脐带间充质干细胞外泌体对慢性阻塞性肺疾病大鼠肺部炎症的作用机制探讨

doi:10.11958/20230708

天津医药 ›› 2023, Vol. 51 ›› Issue (12): 1326-1331.doi: 10.11958/20230708

脐带间充质干细胞外泌体对慢性阻塞性肺疾病大鼠肺部炎症的作用机制探讨

聂进¹(), 刘代顺², 张建勇¹, 刘楚¹, 周亮¹^,^△()

1.遵义医科大学附属医院呼吸与危重症医学科（邮编563000）
2.遵义医科大学

收稿日期:2023-05-16 修回日期:2023-06-15 出版日期:2023-12-15 发布日期:2023-12-22
通讯作者: ^△ E-mail：zhouliang1115@163.com
作者简介:聂进（1988），男，副主任医师，主要从事慢性阻塞性肺疾病与哮喘的临床与基础方面研究。E-mail：864843778@qq.com
基金资助:
国家自然科学基金资助项目(82060010);贵州省科技计划项目(黔科合支撑[2020]4Y162);遵义市科技计划项目(遵市科合HZ字（2019）72号)

The effect and mechanism of exosomes from umbilical cord mesenchymal stem cells on pulmonary inflammation in chronic obstructive pulmonary disease rats

NIE Jin¹(), LIU Daishun², ZHANG Jianyong¹, LIU Chu¹, ZHOU Liang¹^,^△()

1. Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
2. Zunyi Medical University

Received:2023-05-16 Revised:2023-06-15 Published:2023-12-15 Online:2023-12-22
Contact: ^△ E-mail：zhouliang1115@163.com

聂进, 刘代顺, 张建勇, 刘楚, 周亮. 脐带间充质干细胞外泌体对慢性阻塞性肺疾病大鼠肺部炎症的作用机制探讨[J]. 天津医药, 2023, 51(12): 1326-1331.

NIE Jin, LIU Daishun, ZHANG Jianyong, LIU Chu, ZHOU Liang. The effect and mechanism of exosomes from umbilical cord mesenchymal stem cells on pulmonary inflammation in chronic obstructive pulmonary disease rats[J]. Tianjin Medical Journal, 2023, 51(12): 1326-1331.

摘要/Abstract

摘要：

目的探讨人脐带间充质干细胞外泌体对慢性阻塞性肺疾病（COPD）大鼠肺部炎症的作用及机制。方法将18只SD雄性大鼠随机分为Control组、COPD组、COPD+Exo组，每组6只；COPD组、COPD+Exo组大鼠采用香烟烟熏＋脂多糖（LPS）雾化吸入的方法建立COPD大鼠模型，COPD+Exo组经尾静脉注射100 μL人脐带间充质干细胞外泌体稀释液（含2×10⁷个外泌体），Control组和COPD组注射等量的磷酸盐缓冲液。干预后1周处死大鼠，收集外周血、肺泡灌洗液（BALF）和肺组织。HE染色观察大鼠肺组织病理改变，全自动血细胞分析仪计数外周血炎性细胞数目，酶联免疫吸附试验（ELISA）检测BALF和血清中白细胞介素（IL）-1β、IL-6、肿瘤坏死因子（TNF）-α水平，qRT-PCR检测肺组织中IL-1β、IL-6、TNF-α mRNA的表达，Western blot检测肺组织中Toll样受体4（TLR4）、磷酸化核因子κB（p-NF-κB p65）和核因子抑制蛋白（IκBα）的表达。结果 Control组大鼠肺泡结构完整、形态规则；COPD组大鼠肺泡结构紊乱，部分肺泡不规则扩张、融合成肺大疱甚至破裂，肺泡间隔增宽且可见较多炎性细胞浸润。与COPD组比较，COPD+Exo组大鼠肺泡结构较完整，肺泡间隔炎性细胞浸润减少，外周血中炎性细胞减少，BALF、血清及肺组织中IL-1β、IL-6、TNF-α表达水平降低（P<0.05）；肺组织TLR4、IκBα蛋白表达水平升高，p-NF-κB p65表达水平降低（P<0.05）。结论人脐带间充质干细胞外泌体通过调控TLR4/核因子κB（NF-κB）信号通路减轻COPD大鼠的肺部炎症，从而发挥肺保护作用。

关键词: 肺疾病, 慢性阻塞性, 间质干细胞, 外泌体, 炎症, Toll样受体4, NF-κB

Abstract:

Objective To investigate the effect and mechanism of human umbilical cord mesenchymal stem cell exosomes (Exo) on pulmonary inflammation in chronic obstructive pulmonary disease (COPD) rats. Methods A total of 18 male SD rats were randomly divided into the control group, the COPD group and the COPD + Exo group with 6 rats in each group. COPD rat model was estalished by giving cigarette smoke and lipopolysaccharide (LPS) inhalation in the COPD group and the COPD + Exo group. Rats in the COPD + Exo group were injected with 100 μL of human umbilical mesenchymal stem cell exosome diluent (containing 2 × 10⁷ exosomes) via tail vein. The control group and the COPD group were given equal amounts of phosphate buffered solution. One week after intervention, rats were killed and the peripheral blood, alveolar lavage fluid (BALF) and lung tissue samples were collected. The histopathological changes in lung tissue of each group were observed using Hematoxylin and Eosin (HE) staining. The number of inflammatory cells in peripheral blood was counted by fully automated hematology analyzer. The serum levels of IL-1β, IL-6 and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). The expression levels of IL-1β, IL-6 and TNF-α mRNA in lung tissue were detected by qRT-PCR. Western blot assay was used to detect the protein expression levels of TLR4, p-NF-κB p65 and IκBα in lung tissue. Results In the control group, the structure of pulmonary alveolus was intact and regular, while in the COPD group, the structure of alveolus was disordered, some alveolus expanded irregularly, fused into bullae and even ruptured. The alveolar septa were widened and filled with a large number of inflammatory cells. Compared with the COPD group, the COPD + Exo group had more intact alveolar structure and less infiltration of inflammatory cells in the alveolar septum. The inflammatory cells in peripheral blood decreased. The expression levels of IL-1β, IL-6 and TNF-α in serum and lung tissue were decreased (P < 0.05). The expression of TLR4 and IκBα protein in lung tissue were increased, while the expression of p-NF-κb p65 protein decreased (P < 0.05). Conclusion Human umbilical cord mesenchymal stem cell exosomes can alleviate pulmonary inflammation in COPD rats by modulating TLR4/NF-κB signaling pathway, thereby playing a lung-protective effect.

Key words: pulmonary disease, chronic obstructive, mesenchymal stem cells, exosomes, inflammation, Toll-like receptor 4, NF-kappa B

中图分类号:

R563

图/表 8

参考文献 37

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基因名称	引物（5′→3′）	产物大小/bp
IL-1β	上游：GCACAGTTCCCCAACTGGTA	109
	下游：ACACGGGTTCCATGGTGAAG	109
IL-6	上游：CTCTCCGCAAGAGACTTCCA	92
	下游：TCTCCTCTCCGGACTTGTGAA	92
TNF-α	上游：CCACGCTCTTCTGTCTACTG	145
	下游：GCTACGGGCTTGTCACTC	145
GAPDH	上游：CAGGAGGCATTGCTGATGAT	138
	下游：GAAGGCTGGGGCTCATTT	138

基因名称	引物（5′→3′）	产物大小/bp
IL-1β	上游：GCACAGTTCCCCAACTGGTA	109
	下游：ACACGGGTTCCATGGTGAAG	109
IL-6	上游：CTCTCCGCAAGAGACTTCCA	92
	下游：TCTCCTCTCCGGACTTGTGAA	92
TNF-α	上游：CCACGCTCTTCTGTCTACTG	145
	下游：GCTACGGGCTTGTCACTC	145
GAPDH	上游：CAGGAGGCATTGCTGATGAT	138
	下游：GAAGGCTGGGGCTCATTT	138

组别	WBC	NEU	MON	LYM
Control组	0.48±0.07	0.77±0.24	0.03±0.00	0.25±0.00
COPD组	3.10±0.27^a	2.01±0.20^a	0.15±0.01^a	2.63±0.19^a
COPD+Exo组	1.59±0.55^ab	0.35±0.15^b	0.06±0.02^b	1.20±0.47^ab
F	27.197^＊	39.738^＊	51.100^＊	33.116^＊

组别	WBC	NEU	MON	LYM
Control组	0.48±0.07	0.77±0.24	0.03±0.00	0.25±0.00
COPD组	3.10±0.27^a	2.01±0.20^a	0.15±0.01^a	2.63±0.19^a
COPD+Exo组	1.59±0.55^ab	0.35±0.15^b	0.06±0.02^b	1.20±0.47^ab
F	27.197^＊	39.738^＊	51.100^＊	33.116^＊

组别	BALF
组别	IL-1β		IL-6		TNF-α
Control组	55.05±11.49		71.58±8.77		290.51±28.28
COPD组	85.23±13.44^a		104.16±7.92^a		513.71±59.00^a
COPD+Exo组	61.02±6.42^b		84.66±12.84^b		406.74±52.32^ab
F	10.827^＊		13.234^＊		26.634^＊
组别		血清
组别		IL-1β		IL-6		TNF-α
Control组	64.02±6.84		72.00±4.45		309.18±5.25
COPD组	88.54±8.44^a		90.99±0.97^a		483.74±9.74^a
COPD+Exo组	73.22±4.92^b		73.41±7.93^b		364.64±2.40^b
F	9.708^＊		8.036^＊		11.869^＊

脐带间充质干细胞外泌体对慢性阻塞性肺疾病大鼠肺部炎症的作用机制探讨

The effect and mechanism of exosomes from umbilical cord mesenchymal stem cells on pulmonary inflammation in chronic obstructive pulmonary disease rats

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组别	IL-1β	IL-6	TNF-α
Control组	1.00±0.02	1.00±0.10	1.02±0.18
COPD组	3.10±0.31^a	6.58±1.03^a	5.17±0.35^a
COPD+Exo组	1.56±0.12^ab	1.65±0.02^ab	2.52±0.31^ab
F	62.411^＊	51.588^＊	104.294^＊

组别	TLR4	IκBα	p-NF-κB p65
Control组	0.73±0.01	0.50±0.03	0.31±0.02
COPD组	0.30±0.00^a	0.23±0.01^a	0.92±0.10^a
COPD+Exo组	0.56±0.02^ab	0.46±0.02^b	0.58±0.06^ab
F	824.637^＊	130.246^＊	59.341^＊

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