BOC2抑制N-甲酰肽/甲酰肽受体信号通路减轻SAP炎症损伤的机制研究

doi:10.11958/20240774

天津医药 ›› 2024, Vol. 52 ›› Issue (10): 1031-1037.doi: 10.11958/20240774

BOC2抑制N-甲酰肽/甲酰肽受体信号通路减轻SAP炎症损伤的机制研究

张桂贤¹(), 刘大卫¹, 李文畅¹, 蔡隽¹, 宗文辉¹, 刘洪斌², 赵秀梅¹^,^△()

1 天津市医药科学研究所（邮编300020）
2 天津市和平区卫生健康委员会

收稿日期:2024-06-14 修回日期:2024-08-27 出版日期:2024-10-15 发布日期:2024-10-14
通讯作者: △ E-mail：zxmmlg@163.com
作者简介:张桂贤（1981），女，副研究员，主要从事急、慢性胰腺炎药理学方面研究。E-mail：zhangguixian2007@aliyun.com
基金资助:
国家自然科学基金资助项目(82304797);天津市科学技术局重点项目(21JCZDJC01220);天津市科学技术局面上项目(21JCYBJC01680);天津市科学技术局青年项目(23JCQNJC00600);天津市卫生健康科技项目(TJWJ2022MS049);天津市卫生健康科技项目(TJWJ2024MS047)

Mechanism study of BOC2 alleviating SAP inflammatory damage by inhibiting N-formyl peptide/formyl peptide receptor pathway

ZHANG Guixian¹(), LIU Dawei¹, LI Wenchang¹, CAI Jun¹, ZONG Wenhui¹, LIU Hongbin², ZHAO Xiumei¹^,^△()

1 Tianjin Institute of Medical & Pharmaceutical Sciences, Tianjin 300020, China
2 Health Commission of Heping District, Tianjin

Received:2024-06-14 Revised:2024-08-27 Published:2024-10-15 Online:2024-10-14
Contact: △ E-mail：zxmmlg@163.com

张桂贤, 刘大卫, 李文畅, 蔡隽, 宗文辉, 刘洪斌, 赵秀梅. BOC2抑制N-甲酰肽/甲酰肽受体信号通路减轻SAP炎症损伤的机制研究[J]. 天津医药, 2024, 52(10): 1031-1037.

ZHANG Guixian, LIU Dawei, LI Wenchang, CAI Jun, ZONG Wenhui, LIU Hongbin, ZHAO Xiumei. Mechanism study of BOC2 alleviating SAP inflammatory damage by inhibiting N-formyl peptide/formyl peptide receptor pathway[J]. Tianjin Medical Journal, 2024, 52(10): 1031-1037.

摘要/Abstract

摘要：

目的观察BOC-Phe-Leu-Phe-Leu-Phe（BOC2）对重症急性胰腺炎（SAP）大鼠血中6种线粒体N-甲酰肽（NFPs）及胰腺组织中2种甲酰肽受体（FPRs）表达的影响，探讨其减轻SAP炎症损伤的机制。方法将40只雄性SD大鼠随机分为4组：假手术组，模型组，BOC2低、高剂量组（分别为0.1、0.2 mg/kg），每组10只。后3组以胆胰管逆行注射5%牛磺胆酸钠（50 mg/kg）制备SAP模型。造模结束后0.5 h腹腔注射相应剂量药物，4 h取材。苏木精-伊红染色观察胰腺病理改变；蛋白免疫印迹法检测血浆中NFPs的表达；免疫组化法检测胰腺FPRs表达；酶联免疫吸附试验检测血浆中白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNF）-α水平；实时荧光定量聚合酶链反应检测胰腺局部组织炎性因子的表达。结果与模型组比较，BOC2低、高剂量组胰腺出血、腺泡细胞坏死、炎性细胞浸润、水肿等病理现象均改善；胰腺病理评分，血浆线粒体NADH-泛素氧化还原酶链（MT-ND）1、MT-ND2、MT-ND3、MT-ND5、MT-ND6表达，胰腺FPRs表达，血浆及胰腺组织中3种炎性因子表达均下降（P<0.05）。结论 BOC2可通过拮抗线粒体NFPs/FPRs信号通路减少炎性因子产生，减轻SAP炎症损伤。

关键词: 胰腺炎, N-甲酰甲硫氨酰亮氨酰-苯丙氨酸, 受体, 甲酰肽, 线粒体, BOC2, 重症急性胰腺炎

Abstract:

Objective To observe the effect of BOC-Phe-Leu-Phe-Leu-Phe (BOC2) on the expression of six types of mitochondrial N-formyl peptides (NFPs) in blood and two formyl peptide receptors (FPRs) in pancreatic tissue of rats with severe acute pancreatitis (SAP), and to explore its mechanism of alleviating inflammatory damage of SAP. Methods Forty male SD rats were randomly divided into four groups: the sham group, the SAP model group, the BOC2 low-dose and the BOC2 high-dose group (0.1 and 0.2 mg/kg), with 10 animals in each group. The SAP model was prepared by retrograde injection of 5% sodium taurocholate (50 mg/kg) into biliary and pancreatic ducts in the last 3 groups. BOC2 was intraperitoneally injected at 0.5 hours after SAP modeling, and samples were taken 4 hours after modeling. HE staining was used to observe pathological changes in pancreas. Western blot assay was used to detect the expression of NFPs in plasma. IHC staining was used to detect the expression of FPRs in pancreatic tissue. ELISA was used to detect interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α levels in plasma. qPCR was used to detect expression levels of inflammatory factors in local pancreatic tissue. Results Compared with the model group, the BOC2 high-dose group and the BOC2 low- dose group showed improvement in pathological phenomena, such as pancreatic bleeding, acinar cell necrosis, inflammatory cell infiltration and edema. The pancreatic injury score, pancreatic FPRs expression, plasma MT-ND1, MT-ND2, MT-ND3, MT-ND5, MT-ND6 expression, as well as expression levels of three inflammatory factors in plasma and local pancreatic tissue, were significantly reduced (P<0.05). Conclusion BOC2 can reduce the production of inflammatory factors and alleviate SAP inflammatory damage by antagonizing mitochondrial NFPs/FPRs signaling pathway.

Key words: pancreatitis, N-formylmethionine leucyl-phenylalanine, receptors, formyl peptide, mitochondria, BOC2, severe acute pancreatitis

中图分类号:

R576.1

图/表 10

参考文献 22

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基因	引物序列（5′→3′）	产物大小/bp
IL-1β	上游：GCAGCTTTCGACAGTGAGGA	98
	下游：TCTGGACAGCCCAAGTCAAG	98
IL-6	上游：CACTTCACAAGTCGGAGGCT	114
	下游：TCTGACAGTGCATCATCGCT	114
TNF-α	上游：CTCGAGTGACAAGCCCGTAG	187
	下游：GCAGCCTTGTCCCTTGAAGA	187
GAPDH	上游：GACATGCCGCCTGGAGAAAC	92
	下游：AGCCCAGGATGCCCTTTAGT	92

基因	引物序列（5′→3′）	产物大小/bp
IL-1β	上游：GCAGCTTTCGACAGTGAGGA	98
	下游：TCTGGACAGCCCAAGTCAAG	98
IL-6	上游：CACTTCACAAGTCGGAGGCT	114
	下游：TCTGACAGTGCATCATCGCT	114
TNF-α	上游：CTCGAGTGACAAGCCCGTAG	187
	下游：GCAGCCTTGTCCCTTGAAGA	187
GAPDH	上游：GACATGCCGCCTGGAGAAAC	92
	下游：AGCCCAGGATGCCCTTTAGT	92

组别	腹水量/mL	胰腺干湿质量比/（g/g）
假手术组	0	0.51±0.09
模型组	7.89±0.53^a	0.22±0.05^a
BOC2低剂量组	5.39±0.59^ab	0.36±0.06^ab
BOC2高剂量组	3.80±0.46^abc	0.41±0.06^ab
F	520.973^＊＊	31.964^＊＊

组别	腹水量/mL	胰腺干湿质量比/（g/g）
假手术组	0	0.51±0.09
模型组	7.89±0.53^a	0.22±0.05^a
BOC2低剂量组	5.39±0.59^ab	0.36±0.06^ab
BOC2高剂量组	3.80±0.46^abc	0.41±0.06^ab
F	520.973^＊＊	31.964^＊＊

组别	病理评分/分	CD11b阳性细胞数/（个/视野）
假手术组	0	0
模型组	13.32±0.93^a	90.50±6.35^a
BOC2低剂量组	10.27±0.89^ab	47.60±2.95^ab
BOC2高剂量组	5.98±0.75^abc	22.40±2.72^abc
F	601.452^＊＊	1 068.648^＊＊

BOC2抑制N-甲酰肽/甲酰肽受体信号通路减轻SAP炎症损伤的机制研究

Mechanism study of BOC2 alleviating SAP inflammatory damage by inhibiting N-formyl peptide/formyl peptide receptor pathway

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参考文献 22

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组别	MT-ND1	MT-ND2	MT-ND3
假手术组	0.06±0.01	0.13±0.01	0.08±0.01
模型组	0.72±0.02^a	0.64±0.02^a	0.38±0.02^a
BOC2低剂量组	0.34±0.02^ab	0.08±0.01^ab	0.22±0.04^ab
BOC2高剂量组	0.25±0.05^abc	0.09±0.01^ab	0.09±0.01^bc
F	297.968^＊＊	1 952.960^＊＊	100.922^＊＊
组别	MT-ND4	MT-ND5	MT-ND6
假手术组	0.90±0.08	0.27±0.06	0.08±0.01
模型组	0.97±0.09	0.87±0.07^a	0.81±0.08^a
BOC2低剂量组	0.95±0.08	0.46±0.03^ab	0.53±0.02^ab
BOC2高剂量组	0.91±0.08	0.40±0.03^ab	0.29±0.07^abc
F	0.461	85.969^＊＊	98.705^＊＊

组别	FPR1	FPR2
假手术组	64.71±5.37	1.84±0.77
模型组	158.04±8.15^a	90.19±6.47^a
BOC2低剂量组	121.24±10.53^ab	59.72±4.22^ab
BOC2高剂量组	57.85±3.08^abc	20.92±2.53^abc
F	423.016^＊＊	937.290^＊＊

组别	IL-1β	IL-6	TNF-α
假手术组	3.92±0.49	19.48±2.34	15.52±2.42
模型组	14.35±2.81^a	83.36±7.80^a	53.99±5.25^a
BOC2低剂量组	10.22±2.34^ab	62.95±10.10^ab	47.87±5.54^ab
BOC2高剂量组	8.33±1.51^abc	47.98±4.45^abc	35.38±4.06^abc
F	46.966^＊＊	153.786^＊＊	143.213^＊＊

组别	IL-1β	IL-6	TNF-α
假手术组	1.00±0.05	1.00±0.09	1.00±0.06
模型组	8.01±0.66^a	49.72±5.11^a	39.98±3.01^a
BOC2低剂量组	4.01±0.36^ab	18.11±1.80^ab	9.88±1.03^ab
BOC2高剂量组	2.11±0.25^abc	11.45±1.24^abc	4.67±0.77^abc
F	483.861^＊＊	456.466^＊＊	942.534^＊＊

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