SYN008与Xolair®对过敏性哮喘小鼠治疗作用效果比较:炎症与重塑

doi:10.6040/j.issn.1671-7554.0.2024.0846

摘要/Abstract

摘要： 目的分析奥马珠单抗类似药(SYN008)对过敏性哮喘模型小鼠的疗效及与奥马珠单抗原创药(Xolair^®)的疗效比较,为SYN008临床应用提供依据。方法将40只健康BALB/c小鼠随机分为4个组,每组10只。第Ⅰ组为对照组,第Ⅱ~Ⅳ组采用卵清蛋白(ovalbumin, OVA)——氢氧化铝腹腔注射诱发哮喘,且Ⅲ组和Ⅳ组分别用Xolair^®(200 μg/只)和SYN008(200 μg/只)腹腔注射。造模完成后检测各组小鼠血清IgE及肺泡灌洗液(broncho alveolar lavage fluid, BALF)中2型辅助性T细胞(T helper 2 cell, Th2)细胞因子变化;通过苏木素-伊红(hematoxylin-eosin, HE)染色、过碘酸-雪夫(peroxynitrite-schiff, PAS)染色和马松三色(Massons trichrome, Masson)染色观察小鼠肺组织病理变化;并通过实时荧光定量聚合酶链式反应(quantitative real-time PCR, RT-qPCR)、酶联免疫吸附实验(enzyme linked immunosorbent assay, ELISA)、免疫印迹(western blotting, WB)和免疫组化法检测肺组织中转化生长因子β1(transforming growth factor beta 1, TGF-β1)、磷酸化Smad家族成员3(phosphorylated Smad family member 3, P-smad3)和Smad家族成员3(Smad3)、胶原蛋白Ⅲ(collagen Ⅲ, COL3)和黏蛋白(mucin 5AC, MUC5AC)的表达情况。结果与对照组比较,哮喘组小鼠血清IgE和BALF中白细胞介素-4(interleukin 4,IL-4)、IL-5和IL-13含量明显升高(P均<0.001);与Ⅱ组比较,Ⅲ组和Ⅳ组小鼠血清IgE和BALF中IL-4/5/13含量都明显下降(P<0.001,P<0.05,P<0.01,P<0.05;P<0.001,P<0.05,P<0.05,P<0.05);HE、PAS和Masson染色证实了Xolair^®和SYN008可有效减少哮喘小鼠炎细胞聚集、气道杯状细胞化生和胶原沉积,并且两者可以通过抑制肺组织的TGF-β1、P-smad3/Smad3、COL3和MUC5AC减轻气道重塑,且两组各项检测指标均无统计学差异。结论 SYN008可以改善小鼠的过敏性哮喘,且与Xolair^®药效一致,未来有望应用于临床有效治疗过敏性哮喘。

关键词: 奥马珠单抗类似药(SYN008), 奥马珠单抗原创药(Xolair^®, ), 过敏性哮喘, 炎症, 重塑

Abstract: Objective To compare the efficacy of omalizumab analogue(SYN008)with omalizumab original drug(Xolair^®)in allergic asthma mice model, providing a basis for the clinical application of SYN008. Methods Forty healthy BALB/c mice were divided into four groups, with 10 mice in each. Group I was the control group and asthma was induced by intraperitoneal injection of ovalbumin(OVA)-aluminium hydroxide in groups Ⅱ-Ⅳ. Mice in groups Ⅲ and Ⅳ were treated with Xolair^®(200 μg/each)and SYN008(200 μg/each)intraperitoneally, respectively. The levels of IgE in serum and T helper 2 cell(Th2)cytokines in broncho alveolar lavage fluid(BALF)were detected in each group; lung tissues were observed by hematoxylin-eosin(HE)staining, peroxynitrite-schiff(PAS)staining and Massons trichrome(Masson)staining. For the expression of transforming growth factor beta 1(TGF-β1), phosphorylated Smad family member 3(P-smad3)/Smad family member 3(Smad3), collagen Ⅲ(COL3)and mucin 5AC(MUC5AC), lung tissues were examined by quantitative real-time PCR(RT-qPCR), enzyme linked immunosorbent assay(ELISA), western blotting(WB)and immunohistochemistry. Results The levels of IgE in serum and interleukin-4(IL-4), IL-5 and IL-13 in BALF were significantly increased in the group Ⅱ compared with those in the control group(all P<0.001). The levels of IgE in serum and IL-4/5/13 in BALF in groups Ⅲ and Ⅳ were significantly decreased compared with those in the group Ⅱ(P<0.001, P<0.05, P<0.01, P<0.05; P<0.001, P<0.05, P<0.05, P<0.05). HE, PAS and Masson staining confirmed that Xolair^® and SYN008 could effectively reduce inflammatory cell aggregation, airway cuprocyte chemotaxis and collagen deposition in mice with asthma. Xolair^® and SYN008 could attenuate airway remodeling by inhibiting TGF-β1, P-smad3/Smad3, COL3 and MUC5AC in lung tissues, with no reach statistical significance between the two groups in all the assays. Conclusion SYN008 improves allergic asthma in mice and is consistent with the efficacy of Xolair^®, which is expected to be clinically significant for allergic asthma in the future.

Key words: Omalizumab analogue(SYN008), Omalizumab original drug(Xolair^®, ), Allergic asthma, Inflammation, Remodeling

中图分类号:

R562.2

徐新军,邵丽婷,陈颖,刘会芳,杨玉娟,张宇,王浛睿,宋西成. SYN008与Xolair^®对过敏性哮喘小鼠治疗作用效果比较:炎症与重塑[J]. 山东大学学报 (医学版), 2024, 62(12): 1-10.

XU Xinjun, SHAO Liting, CHEN Ying, LIU Huifang, YANG Yujuan, ZHANG Yu, WANG Hanrui, SONG Xicheng. Comparison of the therapeutic effect of SYN008 with Xolair^® in allergic asthma mice: inflammation and remodeling[J]. Journal of Shandong University (Health Sciences), 2024, 62(12): 1-10.

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