Impact of sufentanil on liver injury in burn-induced sepsis rats by regulating JAK2/STAT3 signaling pathway

doi:10.11958/20240681

Abstract

Abstract:

Objective To investigate the effect of sufentanil (suf) on hepatic injury in burn sepsis rats by regulating Janus kinase 2 (JAK2)/signal transduction and transcriptional activator 3 (STAT3) signaling pathway. Methods SD rats were randomly divided into the control group, the model group, the suf low-dose group (0.75 μg/kg), the suf high-dose group (3 μg/kg), the imipenem group (90 mg/kg) and the suf high-dose + kumamycin group (3 μg/kg suf+4 mg/kg kumamycin). Serum liver function indexes including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected. The pathological changes of liver tissue were observed by HE staining. The contents of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-6 were detected by enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotide transferase mediated dUTP nick end labeling (TUNEL) staining was used to detect hepatocyte apoptosis. Western blot assay was used to detect the expression of p-JAK2 and p-STAT3 proteins in liver tissue. Results Compared with the control group, the model group showed elevated serum levels of ALT and AST, swelling of liver cells and infiltration of numerous inflammatory cells in liver tissue. The levels of TNF-α, MCP-1 and IL-6 in liver tissue, apoptosis rate of liver cells, and expression levels of p-JAK2 and p-STAT3 proteins were increased (P<0.05). Compared with the model group, serum levels of ALT and AST were reduced in the suf low-dose group and the suf high-dose group, and pathological damages of liver tissue were improved. The contents of TNF-α, MCP-1 and IL-6 in liver tissue, the apoptosis rate of liver cells, and the expression levels of p-JAK2 and p-STAT3 proteins were reduced (P<0.05). Moreover, changes in above indicators were significantly higher in the suf high dose group of suf than those in the suf low dose group（P<0.05）, and there was no significant difference compared with the imipenem group. Kumamycin inhibited the improvement effect of high-dose suf on liver injury in rats with burn sepsis （P>0.05）. Conclusion Sufentanil may improve liver injury in burn-induced sepsis rats by inhibiting the JAK2/STAT3 signaling pathway.

Key words: burns, sepsis, Sufentanil, Janus kinase 2, STAT3 transcription factor, inflammation, apoptosis

CLC Number:

R631

Figures/Tables 6

References 22

[1]	STANOJCIC M, VINAIK R, ABDULLAHI A, et al. NLRP3 knockout enhances immune infiltration and inflammatory responses and improves survival in a burn sepsis model[J]. Immunology, 2022, 165(1):195-205. doi:10.1111/imm.13427.
[2]	SUN J, ZHANG J, WANG X, et al. Gut-liver crosstalk in sepsis-induced liver injury[J]. Crit Care, 2020, 24(1):614-621. doi:10.1186/s13054-020-03327-1.
[3]	WANG Z, DU X, YU D, et al. Sufentanil alleviates cerebral ischemia-reperfusion injury by inhibiting inflammation and protecting the blood-brain barrier in rats[J]. Eur J Histochem, 2022, 66(1):3328-3336. doi:10.4081/ejh.2022.3328.
[4]	HU Q, WANG Q, HAN C, et al. Sufentanil attenuates inflammation and oxidative stress in sepsis-induced acute lung injury by downregulating KNG1 expression[J]. Mol Med Rep, 2020, 22(5):4298-4306. doi:10.3892/mmr.2020.11526.
[5]	YUAN F H, CHEN L, ZHAO Y, et al. MicroRNA-30a inhibits the liver cell proliferation and promotes cell apoptosis through the JAK/STAT signaling pathway by targeting SOCS-1 in rats with sepsis[J]. J Cell Physiol, 2019, 234(10):17839-17853. doi:10.1002/jcp.28410.
[6]	邓春, 刘睿, 刘进言, 等. 烧伤脓毒症大鼠血清培养巨噬细胞中Nrf2的表达[J]. 中国现代医学杂志, 2012, 22(35):32-37.
	DENG C, LIU R, LIU J Y, et al. Expression of Nrf2 in macrophages cultured with serum from burn sepsis rats[J]. Chin J Modern Med, 2012, 22(35):32-37.
[7]	潘毅, 陈军喜, 闫智杰, 等. 白术内酯Ⅲ调节AMPK/SIRT1/NF-κB信号通路对脓毒症大鼠肝损伤的影响[J]. 实用医学杂志, 2023, 39(7):827-832.
	PAN Y, CHEN J X, YAN Z J, et al. The effect of Atractylodes macrocephala ⅡI regulating the AMPK/SIRT1/NF-κB signaling pathway on liver injury in septic rats[J]. J Prac Med, 2023, 39(7):827-832. doi:10.3969/j.issn.1006-5725.2023.07.006.
[8]	陈菲, 陈霞, 黄财城. 星形胶质细胞外泌体对癫痫大鼠小胶质细胞活化及JAK2/STAT3通路的影响[J]. 卒中与神经疾病, 2022, 29(3):267-273,280.
	CHEN F, CHEN X, HUANG C C. Effects of astrocyte exosomes on microglial cell activation and JAK2/STAT3 pathway in epileptic rats[J]. Stroke and Neurol, 2022, 29(3):267-273,280. doi:10.3969/j.issn.1007-0478.2022.03.015.
[9]	LI Z, LIU T, FENG Y, et al. PPARγ alleviates sepsis-induced liver injury by inhibiting hepatocyte pyroptosis via inhibition of the ROS/TXNIP/NLRP3 signaling pathway[J]. Oxid Med Cell Longev, 2022, 2022(1):1269747-1269761. doi:10.1155/2022/1269747.
[10]	王志华, 代雪曼, 段红年, 等. 虫草素对脓毒症幼鼠急性肝损伤的改善作用[J]. 西北药学杂志, 2023, 38(2):69-74.
	WANG Z H, DAI X M, DUAN H N, et al. The improvement effect of cordycepin on acute liver injury in young rats with sepsis[J]. Northwest Pharm J, 2023, 38(2):69-74. doi:10.3969/j.issn.1004-2407.2023.02.012.
[11]	王慧, 张鑫, 薛乾隆, 等. 基于肝脏特异性PPARγ敲除小鼠研究沙棘多糖减轻脓毒症诱导肝损伤的作用及机制[J]. 中国免疫学杂志, 2022, 38(7):789-794.
	WANG H, ZHANG X, XUE Q L, et al. Study on the effect and mechanism of sea buckthorn polysaccharides in alleviating sepsis induced liver injury based on liver specific PPARγ knockout mice[J]. Chin J Immunol, 2022, 38(7):789-794. doi:10.3969/j.issn.1000-484X.2022.07.004.
[12]	卓玉珍, 杨磊, 鹿燕敏, 等. 凉血活血方通过抑制NLRP3炎性小体活化保护脓毒症急性肺损伤小鼠的实验研究[J]. 中国中西医结合外科杂志, 2022, 28(2):173-178.
	ZHUO Y Z, YANG L, LU Y M, et al. Experimental study of liangxue huoxue decoction ameliorates sepsis-induced ALI in mice by inhibiting NLRP 3 Inflammasome[J]. 2022, 28(2):173-178. doi:10.3969/j.issn.1007-6948.2022.02.005.
[13]	LIAN Y H, FANG J, ZHOU H D, et al. Sufentanil preconditioning protects against hepatic ischemia-reperfusion injury by suppressing inflammation[J]. Med Sci Monit, 2019, 25(1):2265-2273. doi:10.12659/MSM.913145.
[14]	ZHOU L, YANG X, SHU S, et al. Sufentanil protects the liver from ischemia/reperfusion-induced inflammation and apoptosis by inhibiting ATF4-induced TP53BP2 expression[J]. Inflammation, 2021, 44(3):1160-1174. doi:10.1007/s10753-020-01410-x.
[15]	马祥倜, 殷姜文, 武园园, 等. 舒芬太尼减轻大鼠肝缺血再灌注损伤的机制研究[J]. 天津医药, 2022, 50(12):1282-1286.
	MA X T, YIN J W, WU Y Y, et al. Mechanism of sufentanil in alleviating liver ischemia-reperfusion injury in rats[J]. Tianjin Med J, 2022, 50(12):1282-1286. doi:10.11958/20220293.
[16]	陈金梦, 徐杰, 路坤, 等. 地塞米松磷酸钠联合亚胺培南及替加环素治疗脓毒症的疗效及安全性分析[J]. 山东第一医科大学(山东省医学科学院)学报, 2023, 44(10):743-747.
	CHEN J M, XU J, LU K, et al. Efficacy and safety analysis of dexamethasone sodium phosphate combined with imipenem and tigecycline in the treatment of sepsis[J]. J Shandong First Med Univ(Shandong Acade of Med Sci), 2023, 44(10):743-747. doi:10.3969/j.issn.2097-0005.2023.10.005.
[17]	AZAWI H, MOSHOLT S, FODE M. Unilateral ultrasound-guided transversus abdominis plane block after nephrectomy;postoperative pain and use of opioids[J]. Nephrourol Mon, 2016, 8(2):e35356. doi: 10.5812/numonthly.35356.
[18]	HE X, KANG K, PAN D, et al. FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway[J]. Int J Mol Med, 2022, 49(5):67-78. doi:10.3892/ijmm.2022.5123.
[19]	SUN M, ZHAO X, LI X, et al. Aerobic exercise ameliorates liver injury in Db/Db mice by attenuating oxidative stress,apoptosis and inflammation through the Nrf2 and JAK2/STAT3 signalling pathways[J]. J Inflamm Res, 2023, 16(1):4805-4819. doi:10.2147/JIR.S426581.
[20]	HE Z, LIU J, LIU Y. Daphnetin attenuates intestinal inflammation,oxidative stress,and apoptosis in ulcerative colitis via inhibiting REG3A-dependent JAK2/STAT3 signaling pathway[J]. Environ Toxicol, 2023, 38(9):2132-2142. doi:10.1002/tox.23837.
[21]	XU Y, ZHANG D, YANG H, et al. Hepatoprotective effect of genistein against dimethylnitrosamine-induced liver fibrosis in rats by regulating macrophage functional properties and inhibiting the JAK2/STAT3/SOCS3 signaling pathway[J]. Front Biosci(Landmark Ed), 2021, 26(12):1572-1584. doi:10.52586/5050.
[22]	MA Z, PENG L, SHENG Y, et al. Anti-inflammatory effect of columbianadin against d-galactose-induced liver injury in vivo via the JAK2/STAT3 and JAK2/p38/NF-κB pathways[J]. Pharmaceuticals(Basel), 2024, 17(3):378-391. doi:10.3390/ph17030378.

组别	ALT	AST
对照组	66.36±4.58	130.24±8.63
模型组	303.23±15.58^a	412.23±23.34^a
suf低剂量组	266.65±12.36^b	343.66±15.52^b
suf高剂量组	108.83±5.12^bc	175.54±8.33^bc
亚胺培南组	110.22±5.34^bc	180.03±8.55^bc
suf高剂量+库马霉素组	189.95±7.37^d	295.54±12.27^d
F	1 245.098^＊	770.683^＊

组别	ALT	AST
对照组	66.36±4.58	130.24±8.63
模型组	303.23±15.58^a	412.23±23.34^a
suf低剂量组	266.65±12.36^b	343.66±15.52^b
suf高剂量组	108.83±5.12^bc	175.54±8.33^bc
亚胺培南组	110.22±5.34^bc	180.03±8.55^bc
suf高剂量+库马霉素组	189.95±7.37^d	295.54±12.27^d
F	1 245.098^＊	770.683^＊

组别	TNF-α	MCP-1	IL-6
对照组	60.23±4.12	82.25±3.79	36.68±1.72
模型组	231.15±10.55^a	245.56±10.11^a	121.22±5.33^a
suf低剂量组	185.57±8.44^b	203.34±9.88^b	102.26±4.75^b
suf高剂量组	106.67±5.03^bc	121.23±5.78^bc	59.96±2.18^bc
亚胺培南组	109.44±5.26^bc	125.56±6.64^bc	61.76±2.95^bc
suf高剂量+ 库马霉素组	165.53±7.21^d	173.59±6.88^d	95.23±4.15^d
F	458.472^＊	384.524^＊	428.566^＊

组别	TNF-α	MCP-1	IL-6
对照组	60.23±4.12	82.25±3.79	36.68±1.72
模型组	231.15±10.55^a	245.56±10.11^a	121.22±5.33^a
suf低剂量组	185.57±8.44^b	203.34±9.88^b	102.26±4.75^b
suf高剂量组	106.67±5.03^bc	121.23±5.78^bc	59.96±2.18^bc
亚胺培南组	109.44±5.26^bc	125.56±6.64^bc	61.76±2.95^bc
suf高剂量+ 库马霉素组	165.53±7.21^d	173.59±6.88^d	95.23±4.15^d
F	458.472^＊	384.524^＊	428.566^＊

组别	p-JAK2/JAK2	p-STAT3/STAT3
对照组	0.36±0.02	0.15±0.01
模型组	0.87±0.08^a	0.73±0.07^a
suf低剂量组	0.69±0.06^b	0.53±0.05^b
suf高剂量组	0.49±0.04^bc	0.28±0.02^bc
亚胺培南组	0.51±0.05^bc	0.29±0.02^bc
suf高剂量+库马霉素组	0.66±0.05^d	0.41±0.04^d
F	68.753^＊	156.279^＊