8（80.00）^*	5（50.00）^*	2（20.00）^*
Sh-NC	10（100.00）	9（90.00）	5（50.00）^*	3（30.00）^*
Sh-FV	10（100.00）	10（100.00）^#	8（80.00）^△#	6（60.00）^△#
Anisomycin	10（100.00）	8（80.00）^○	6（60.00）^○	3（30.00）^○

Protective effect of silencing coagulation factor V gene on septic rats by inhibiting JNK1/2 and p38 MAPK signaling pathways

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 9

References 27

Related Articles 11

Metrics

Comments

Recommended 10

[1]	Jinyu LI,Zhonghui LI,Aibin CHENG,Xuan BU,Jing BAI,Jianjun WANG. Improvement effect of TREM-1 inhibitory peptide LR12 on myocardial injury in septic mice and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2026, 52(2): 366-374.
[2]	Jingyuan WANG,Fang CHEN,Yancun LIU,Shixin LI,Songtao SHOU. Effect of USF2 knockdown on coagulation dysfunction in septic rats and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 171-181.
[3]	Yaping LI,Chunyan TAN,Lujie ZHAO,Jiayi ZHAO,Ting LI,Xiao YANG,Xiaoyun YANG. Inductive effect of lysophosphatidic acid combined with 6-hydroxydopamine on apoptosis of SH-SY5Y cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 152-161.
[4]	Tao SUN,Zhiyin DAI,Xuan LI,Chaopu ZHANG,Shu DING,Jianwei ZHAO. Predictive value of pan-immune-inflammation index for major adverse cardiovascular events within 1 year after PCI in elderly patients with coronary heart disease [J]. Journal of Jilin University(Medicine Edition), 2025, 51(6): 1655-1660.
[5]	Kun YANG,Qianyao FU,Yongqiang SUN,Kun YANG,Jun MENG. Protective effect of dexmedetomidine on intestinal mucosal injury in rats with enterogenous sepsis and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2025, 51(4): 855-865.
[6]	Ming xing YANG,Wen DONG,Ji LI. Inductive effect of peiminine on apoptosis of lung cancer A549 cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2022, 48(3): 711-717.
[7]	ZHANG Xiaoxuan, MA Zheng, YU Ning, JIAO Guangmei, DOU Zhijie, ZHAO Liang, GAO Yanjun. Inhibitory effect of butylphthalide on hippocampal neuron apoptosis in ischemic stroke rats and itsinfluence in p38 MAPK signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2019, 45(05): 1086-1091.
[8]	ZHENG Guilang, GUO Yuxiong, LYU Juanjuan, HUANG Jinda, LIU Cui, ZENG Qiyi. Protective effect of overexpression of uncoupling protein 2 on mitochondria in cardiomyocytes of rats with sepsis [J]. Journal of Jilin University Medicine Edition, 2018, 44(04): 698-703.
[9]	QIU Lijie, ZHANG Ye, ZHANG Wenjing, QIAN Donghua. Meta-analysis on curative effects of statins in treatment of pneumoniaor or sepsis [J]. Journal of Jilin University Medicine Edition, 2016, 42(02): 336-344.
[10]	LU Feiping, CHEN Wei, ZHEN Jie, MA Li. Changes of lymphocyte subsets in elderly patients with sepsis before and after immune modulation therapy [J]. Journal of Jilin University Medicine Edition, 2015, 41(05): 994-997.
[11]	LIU Hua-Wen, XU Xiang-Hong, LANG Sen-Yang, CAi Ai-Min. Expression of p38MAPK in cultured cortical neurons in vitro and intervention effect of W-7 [J]. J4, 2011, 37(1): 47-50.