Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: Promising therapy against post-COVID-19 pulmonary fibrosis

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2024-02-15 DOI:10.1111/fcp.12994

Reham Hussein Mohamed, Nesma Hussein Abdel hay, Nesma Mohamed Fawzy, Yomna M. Tamim, M. M. Doaa Karem, Dalia Ahmed Yousef Yehia, Omnia M. Abdel Maksoud, Dina S. Abdelrahim

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引用次数: 0

Abstract

Background

Rho kinase (ROCK) pathway plays a critical role in post-COVID-19 pulmonary fibrosis (PCPF) and its intervention with angiotensin-converting enzyme 2 (ACE2) and vascular endothelial growth factor (VEGF) will be a potential therapeutic target.

Objectives

The present study was conducted to investigate the efficacy of zoledronate (ZA) on carbon tetrachloride (CCl4) induced pulmonary fibrosis (PF) in rats through targeting ACE2, ROCK, and VEGF signaling pathways.

Methods

Fifty male Wistar rats were divided into five groups: control, vehicle-treated, PF, PF-ZA 50, and PF-ZA 100 groups. ZA was given in two different doses 100 and 50 μg/kg/week intraperitoneally. After anesthesia, mean arterial blood pressure (MBP) was measured. After scarification, lung coefficient was calculated. Lung levels of ACE 2, interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), VEGF, glutathione (GSH), and superoxide dismutase (SOD) were measured. Expression of ROCK, phosphorylated myosin phosphatase target subunit 1 (P-MYPT1), and matrix metalloproteinase (MMP-1), along with histopathological changes and immune-histochemical staining for lung α-smooth muscle actin (α-SMA), tumor necrosis factor-alpha (TNFα), and caspase-3, were evaluated.

Results

ZA significantly prevented the decrease in MBP. ZA significantly increased ACE2, GSH, and SOD and significantly decreased IL-1β, TGF-β, and VEGF in lung in comparison to PF group. ZA prevented the histopathological changes induced by CCl4. ZA inhibited lung expression of ROCK, P-MYPT1, MMP-1, α-SMA, TNFα, and caspase-3 with significant differences favoring the high dose intervention.

Conclusion

ZA in a dose-dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF.

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唑来膦酸盐靶向甲羟戊酸途径可改善大鼠模型中的肺纤维化：COVID-19后肺纤维化有望治愈

背景：Rho激酶（ROCK）通路在COVID-19后肺纤维化（PCPF）中发挥关键作用，其与血管紧张素转换酶2（ACE2）和血管内皮生长因子（VEGF）的干预将成为潜在的治疗靶点：本研究旨在探讨唑来膦酸钠（ZA）通过靶向 ACE2、ROCK 和血管内皮生长因子信号通路对四氯化碳（CCl4）诱导的大鼠肺纤维化（PF）的疗效：将 50 只雄性 Wistar 大鼠分为五组：对照组、药物治疗组、PF 组、PF-ZA 50 组和 PF-ZA 100 组。腹腔注射 100 和 50 μg/kg/week 两种不同剂量的ZA。麻醉后，测量平均动脉血压（MBP）。结疤后，计算肺系数。测量了肺中 ACE 2、白细胞介素-1β（IL-1β）、转化生长因子-β（TGF-β）、血管内皮生长因子、谷胱甘肽（GSH）和超氧化物歧化酶（SOD）的水平。还评估了ROCK、磷酸化肌球蛋白磷酸酶靶亚基1（P-MYPT1）和基质金属蛋白酶（MMP-1）的表达，以及组织病理学变化和肺α-平滑肌肌动蛋白（α-SMA）、肿瘤坏死因子α（TNFα）和Caspase-3的免疫组织化学染色：结果：ZA明显阻止了MBP的下降。与 PF 组相比，ZA 能明显增加肺中的 ACE2、GSH 和 SOD，明显降低 IL-1β、TGF-β 和 VEGF。ZA能防止CCl4引起的组织病理学变化。ZA可抑制肺部ROCK、P-MYPT1、MMP-1、α-SMA、TNFα和caspase-3的表达，高剂量干预组与对照组有显著差异：结论：ZA通过靶向甲羟戊酸通路，以剂量依赖的方式阻止了CCl4对肺部的病理效应。结论：ZA通过靶向甲羟戊酸通路，以剂量依赖性的方式阻止了CCl4对肺部的病理效应，是一种很有前景的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.