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
Mai A Abd-Elmawla, Heba R Ghaiad, Enas S Gad, Kawkab A Ahmed, Maha Abdelmonem
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..
References
Ambardar, Hightower, Huprikar, Post-COVID-19 pulmonary fibrosis: novel sequelae of the current pandemic, J Clin Med,
doi:10.3390/jcm10112452Chen, Wang, Wang, Blockade of advanced glycation end product formation attenuates bleomycininduced pulmonary fibrosis in rats, Respir Res,
doi:10.1186/1465-9921-10-55Ci, Li, Yu, Avermectin exerts antiinflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway, Fundam Clin Pharmacol,
doi:10.1111/j.1472-8206.2009.00684.xGad, Salama, El-Shafie, The anti-fibrotic and anti-inflammatory potential of bone marrow-derived mesenchymal stem cells and nintedanib in bleomycininduced lung fibrosis in rats, Inflammation,
doi:10.1007/s10753-019-01101-2Gazdhar, Susuri, Hostettler, HGF expressing stem cells in usual interstitial pneumonia originate from the bone marrow and are antifibrotic, PLoS ONE,
doi:10.1371/journal.pone.0065453Huang, Xia, Huang, HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury, Mol Med Rep,
doi:10.3892/mmr.2019.10575Jiang, Geng, Warren, Hypoxia inducible factor-1α (HIF-1α) mediates NLRP3 inflammasomedependent-pyroptotic and apoptotic cell death following ischemic stroke, Neuroscience,
doi:10.1016/j.neuroscience.2020.09.036Kan, Chen, Huang, Effect of Palrnatine on lipopolysaccharide-induced acute lung injury by inhibiting activation of the Akt/NF-κB pathway, J Zhejiang Univ-Sci B (Biomed & Biotechnol),
doi:10.1631/jzus.B2000583Kosyna, Nagel, Kluxen, The importin α/β-specific inhibitor ivermectin affects HIF-dependent hypoxia response pathways, Biol Chem,
doi:10.1515/hsz-2015-0171Krolewiecki, Lifschitz, Moragas, Antiviral effect of high-dose ivermectin in adults with COVID-19: a proof-of-concept randomized trial,
doi:10.1016/j.eclinm.2021.100959Latz, Xiao, Stutz, Activation and regulation of the inflammasomes, Nat Rev Immunol,
doi:10.1038/nri3452Lechowicz, Drożdżal, Machaj, COVID-19: the potential treatment of pulmonary fibrosis associated with SARS-CoV-2 infection, J Clin Med,
doi:10.3390/jcm9061917Lin, Barravecchia, Kottmann, Caveolin-1 gene therapy inhibits inflammasome activation to protect from bleomycin-induced pulmonary fibrosis, Sci Rep,
doi:10.1038/s41598-019-55819-yLiu, Lu, Kang, Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium, BMC Pulm Med,
doi:10.1186/s12890-017-0405-7Mansour, 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.2021.108004Mittal, 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.2020.110364Raghu, 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)30421-0Rodrigues, 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.20201707Ruiz-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.00441-17Sagoo, 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.4016Shin, 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-zVriend, Reiter, Melatonin and the von Hippel-Lindau/ HIF-1 oxygen sensing mechanism: a review, Biochim Biophys Acta Rev Cancer,
doi:10.1016/j.bbcan.2016.02.004Wang, Li, Chen, Resveratrol alleviates bleomycin-induced pulmonary fibrosis via suppressing HIF-1α and NF-κB expression, Aging,
doi:10.18632/aging.202420Wang, Wang, Fang, Danggui Buxue Tang ameliorates bleomycin-induced pulmonary fibrosis by suppressing the TLR4/NLRP3 signaling pathway in rats, Evid Based Complement Alternat Med,
doi:10.1155/2021/8030143Zhang, Song, Ci, Ivermectin inhibits LPSinduced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflammation Res,
doi:10.1007/s00011-008-8007-8{ 'indexed': {'date-parts': [[2023, 7, 22]], 'date-time': '2023-07-22T19:28:16Z', 'timestamp': 1690054096061},
'reference-count': 35,
'publisher': 'Zhejiang University Press',
'license': [ { 'start': { 'date-parts': [[2023, 7, 1]],
'date-time': '2023-07-01T00:00:00Z',
'timestamp': 1688169600000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'},
{ 'start': { 'date-parts': [[2023, 7, 1]],
'date-time': '2023-07-01T00:00:00Z',
'timestamp': 1688169600000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'}],
'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False},
'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>',
'DOI': '10.1631/jzus.b2200385',
'type': 'journal-article',
'created': {'date-parts': [[2023, 7, 1]], 'date-time': '2023-07-01T00:01:59Z', 'timestamp': 1688169719000},
'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 1,
'title': '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',
'prefix': '10.1631',
'author': [ { 'ORCID': 'http://orcid.org/0000-0001-7582-7617',
'authenticated-orcid': False,
'given': 'Mai A.',
'family': 'Abd-Elmawla',
'sequence': 'first',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-4765-0353',
'authenticated-orcid': False,
'given': 'Heba R.',
'family': 'Ghaiad',
'sequence': 'additional',
'affiliation': []},
{'given': 'Enas S.', 'family': 'Gad', 'sequence': 'additional', 'affiliation': []},
{'given': 'Kawkab A.', 'family': 'Ahmed', 'sequence': 'additional', 'affiliation': []},
{'given': 'Maha', 'family': 'Abdelmonem', 'sequence': 'additional', 'affiliation': []}],
'member': '635',
'published-online': {'date-parts': [[2023, 7, 1]]},
'reference': [ { 'issue': '11',
'key': '38_CR1',
'doi-asserted-by': 'publisher',
'first-page': '2452',
'DOI': '10.3390/jcm10112452',
'volume': '10',
'author': 'SR Ambardar',
'year': '2021',
'unstructured': 'Ambardar SR, Hightower SL, Huprikar NA, et al., 2021. Post-COVID-19 '
'pulmonary fibrosis: novel sequelae of the current pandemic. J Clin Med, '
'10(11):2452. https://doi.org/10.3390/jcm10112452',
'journal-title': 'J Clin Med'},
{ 'issue': '18',
'key': '38_CR2',
'doi-asserted-by': 'publisher',
'first-page': '1350',
'DOI': '10.1056/NEJM200005043421807',
'volume': '342',
'author': 'GC Blobe',
'year': '2000',
'unstructured': 'Blobe GC, Schiemann WP, Lodish HF, 2000. Role of transforming growth '
'factor β in human disease. N Engl J Med, 342(18):1350–1358. '
'https://doi.org/10.1056/nejm200005043421807',
'journal-title': 'N Engl J Med'},
{ 'issue': '5',
'key': '38_CR3',
'doi-asserted-by': 'publisher',
'first-page': '2111',
'DOI': '10.1016/j.chest.2021.03.003',
'volume': '159',
'author': 'D Buonfrate',
'year': '2021',
'unstructured': 'Buonfrate D, Bisoffi Z, 2021. Standard dose ivermectin for COVID-19. '
'Chest, 159(5):2111–2112. https://doi.org/10.1016/j.chest.2021.03.003',
'journal-title': 'Chest'},
{ 'key': '38_CR4',
'doi-asserted-by': 'publisher',
'first-page': '104787',
'DOI': '10.1016/j.antiviral.2020.104787',
'volume': '178',
'author': 'L Caly',
'year': '2020',
'unstructured': 'Caly L, Druce JD, Catton MG, et al., 2020. The FDA-approved drug '
'ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral '
'Res, 178:104787. https://doi.org/10.1016/j.antiviral.2020.104787',
'journal-title': 'Antiviral Res'},
{ 'key': '38_CR5',
'doi-asserted-by': 'publisher',
'first-page': '55',
'DOI': '10.1186/1465-9921-10-55',
'volume': '10',
'author': 'L Chen',
'year': '2009',
'unstructured': 'Chen L, Wang T, Wang X, et al., 2009. Blockade of advanced glycation end '
'product formation attenuates bleomycin-induced pulmonary fibrosis in '
'rats. Respir Res, 10:55. https://doi.org/10.1186/1465-9921-10-55',
'journal-title': 'Respir Res'},
{ 'key': '38_CR6',
'doi-asserted-by': 'publisher',
'first-page': '1575',
'DOI': '10.2147/JIR.S304180',
'volume': '14',
'author': 'TT Chen',
'year': '2021',
'unstructured': 'Chen TT, Xiao F, Li N, et al., 2021. Inflammasome as an effective '
'platform for fibrosis therapy. J Inflamm Res, 14:1575–1590. '
'https://doi.org/10.2147/JIR.S304180',
'journal-title': 'J Inflamm Res'},
{ 'issue': '4',
'key': '38_CR7',
'doi-asserted-by': 'publisher',
'first-page': '449',
'DOI': '10.1111/j.1472-8206.2009.00684.x',
'volume': '23',
'author': 'XX Ci',
'year': '2009',
'unstructured': 'Ci XX, Li HY, Yu QL, et al., 2009. Avermectin exerts anti-inflammatory '
'effect by downregulating the nuclear transcription factor kappa-B and '
'mitogen-activated protein kinase activation pathway. Fundam Clin '
'Pharmacol, 23(4): 449–455. '
'https://doi.org/10.1111/j.1472-8206.2009.00684.x',
'journal-title': 'Fundam Clin Pharmacol'},
{ 'key': '38_CR8',
'doi-asserted-by': 'publisher',
'first-page': '591393',
'DOI': '10.3389/fphar.2020.591393',
'volume': '11',
'author': 'N Ding',
'year': '2020',
'unstructured': 'Ding N, Wei B, Fu XH, et al., 2020. Natural products that target the '
'NLRP3 inflammasome to treat fibrosis. Front Pharmacol, 11:591393. '
'https://doi.org/10.3389/fphar.2020.591393',
'journal-title': 'Front Pharmacol'},
{ 'issue': '1',
'key': '38_CR9',
'doi-asserted-by': 'publisher',
'first-page': '123',
'DOI': '10.1007/s10753-019-01101-2',
'volume': '43',
'author': 'ES Gad',
'year': '2020',
'unstructured': 'Gad ES, Salama AAA, El-Shafie MF, et al., 2020. The anti-fibrotic and '
'anti-inflammatory potential of bone marrow-derived mesenchymal stem '
'cells and nintedanib in bleomycin-induced lung fibrosis in rats. '
'Inflammation, 43(1):123–134. https://doi.org/10.1007/s10753-019-01101-2',
'journal-title': 'Inflammation'},
{ 'issue': '6',
'key': '38_CR10',
'doi-asserted-by': 'publisher',
'first-page': 'e65453',
'DOI': '10.1371/journal.pone.0065453',
'volume': '8',
'author': 'A Gazdhar',
'year': '2013',
'unstructured': 'Gazdhar A, Susuri N, Hostettler K, et al., 2013. HGF expressing stem '
'cells in usual interstitial pneumonia originate from the bone marrow and '
'are antifibrotic. PLoS ONE, 8(6): e65453. '
'https://doi.org/10.1371/journal.pone.0065453',
'journal-title': 'PLoS ONE'},
{ 'key': '38_CR11',
'doi-asserted-by': 'publisher',
'unstructured': 'Gonçalves K, Vasconcelos A, Barbirato D, et al., 2020. Therapeutic '
'potential of ivermectin for COVID-19. Authorea, preprint. '
'https://doi.org/10.22541/au.159050476.60928563',
'DOI': '10.22541/au.159050476.60928563'},
{ 'key': '38_CR12',
'doi-asserted-by': 'publisher',
'first-page': '713572',
'DOI': '10.3389/fphar.2021.713572',
'volume': '12',
'author': 'YY Han',
'year': '2021',
'unstructured': 'Han YY, Jiang M, He RL, et al., 2021. Mefunidone ameliorates '
'bleomycin-induced pulmonary fibrosis in mice. Front Pharmacol, '
'12:713572. https://doi.org/10.3389/fphar.2021.713572',
'journal-title': 'Front Pharmacol'},
{ 'issue': '4',
'key': '38_CR13',
'doi-asserted-by': 'publisher',
'first-page': '3424',
'DOI': '10.3892/mmr.2019.10575',
'volume': '20',
'author': 'JJ Huang',
'year': '2019',
'unstructured': 'Huang JJ, Xia J, Huang LL, et al., 2019. HIF-1α promotes NLRP3 '
'inflammasome activation in bleomycin-induced acute lung injury. Mol Med '
'Rep, 20(4):3424–3432. https://doi.org/10.3892/mmr.2019.10575',
'journal-title': 'Mol Med Rep'},
{ 'key': '38_CR14',
'doi-asserted-by': 'publisher',
'first-page': '126',
'DOI': '10.1016/j.neuroscience.2020.09.036',
'volume': '448',
'author': 'Q Jiang',
'year': '2020',
'unstructured': 'Jiang Q, Geng XK, Warren J, et al., 2020. Hypoxia inducible factor-1α '
'(HIF-1α) mediates NLRP3 inflammasome-dependent-pyroptotic and apoptotic '
'cell death following ischemic stroke. Neuroscience, 448:126–139. '
'https://doi.org/10.1016/j.neuroscience.2020.09.036',
'journal-title': 'Neuroscience'},
{ 'issue': '11',
'key': '38_CR15',
'doi-asserted-by': 'publisher',
'first-page': '929',
'DOI': '10.1631/jzus.B2000583',
'volume': '22',
'author': 'XC Kan',
'year': '2021',
'unstructured': 'Kan XC, Chen YS, Huang BX, et al., 2021. Effect of Palrnatine on '
'lipopolysaccharide-induced acute lung injury by inhibiting activation of '
'the Akt/NF-κB pathway. J Zhejiang Univ-Sci B (Biomed & Biotechnol), '
'22(11):929–940. https://doi.org/10.1631/jzus.B2000583',
'journal-title': 'J Zhejiang Univ-Sci B (Biomed & Biotechnol)'},
{ 'issue': '12',
'key': '38_CR16',
'doi-asserted-by': 'publisher',
'first-page': '1357',
'DOI': '10.1515/hsz-2015-0171',
'volume': '396',
'author': 'FK Kosyna',
'year': '2015',
'unstructured': 'Kosyna FK, Nagel M, Kluxen L, et al., 2015. The importin α/β-specific '
'inhibitor ivermectin affects HIF-dependent hypoxia response pathways. '
'Biol Chem, 396(12):1357–1367. https://doi.org/10.1515/hsz-2015-0171',
'journal-title': 'Biol Chem'},
{ 'key': '38_CR17',
'doi-asserted-by': 'publisher',
'first-page': '100959',
'DOI': '10.1016/j.eclinm.2021.100959',
'volume': '37',
'author': 'A Krolewiecki',
'year': '2021',
'unstructured': 'Krolewiecki A, Lifschitz A, Moragas M, et al., 2021. Antiviral effect of '
'high-dose ivermectin in adults with COVID-19: a proof-of-concept '
'randomized trial. eClinicalMedicine, 37:100959. '
'https://doi.org/10.1016/j.eclinm.2021.100959',
'journal-title': 'eClinicalMedicine'},
{ 'issue': '6',
'key': '38_CR18',
'doi-asserted-by': 'publisher',
'first-page': '397',
'DOI': '10.1038/nri3452',
'volume': '13',
'author': 'E Latz',
'year': '2013',
'unstructured': 'Latz E, Xiao TS, Stutz A, 2013. Activation and regulation of the '
'inflammasomes. Nat Rev Immunol, 13(6):397–411. '
'https://doi.org/10.1038/nri3452',
'journal-title': 'Nat Rev Immunol'},
{ 'issue': '6',
'key': '38_CR19',
'doi-asserted-by': 'publisher',
'first-page': '1917',
'DOI': '10.3390/jcm9061917',
'volume': '9',
'author': 'K Lechowicz',
'year': '2020',
'unstructured': 'Lechowicz K, Drożdżal S, Machaj F, et al., 2020. COVID-19: the potential '
'treatment of pulmonary fibrosis associated with SARS-CoV-2 infection. J '
'Clin Med, 9(6):1917. https://doi.org/10.3390/jcm9061917',
'journal-title': 'J Clin Med'},
{ 'key': '38_CR20',
'doi-asserted-by': 'publisher',
'first-page': '19643',
'DOI': '10.1038/s41598-019-55819-y',
'volume': '9',
'author': 'X Lin',
'year': '2019',
'unstructured': 'Lin X, Barravecchia M, Kottmann RM, et al., 2019. Caveolin-1 gene '
'therapy inhibits inflammasome activation to protect from '
'bleomycin-induced pulmonary fibrosis. Sci Rep, 9: 19643. '
'https://doi.org/10.1038/s41598-019-55819-y',
'journal-title': 'Sci Rep'},
{ 'key': '38_CR21',
'doi-asserted-by': 'publisher',
'first-page': '63',
'DOI': '10.1186/s12890-017-0405-7',
'volume': '17',
'author': 'Y Liu',
'year': '2017',
'unstructured': 'Liu Y, Lu FA, Kang LR, et al., 2017. Pirfenidone attenuates '
'bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 '
'equilibrium. BMC Pulm Med, 17:63. '
'https://doi.org/10.1186/s12890-017-0405-7',
'journal-title': 'BMC Pulm Med'},
{ 'key': '38_CR22',
'doi-asserted-by': 'publisher',
'first-page': '108004',
'DOI': '10.1016/j.intimp.2021.108004',
'volume': '99',
'author': 'SM Mansour',
'year': '2021',
'unstructured': 'Mansour SM, Shamma RN, Ahmed KA, et al., 2021. Safety of inhaled '
'ivermectin as a repurposed direct drug for treatment of COVID-19: a '
'preclinical tolerance study. Int Immunopharmacol, 99:108004. '
'https://doi.org/10.1016/j.intimp.2021.108004',
'journal-title': 'Int Immunopharmacol'},
{ 'key': '38_CR23',
'doi-asserted-by': 'publisher',
'first-page': '110364',
'DOI': '10.1016/j.mehy.2020.110364',
'volume': '146',
'author': 'N Mittal',
'year': '2021',
'unstructured': 'Mittal N, Mittal R, 2021. Inhaled route and anti-inflammatory action of '
'ivermectin: do they hold promise in fighting against COVID-19? Med '
'Hypotheses, 146:110364. https://doi.org/10.1016/j.mehy.2020.110364',
'journal-title': 'Med Hypotheses'},
{ 'issue': '1',
'key': '38_CR24',
'doi-asserted-by': 'publisher',
'first-page': '22',
'DOI': '10.1016/S2213-2600(16)30421-0',
'volume': '5',
'author': 'G Raghu',
'year': '2017',
'unstructured': 'Raghu G, Brown KK, Collard HR, et al., 2017. Efficacy of simtuzumab '
'versus placebo in patients with idiopathic pulmonary fibrosis: a '
'randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med, '
'5(1):22–32. https://doi.org/10.1016/S2213-2600(16)30421-0',
'journal-title': 'Lancet Respir Med'},
{ 'issue': '3',
'key': '38_CR25',
'doi-asserted-by': 'publisher',
'first-page': 'e20201707',
'DOI': '10.1084/jem.20201707',
'volume': '218',
'author': 'TS Rodrigues',
'year': '2021',
'unstructured': 'Rodrigues TS, de Sá KSG, Ishimoto AY, et al., 2021. Inflammasomes are '
'activated in response to SARS-CoV-2 infection and are associated with '
'COVID-19 severity in patients. J Exp Med, 218(3):e20201707. '
'https://doi.org/10.1084/jem.20201707',
'journal-title': 'J Exp Med'},
{ 'issue': '16',
'key': '38_CR26',
'doi-asserted-by': 'publisher',
'first-page': 'e00441',
'DOI': '10.1128/JVI.00441-17',
'volume': '91',
'author': 'M Ruiz-Riol',
'year': '2017',
'unstructured': 'Ruiz-Riol M, Berdnik D, Llano A, et al., 2017. Identification of '
'interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune '
'axis for in vivo HIV control. J Virol, 91(16):e00441–17. '
'https://doi.org/10.1128/jvi.00441-17',
'journal-title': 'J Virol'},
{ 'issue': '1',
'key': '38_CR27',
'doi-asserted-by': 'publisher',
'first-page': '64',
'DOI': '10.1038/nm.4016',
'volume': '22',
'author': 'P Sagoo',
'year': '2016',
'unstructured': 'Sagoo P, Garcia Z, Breart B, et al., 2016. In vivo imaging of '
'inflammasome activation reveals a subcapsular macrophage burst response '
'that mobilizes innate and adaptive immunity. Nat Med, 22(1):64–71. '
'https://doi.org/10.1038/nm.4016',
'journal-title': 'In vivo imaging of inflammasome activation reveals a subcapsular '
'macrophage burst response that mobilizes innate and adaptive immunity. '
'Nat Med'},
{ 'issue': '3',
'key': '38_CR28',
'first-page': '1',
'volume': '31',
'author': 'JW Shin',
'year': '2010',
'unstructured': 'Shin JW, Seol IC, Son CG, 2010. Interpretation of animal dose and human '
'equivalent dose for drug development. J Korean Orient Med, 31(3):1–7.',
'journal-title': 'J Korean Orient Med'},
{ 'key': '38_CR29',
'doi-asserted-by': 'publisher',
'first-page': '397',
'DOI': '10.1186/s12917-020-02612-z',
'volume': '16',
'author': 'DK Sia',
'year': '2020',
'unstructured': 'Sia DK, Mensah KB, Opoku-Agyemang T, et al., 2020. Mechanisms of '
'ivermectin-induced wound healing. BMC Vet Res, 16:397. '
'https://doi.org/10.1186/s12917-020-02612-z',
'journal-title': 'BMC Vet Res'},
{ 'key': '38_CR30',
'doi-asserted-by': 'publisher',
'first-page': '1481',
'DOI': '10.1007/s12325-016-0380-z',
'volume': '33',
'author': 'M Steinhoff',
'year': '2016',
'unstructured': 'Steinhoff M, Vocanson M, Voegel JJ, et al., 2016. Topical ivermectin 10 '
'mg/g and oral doxycycline 40 mg modified-release: current evidence on '
'the complementary use of anti-inflammatory rosacea treatments. Adv Ther, '
'33:1481–1501. https://doi.org/10.1007/s12325-016-0380-z',
'journal-title': 'Adv Ther'},
{ 'issue': '2',
'key': '38_CR31',
'doi-asserted-by': 'publisher',
'first-page': '328',
'DOI': '10.1016/j.yexcr.2017.05.028',
'volume': '357',
'author': 'R Tian',
'year': '2017',
'unstructured': 'Tian R, Zhu Y, Yao JY, et al., 2017. NLRP3 participates in the '
'regulation of EMT in bleomycin-induced pulmonary fibrosis. Exp Cell Res, '
'357(2):328–334. https://doi.org/10.1016/j.yexcr.2017.05.028',
'journal-title': 'Exp Cell Res'},
{ 'issue': '2',
'key': '38_CR32',
'doi-asserted-by': 'publisher',
'first-page': '176',
'DOI': '10.1016/j.bbcan.2016.02.004',
'volume': '1865',
'author': 'J Vriend',
'year': '2016',
'unstructured': 'Vriend J, Reiter RJ, 2016. Melatonin and the von Hippel–Lindau/HIF-1 '
'oxygen sensing mechanism: a review. Biochim Biophys Acta Rev Cancer, '
'1865(2):176–183. https://doi.org/10.1016/j.bbcan.2016.02.004',
'journal-title': 'Biochim Biophys Acta Rev Cancer'},
{ 'key': '38_CR33',
'doi-asserted-by': 'publisher',
'first-page': '8030143',
'DOI': '10.1155/2021/8030143',
'volume': '2021',
'author': 'JP Wang',
'year': '2021',
'unstructured': 'Wang JP, Wang H, Fang F, et al., 2021. Danggui Buxue Tang ameliorates '
'bleomycin-induced pulmonary fibrosis by suppressing the TLR4/NLRP3 '
'signaling pathway in rats. Evid Based Complement Alternat Med, '
'2021:8030143. https://doi.org/10.1155/2021/8030143',
'journal-title': 'Evid Based Complement Alternat Med'},
{ 'issue': '3',
'key': '38_CR34',
'doi-asserted-by': 'publisher',
'first-page': '4605',
'DOI': '10.18632/aging.202420',
'volume': '13',
'author': 'ZY Wang',
'year': '2021',
'unstructured': 'Wang ZY, Li XN, Chen H, et al., 2021. Resveratrol alleviates '
'bleomycin-induced pulmonary fibrosis via suppressing HIF-1α and NF-κB '
'expression. Aging, 13(3):4605–4616. '
'https://doi.org/10.18632/aging.202420',
'journal-title': 'Aging'},
{ 'issue': '11',
'key': '38_CR35',
'doi-asserted-by': 'publisher',
'first-page': '524',
'DOI': '10.1007/s00011-008-8007-8',
'volume': '57',
'author': 'X Zhang',
'year': '2008',
'unstructured': 'Zhang X, Song Y, Ci X, et al., 2008. Ivermectin inhibits LPS-induced '
'production of inflammatory cytokines and improves LPS-induced survival '
'in mice. Inflammation Res, 57(11):524–529. '
'https://doi.org/10.1007/s00011-008-8007-8',
'journal-title': 'Inflammation Res'}],
'container-title': 'Journal of Zhejiang University-SCIENCE B',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1631/jzus.B2200385.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://link.springer.com/article/10.1631/jzus.B2200385/fulltext.html',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://link.springer.com/content/pdf/10.1631/jzus.B2200385.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2023, 7, 1]],
'date-time': '2023-07-01T00:02:02Z',
'timestamp': 1688169722000},
'score': 1,
'resource': {'primary': {'URL': 'https://link.springer.com/10.1631/jzus.B2200385'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 7, 1]]},
'references-count': 35,
'alternative-id': ['38'],
'URL': 'http://dx.doi.org/10.1631/jzus.B2200385',
'relation': {},
'ISSN': ['1673-1581', '1862-1783'],
'subject': [ 'General Pharmacology, Toxicology and Pharmaceutics', 'General Veterinary',
'General Biochemistry, Genetics and Molecular Biology', 'General Medicine'],
'container-title-short': 'J. Zhejiang Univ. Sci. B',
'published': {'date-parts': [[2023, 7, 1]]},
'assertion': [ { 'value': '31 July 2022',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '11 December 2022',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '1 July 2023',
'order': 3,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}}]}
