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

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.