Abstract
Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-β1 (TGF-β1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin-1β (IL-1β) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-κB (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-β1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF-1α and NF-κB.
摘要
伊维菌素是美国食品药品监督管理局(FDA)批准的抗寄生虫剂, 具有抗病毒和抗炎特性. 尽管最近有研究表明伊维菌素在呼吸系统损伤中可能具有抗炎活性, 但其对肺纤维化(PF)的潜在影响尚未得到验证. 本研究旨在探讨伊维菌素(0.6 mg/kg)在PF大鼠模型中减轻博来霉素诱导的生化紊乱和组织学变化的效果. 这可用于验证伊维菌素作为治疗特发性PF在临床上的效用. 在本研究中, 伊维菌素减轻了博来霉素诱发的肺损伤, 表现为炎症细胞浸润减少以及炎症和纤维化评分降低. 值得注意的是, 伊维菌素减少了胶原纤维的沉积并抑制了转化生长因子-β1(TGF-β1)和纤连蛋白的表达, 突显了其抗纤维化活性. 本研究首次揭示伊维菌素可以抑制NOD样受体家族含吡啶结构域蛋白3(NLRP3)炎症小体, 表现为NLRP3和含有半胱天冬酶募集结构域的凋亡相关斑点样蛋白(ASC)基因的表达减少, 以及白细胞介素-1β(IL-1β)水平的下降. 此外, 伊维菌素抑制细胞内核因子-κB(NF-κB)和缺氧诱导因子-1α(HIF-1α)蛋白的表达, 同时降低氧化应激和凋亡标志物的水平. 本研究表明, 伊维菌素可以改善博来霉素引起的肺部炎症和纤维化, 并且部分功能是通过下调TGF-β1和纤连蛋白以及通过调节HIF-1α和NF-κB的表达抑制NLRP3炎性小体来介导的.
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This work was supported by Open Access funding provided by the Science, Technology & Innovation Funding Authority (STDF) in cooperation with the Egyptian Knowledge Bank (EKB).
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All authors contributed to the study conception and design. Mai A. ABD-ELMAWLA, Heba R. GHAIAD, and Maha ABDELMONEM: study conception, material preparation, data collection & analysis, and writing; Enas S. GAD and Kawkab A. AHMED: material preparation, data collection & analysis, and writing. All authors wrote the first draft of the manuscript, and they all commented on previous versions of the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. The authors declare that all data were generated in-house and that no paper mill was used.
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Mai A. ABD-ELMAWLA, Heba R. GHAIAD, Enas S. GAD, Kawkab A. AHMED, and Maha ABDELMONEM declare that they have no conflict of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed. All animals’ procedures were performed in accordance with the Research Ethics Committee of the Faculty of Pharmacy, Cairo University (REC-FOPCU), Egypt (No. BC3203) and with the Helsinki Declaration of 1975, as revised in 2013.
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Abd-Elmawla, M.A., Ghaiad, H.R., Gad, E.S. et al. Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis. J. Zhejiang Univ. Sci. B 24, 723–733 (2023). https://doi.org/10.1631/jzus.B2200385
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DOI: https://doi.org/10.1631/jzus.B2200385
Key words
- Intra-tracheal instillation
- Immunohistochemistry
- Transforming growth factor-β1 (TGF-β1)
- Nuclear factor-κB (NF-κB)
- Lung fibrosis
关键词
- 气管内滴注
- 免疫组化
- 转化生长因子-β1(TGF-β1)
- 核转录因子-κB(NF-κB)
- 肺纤维化