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

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

doi:10.1111/fcp.12994

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

Fundam Clin Pharmacol. 2024 Feb 15. doi: 10.1111/fcp.12994. Online ahead of print.

Authors

Reham Hussein Mohamed¹, Nesma Hussein Abdel Hay², Nesma Mohamed Fawzy², Yomna M Tamim¹, M M Doaa Karem³, Dalia Ahmed Yousef Yehia³, Omnia M Abdel Maksoud⁴, Dina S Abdelrahim^{1

5}

Affiliations

¹ Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
² Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
³ Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
⁴ Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt.
⁵ Department of Pharmacology, Faculty of Medicine, Modern Technology and Information University, Cairo, Egypt.

PMID: 38357833
DOI: 10.1111/fcp.12994

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.

Keywords: ACE2; COVID-19; ROCK; VEGF; pulmonary fibrosis; zoledronate.