一种逆转录修饰肽通过影响免疫细胞的甘油磷脂和嘌呤代谢来减轻卵清蛋白诱导的哮喘模型

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Shumei Ma , Kuan Yang , Zhihong Li , Liang Li , Yue Feng , Xiaowei Wang , Jiahui Wang , Zhengdan Zhu , Zhiyong Wang , Juan Wang , Yizhun Zhu , Li Liu
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引用次数: 0

摘要

过敏性哮喘是一种涉及多种炎症细胞的异质性疾病。免疫失衡或免疫微环境的改变是过敏性哮喘发生炎症的根本原因。Tetraspanin CD81具有特殊的跨膜结构,可作为受体聚集和信号传递的平台,参与细胞增殖、分化、粘附和迁移等生理过程。先前的研究表明,靶向cd81的肽模拟物具有抗过敏性肺部炎症的作用。然而,由于多肽类药物的代谢稳定性较低,其可用药性受到限制。本研究旨在制备一种代谢稳定的抗cd81肽,评价其抗炎作用并建立其作用机制。在前人报道的基础上,我们通过逆转录肽逆修饰得到了一个代谢稳定性高的新化合物PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH)。采用增强型高效液相色谱-串联质谱法研究了PD00的体内外代谢稳定性。利用分子对接和表面等离子体共振技术研究了PD00和CD81的亲和关系。采用卵清蛋白(OVA)诱导哮喘模型评价PD00的体内作用。不同浓度的PD00(175、350 μg/kg)给药10 d。实验结束时检测小鼠气道对乙酰-β-甲胆碱(acetyl-β-methacholine, Mch)的高反应性(hyperresponsiveness, AHR)、支气管肺泡灌洗液炎症细胞计数及血清ova特异性IgE水平。收集肺组织进行苏木精和伊红染色、非靶向代谢组学分析和单细胞转录组测序。PD00对CD81具有高亲和力;因此,给药PD00可显著改善OVA致敏和暴露后小鼠的AHR和气道炎症。血清ova特异性IgE水平显著降低。此外,PD00处理增加了免疫细胞的甘油磷脂和嘌呤代谢。综上所述,PD00可能调节甘油磷脂和嘌呤代谢途径,改善哮喘的病理生理特征。这些发现表明,PD00是一种治疗哮喘的潜在化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells

Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography–tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 μg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-β-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.

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来源期刊
CiteScore
6.20
自引率
0.00%
发文量
41
审稿时长
42 days
期刊介绍: Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.
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