Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis
et al., Journal of Zhejiang University-SCIENCE B, doi:10.1631/jzus.B2200385, Jul 2023
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
Animal study showing that ivermectin alleviated pulmonary inflammation and fibrosis induced by bleomycin in a rat model. Authors note this may add to the clinical usefulness of ivermectin for patients with pulmonary fibrosis from COVID-19 or other causes. Results suggest that ivermectin's benefits in reducing lung inflammation and fibrosis involve inhibition of pro-inflammatory signaling pathways NLRP3 inflammasome, NF-kB, and HIF-1α.
74 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N771, Dengue37,72,73 , HIV-173, Simian virus 4074, Zika37,75,76 , West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
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Abd-Elmawla et al., 1 Jul 2023, peer-reviewed, 5 authors.
Contact: jzus_b@zju.edu.cn, heba.mosalam@pharma.cu.edu.eg, mei.abdelmawla@pharma.cu.edu.eg.
伊维菌素抑制NLRP3炎症小体可改善博来霉素诱导的肺纤维化
Journal of Zhejiang University-SCIENCE B, doi:10.1631/jzus.b2200385
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.
Author contributions 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.
Compliance with ethics guidelines 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.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you..
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Lechowicz, Drożdżal, Machaj, COVID-19: the potential treatment of pulmonary fibrosis associated with SARS-CoV-2 infection, J Clin Med, doi:10.3390/jcm9061917
Lin, Barravecchia, Kottmann, Caveolin-1 gene therapy inhibits inflammasome activation to protect from bleomycin-induced pulmonary fibrosis, Sci Rep, doi:10.1038/s41598-019-55819-y
Liu, Lu, Kang, Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium, BMC Pulm Med, doi:10.1186/s12890-017-0405-7
Mansour, Shamma, Ahmed, Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: a preclinical tolerance study, Int Immunopharmacol, doi:10.1016/j.intimp.2021.108004
Mittal, Mittal, Inhaled route and anti-inflammatory action of ivermectin: do they hold promise in fighting against COVID-19?, Med Hypotheses, doi:10.1016/j.mehy.2020.110364
Raghu, Brown, Collard, Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial, Lancet Respir Med, doi:10.1016/S2213-2600(16)30421-0
Rodrigues, De Sá, Ishimoto, Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients, J Exp Med, doi:10.1084/jem.20201707
Ruiz-Riol, Berdnik, Llano, Identification of interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune axis for in vivo HIV control, J Virol, doi:10.1128/jvi.00441-17
Sagoo, Garcia, Breart, In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity, Nat Med, doi:10.1038/nm.4016
Shin, Seol, Son, Interpretation of animal dose and human equivalent dose for drug development, J Korean Orient Med
Sia, Mensah, Opoku-Agyemang, Topical ivermectin 10 mg/g and oral doxycycline 40 mg modifiedrelease: current evidence on the complementary use of antiinflammatory rosacea treatments, BMC Vet Res, doi:10.1186/s12917-020-02612-z
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"abstract": "<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>NLRP3</jats:italic> and the apoptosis-associated speck-like protein containing a caspase recruitment domain (<jats:italic>ASC</jats:italic>), 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.</jats:p>",
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