Study on the mechanism of CD147 in regulating airway remodeling in asthma rats based on Akt-FoxO3-NF-κB signaling axis

doi:10.3760/cma.j.cn441417-20241202-09015

Abstract

Abstract:

Objective　To investigate the mechanism of CD147 in regulating airway remodeling in asthma rats based on the protein kinase B/forkhead box protein O3/nuclear factor-κB (Akt-FoxO3-NF-κB) signaling axis. Methods　Seventy SPF-grade SD rats were selected, aged 7-8 weeks, weight (200±20) g. Control group, model group, IgG group, anti-CD147 group and anti-CD147+SC-79 group, 12 rats in each group. In the anti-CD147+SC-79 group, 7 mg/kg of CD147 antibody was intraperitoneally injected and 0.04 μg/kg of SC-79 was injected through the tail vein. In the anti-CD147 group, 7 mg/kg of CD147 antibody was intraperitoneally injected and the same amount of normal saline was injected through the tail vein. In the IgG group, 7 mg/kg of IgG was intraperitoneally injected and the same amount of normal saline was injected through the tail vein. Both the control group and the model group were intraperitoneally injected and tail vein injected with the same amount of normal saline. Once a day, with continuous intervention for 4 weeks. The airway resistance (nebulized inhalation of different concentrations of acetylcholine), the number of inflammatory cells, the levels of inflammatory factors, the pathological changes of lung tissue, the expressions of transforming growth factor -β1 (TGF-β1) and α -smooth muscle actin (α-SMA), and the expressions of Akt-FoxO3-NF-κB signal axis-related proteins were compared 24 hours after the last administration in each group. One-way analysis of variance and SNK-q test were used for statistical analysis. Results　After aerosol inhalation of different concentrations of acetylcholine, the airway resistance of the model group was higher than that of the control group (P<0.05). The airway resistance of anti-CD147 group was lower than that of IgG group (P<0.05). The airway resistance of anti-CD147+SC-79 group was higher than that of anti-CD147 group (P<0.05). The numbers of macrophages, lymphocytes, neutrophils and eosinophils in the model group were higher than those in the control group (all P<0.05). The numbers of macrophages, lymphocytes, neutrophils and eosinophils in anti-CD147 group were lower than those in IgG group (all P<0.05). The numbers of macrophages, lymphocytes, neutrophils and eosinophils in anti-CD147+SC-79 group were higher than those in anti-CD147 group (all P<0.05). The levels of IL-4, IL-5 and IL-13 in the model group were higher than those in the control group (all P<0.05). The levels of IL-4, IL-5 and IL-13 in anti-CD147 group were lower than those in IgG group (all P<0.05). The levels of IL-4, IL-5 and IL-13 in anti-CD147+SC-79 group were higher than those in anti-CD147 group (all P<0.05). The expressions of TGF-β1 and α-SMA in the model group were higher than those in the control group (0.89±0.09 vs. 0.36±0.04, 0.80±0.09 vs. 0.27±0.03) (both P<0.05). The expressions of TGF-β1 and α-SMA in anti-CD147 group were lower than those in IgG group (0.47±0.05 vs. 0.85±0.09, 0.34±0.04 vs. 0.77±0.08) (both P<0.05). The expressions of TGF-β1 and α-SMA in anti-CD147+SC-79 group were higher than those in anti-CD147 group (0.80±0.09 vs. 0.47±0.05, 0.72±0.08 vs. 0.34±0.04) (both P<0.05). The expression of p-Akt/Akt, p-FoxO3a/FoxO3a, p-NF-κB p65/NF-κB p65 in model group were higher than those in the control group (0.93±0.10 vs. 0.44±0.05, 0.86±0.09 vs. 0.37±0.04, 0.76±0.08 vs. 0.33±0.04) (all P<0.05). The expression of p-Akt/Akt, p-FoxO3a/FoxO3a, p-NF-κB p65/NF-κB p65 in anti-CD147 group were lower than those in the IgG group (0.48±0.05 vs. 0.90±0.10, 0.41±0.05 vs. 0.82±0.09, 0.38±0.04 vs. 0.74±0.08) (all P<0.05). The expression of p-Akt/Akt, p-FoxO3a/FoxO3a, p-NF-κB p65/NF-κB p65 in anti-CD147+SC-79 group were higher than those in the anti-CD147 group (0.87±0.09 vs. 0.48±0.05, 0.79±0.08 vs. 0.41±0.05, 0.70±0.08 vs. 0.38±0.04) (all P<0.05). Conclusion　CD147 antibody can alleviate airway remodeling in asthma rats and is associated with inhibition of the Akt-FoxO3-NF-κB signaling axis.

Key words:

Asthma, , Protein kinase B/forkhead box protein O3/nuclear factor-κB signaling axis, , CD147, , Airway remodeling, 　Animal experiment

摘要：

目的　基于蛋白激酶B/叉头框蛋白O3/核转录因子-κB（Akt-FoxO3-NF-κB）信号轴探讨CD147调控哮喘大鼠气道重塑作用机制。方法　选取SPF级健康成年雄性SD大鼠70只，鼠龄7～8周，体重（200±20）g。对照组、模型组、IgG组、CD147抗体组、CD147抗体+SC-79组，每组12只大鼠。CD147抗体+SC-79组腹腔注射7 mg/kg CD147抗体，尾静脉注射0.04 μg/kg SC-79；CD147抗体组腹腔注射7 mg/kg CD147抗体，尾静脉注射等量生理盐水；IgG组腹腔注射7 mg/kg IgG，尾静脉注射等量生理盐水；对照组、模型组均腹腔注射及尾静脉注射等量生理盐水；1次/d，连续干预4周。比较各组末次给药24 h后气道阻力（雾化吸入不同浓度乙酰胆碱）、炎症细胞数目、炎症因子水平、肺组织病理变化、转化生长因子-β1（TGF-β1）和α-平滑肌肌动蛋白（α-SMA）表达、Akt-FoxO3-NF-κB信号轴相关蛋白表达。采用单因素方差分析、SNK-q检验进行统计学分析。结果　不同浓度乙酰胆碱雾化吸入后，模型组气道阻力均高于对照组（均P<0.05）；CD147抗体组气道阻力均低于IgG组（均P<0.05）；CD147抗体+SC-79组气道阻力均高于CD147抗体组（均P<0.05）。模型组巨噬细胞、淋巴细胞、中性粒细胞、嗜酸性粒细胞数目均高于对照组（均P<0.05）；CD147抗体组巨噬细胞、淋巴细胞、中性粒细胞、嗜酸性粒细胞数目均低于IgG组（均P<0.05）；CD147抗体+SC-79组巨噬细胞、淋巴细胞、中性粒细胞、嗜酸性粒细胞数目均高于CD147抗体组（均P<0.05）。模型组IL-4、IL-5、IL-13水平均高于对照组（均P<0.05）；CD147抗体组IL-4、IL-5、IL-13水平均低于IgG组（均P<0.05）；CD147抗体+SC-79组IL-4、IL-5、IL-13水平均高于CD147抗体组（均P<0.05）。模型组TGF-β1、α-SMA表达均高于对照组（0.89±0.09比0.36±0.04、0.80±0.09比0.27±0.03）（均P<0.05）；CD147抗体组TGF-β1、α-SMA表达均低于IgG组（0.47±0.05比0.85±0.09、0.34±0.04比0.77±0.08）（均P<0.05）；CD147抗体+SC-79组TGF-β1、α-SMA表达均高于CD147抗体组（0.80±0.09比0.47±0.05、0.72±0.08比0.34±0.04）（均P<0.05）。模型组p-Akt/Akt、p-FoxO3a/FoxO3a、p-NF-κB p65/NF-κB p65表达均高于对照组（0.93±0.10比0.44±0.05、0.86±0.09比0.37±0.04、0.76±0.08比0.33±0.04）（均P<0.05）；CD147抗体组p-Akt/Akt、p-FoxO3a/FoxO3a、p-NF-κB p65/NF-κB p65表达均低于IgG组（0.48±0.05比0.90±0.10、0.41±0.05比0.82±0.09、0.38±0.04比0.74±0.08）（均P<0.05）；CD147抗体+SC-79组p-Akt/Akt、p-FoxO3a/FoxO3a、p-NF-κB p65/NF-κB p65表达均高于CD147抗体组（0.87±0.09比0.48±0.05、0.79±0.08比0.41±0.05、0.70±0.08比0.38±0.04）（均P<0.05）。结论　CD147抗体可减轻哮喘大鼠气道重塑，与抑制Akt-FoxO3-NF-κB信号轴相关。

关键词:

哮喘, 蛋白激酶B/叉头框蛋白O3/核转录因子-κB信号轴, CD147, 气道重塑, 动物实验

Sang Yang, Han Xinpeng, Yan Yuling, Zhang Shaoyi.

Study on the mechanism of CD147 in regulating airway remodeling in asthma rats based on Akt-FoxO3-NF-κB signaling axis [J]. International Medicine and Health Guidance News, 2025, 31(9): 1482-1488.

桑杨韩新鹏闫育玲张少毅.

基于Akt-FoxO3-NF-κB信号轴研究CD147调控哮喘大鼠气道重塑作用机制 [J]. 国际医药卫生导报, 2025, 31(9): 1482-1488.

References

[1] Miller RL, Grayson MH, Strothman K. Advances in asthma: new understandings of asthma's natural history, risk factors, underlying mechanisms, and clinical management[J]. J Allergy Clin Immunol, 2021, 148(6):1430-1441. DOI: 10.1016/j.jaci.2021.10.001.

[2] Gans MD, Gavrilova T. Understanding the immunology of asthma: pathophysiology, biomarkers, and treatments for asthma endotypes[J]. Paediatr Respir Rev, 2020, 36:118-127. DOI: 10.1016/j.prrv.2019.08.002.

[3] Sharma S, Gerber AN, Kraft M, et al. Asthma pathogenesis: phenotypes, therapies, and gaps: summary of the aspen lung conference 2023[J]. Am J Respir Cell Mol Biol, 2024, 71(2):154-168. DOI: 10.1165/rcmb.2024-0082WS.

[4] Li Z, Cheng T, Guo Y, et al. CD147 induces asthmatic airway remodeling and activation of circulating fibrocytes in a mouse model of asthma[J]. Respir Res, 2024, 25(1):6. DOI: 10.1186/s12931-023-02646-5.

[5]宋思雨,丁露,李雅馨,等.基于网络药理学探讨补阳还五汤治疗特发性肺纤维化的生物学机制[J].中国老年学杂志,2022,42(12):2988-2994.DOI:10.3969/j.issn.1005-9202. 2022.12.040.

[6] Yan Y, Liu L, Dou Z, et al. Soufeng Yuchuan decoction mitigates the ovalbumin-induced lung damage in a rat model of asthma[J]. Biomed Pharmacother, 2020, 125:109933. DOI: 10.1016/j.biopha.2020.109933.

[7]胡冰,张艺森.基于Akt/ERK/NF-κB信号通路探究松果菊苷对缺氧性肺动脉高压新生大鼠肺血管重塑的影响[J].中草药,2022,53(23):7449-7454.DOI:10.7501/j.issn. 0253-2670.2022.23.015.

[8]王苗庆,张明阳,陈若,等.CD147抗体对肺间质纤维化小鼠体内Treg细胞的影响[J].空军军医大学学报,2022,43(6):715-719.DOI:10.13276/j.issn.2097-1656.2022.06.011.

[9]刘健.支气管哮喘气道重塑机制的研究进展[J].中国现代医学杂志,2022,32(12):51-54.DOI:10.3969/j.issn. 1005-8982.2022.12.009.

[10] Guindolet D, Gabison EE. Role of CD147 (EMMPRIN/basigin) in tissue remodeling[J]. Anat Rec (Hoboken), 2020, 303(6):1584-1589. DOI: 10.1002/ar.24089.

[11] Chuliá-Peris L, Carreres-Rey C, Gabasa M, et al. Matrix metalloproteinases and their inhibitors in pulmonary fibrosis: EMMPRIN/CD147 comes into play[J]. Int J Mol Sci, 2022, 23(13):6894. DOI: 10.3390/ijms23136894.

[12] Wu J, Chen L, Qin C, et al. CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis[J]. Signal Transduct Target Ther, 2022, 7(1):382. DOI: 10.1038/s41392-022-01230-5.

[13] Yu Q, Yang D, Chen X, et al. CD147 increases mucus secretion induced by cigarette smoke in COPD[J]. BMC Pulm Med, 2019, 19(1):29. DOI: 10.1186/s12890-019-0791-0.

[14]韩勃,左俊丽,乔廉洁.花青素调控CD147/MMP-9通路改善哮喘模型小鼠气道炎症的作用研究[J].国际医药卫生导报,2024,30(22):3828-3833.DOI:10.3760/cma.j.issn.1007-1245.2024.22.028.

[15]雷俊.牛蒡子苷元抑制TLR4/TRAF6/NF-κB信号通路对哮喘模型大鼠气道重塑和Th1/Th2免疫平衡的影响[J].免疫学杂志,2023,39(1):12-20.DOI:10.13431/j.cnki.immunol.j.20230002.

[16] Scott G, Asrat S, Allinne J, et al. IL-4 and IL-13, not eosinophils, drive type 2 airway inflammation, remodeling and lung function decline[J]. Cytokine, 2023, 162:156091. DOI: 10.1016/j.cyto.2022.156091.

[17] Jiang T, Zhao D, Zheng Z, et al. Sigma-1 receptor alleviates airway inflammation and airway remodeling through AMPK/CXCR4 signal pathway[J]. Inflammation, 2022, 45(3):1298-1312. DOI: 10.1007/s10753-022-01621-4.

[18]向双娣,程林辉,喻强强,等.益气温阳护卫汤调控PI3K/Akt/mTOR自噬途径治疗支气管哮喘大鼠机制[J].中国实验方剂学杂志,2023,29(14):38-46.DOI:10.13422/j.cnki.syfjx.20230637.

[19] Li X, Yang N. Exosome miR-223-3p in the bone marrow-derived mesenchymal stem cells alleviates the inflammation and airway remodeling through NLRP3-induced ASC/caspase-1/GSDMD signaling pathway[J]. Int Immunopharmacol, 2023, 123:110746. DOI: 10.1016/j.intimp.2023.110746.

[20] Savin IA, Zenkova MA, Sen'kova AV. Bronchial asthma, airway remodeling and lung fibrosis as successive steps of one process[J]. Int J Mol Sci, 2023, 24(22):16042. DOI: 10.3390/ijms242216042.

[21] Xu J, Yu Z, Liu X. Angiotensin-(1-7) suppresses airway inflammation and airway remodeling via inhibiting ATG5 in allergic asthma[J]. BMC Pulm Med, 2023, 23(1):422. DOI: 10.1186/s12890-023-02719-7.

[22] Dong L, Wang Y, Zheng T, et al. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice[J]. Stem Cell Res Ther, 2021, 12(1):4. DOI: 10.1186/s13287-020-02072-0.

[23] Jia C, Yang M, Xiao G, et al. ESL attenuates BLM-induced IPF in mice: dual mediation of the TLR4/NF-κB and TGF-β1/PI3K/Akt/FOXO3a pathways[J]. Phytomedicine, 2024, 132:155545. DOI: 10.1016/j.phymed.2024.155545.

[24] Guo W, Hu Z. SRPK1 promotes sepsis-induced acute lung injury via regulating PI3K/AKT/FOXO3 signaling[J]. Immunopharmacol Immunotoxicol, 2023, 45(2):203-212. DOI: 10.1080/08923973.2022.2134789.

[25] Ma Z, Yu R, Zhu Q, et al. CXCL16/CXCR6 axis promotes bleomycin-induced fibrotic process in MRC-5 cells via the PI3K/AKT/FOXO3a pathway[J]. Int Immunopharmacol, 2020, 81:106035. DOI: 10.1016/j.intimp.2019.106035.