{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:07:01Z","timestamp":1782212821848,"version":"3.54.5"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gretals australia Pty Ltd"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The primary flavonoid, pinocembrin, is thought to have a variety of medical uses which relate to its reported anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer properties. Some studies have reported that this flavonoid has anti-fibrotic activities. In this study, we investigated whether pinocembrin would impede fibrosis, dampen inflammation and improve lung function in a large animal model of pulmonary fibrosis. Fibrosis was induced in two localized lung segments in each of the 10 sheep participating in the study. This was achieved via two infusions of bleomycin delivered bronchoscopically at a two-week interval. Another lung segment in the same sheep was left untreated, and was used as a healthy control. The animals were kept for a little over 5 weeks after the final infusion of bleomycin. Pinocembrin, isolated from <jats:italic>Eucalyptus<\/jats:italic> leaves, was administered to one of the two bleomycin damaged lung segments at a dose of 7 mg. This dose was given once-weekly over 4-weeks, starting one week after the final bleomycin infusion. Lung compliance (as a measure of stiffness) was significantly improved after four weekly administrations of pinocembrin to bleomycin-damaged lung segments. There were significantly lower numbers of neutrophils and inflammatory cells in the bronchoalveolar lavage of bleomycin-infused lung segments that were treated with pinocembrin. Compared to bleomycin damaged lung segments without drug treatment, pinocembrin administration was associated with significantly lower numbers of immuno-positive CD8<jats:sup>+<\/jats:sup> and CD4<jats:sup>+<\/jats:sup> T cells in the lung parenchyma. Histopathology scoring data showed that pinocembrin treatment was associated with significant improvement in inflammation and overall pathology scores. Hydroxy proline analysis showed that the administration of pinocembrin did not reduce the increased collagen content that was induced by bleomycin in this model. Analyses of Masson\u2019s Trichrome stained sections showed that pinocembrin treatment significantly reduced the connective tissue content in lung segments exposed to bleomycin when compared to bleomycin-infused lungs that did not receive pinocembrin. The striking anti-inflammatory and modest anti-fibrotic remodelling effects of pinocembrin administration were likely linked to the compound\u2019s ability to improve lung pathology and functional compliance in this animal model of pulmonary fibrosis.<\/jats:p>","DOI":"10.1371\/journal.pone.0260719","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T19:35:42Z","timestamp":1638473742000},"page":"e0260719","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["The efficacy and safety of pinocembrin in a sheep model of bleomycin-induced pulmonary fibrosis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3415-7968","authenticated-orcid":true,"given":"Habtamu B.","family":"Derseh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason Q. D.","family":"Goodger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre Y.","family":"Scheerlinck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrishan S.","family":"Samuel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E.","family":"Woodrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5889-1393","authenticated-orcid":true,"given":"Enzo A.","family":"Palombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair","family":"Cumming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Snibson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"issue":"7","key":"pone.0260719.ref001","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s00210-021-02067-5","article-title":"Protective and therapeutic effects of the flavonoid \"pinocembrin\" in indomethacin-induced acute gastric ulcer in rats: impact of anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms","volume":"394","author":"AA El-Demerdash","year":"2021","journal-title":"Naunyn-Schmiedeberg\u2019s archives of pharmacology"},{"key":"pone.0260719.ref002","doi-asserted-by":"crossref","first-page":"107230","DOI":"10.1016\/j.intimp.2020.107230","article-title":"Pinocembrin relieves lipopolysaccharide and bleomycin induced lung inflammation via inhibiting TLR4-NF-kappaB-NLRP3 inflammasome signaling pathway","volume":"90","author":"W Gan","year":"2021","journal-title":"International immunopharmacology"},{"issue":"2","key":"pone.0260719.ref003","doi-asserted-by":"crossref","DOI":"10.3390\/biom8020041","article-title":"Pinocembrin(-)Lecithin Complex: Characterization, Solubilization, and Antioxidant Activities","volume":"8","author":"X Yang","year":"2018","journal-title":"Biomolecules"},{"key":"pone.0260719.ref004","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jneuroim.2017.11.006","article-title":"Pinocembrin alleviates cognition deficits by inhibiting inflammation in diabetic mice","volume":"314","author":"B Pei","year":"2018","journal-title":"J Neuroimmunol"},{"key":"pone.0260719.ref005","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.fsi.2016.07.038","article-title":"Pinocembrin attenuates lipopolysaccharide-induced inflammatory responses in Labeo rohita macrophages via the suppression of the NF-kappaB signalling pathway","volume":"56","author":"SS Giri","year":"2016","journal-title":"Fish Shellfish Immunol"},{"key":"pone.0260719.ref006","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejphar.2015.06.003","article-title":"Pinocembrin inhibits lipopolysaccharide-induced inflammatory mediators production in BV2 microglial cells through suppression of PI3K\/Akt\/NF-kappaB pathway","volume":"761","author":"LT Zhou","year":"2015","journal-title":"European journal of pharmacology"},{"issue":"3","key":"pone.0260719.ref007","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1007\/s12035-015-9125-2","article-title":"The Natural Flavonoid Pinocembrin: Molecular Targets and Potential Therapeutic Applications","volume":"53","author":"X Lan","year":"2016","journal-title":"Mol Neurobiol"},{"key":"pone.0260719.ref008","doi-asserted-by":"crossref","first-page":"547966","DOI":"10.3389\/fphar.2020.547966","article-title":"Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression","volume":"11","author":"T Ye","year":"2020","journal-title":"Front Pharmacol"},{"key":"pone.0260719.ref009","doi-asserted-by":"crossref","first-page":"105926","DOI":"10.1016\/j.intimp.2019.105926","article-title":"Pinocembrin attenuates autonomic dysfunction and atrial fibrillation susceptibility via inhibition of the NF-kappaB\/TNF-alpha pathway in a rat model of myocardial infarction","volume":"77","author":"T Ye","year":"2019","journal-title":"International immunopharmacology"},{"issue":"2","key":"pone.0260719.ref010","doi-asserted-by":"crossref","first-page":"307","DOI":"10.5604\/01.3001.0010.8662","article-title":"Antifibrotic Mechanism of Pinocembrin: Impact on Oxidative Stress, Inflammation and TGF-beta \/Smad Inhibition in Rats","volume":"17","author":"MM Said","year":"2018","journal-title":"Ann Hepatol"},{"issue":"8","key":"pone.0260719.ref011","article-title":"Pinocembrin Ameliorates Skin Fibrosis via Inhibiting TGF-beta1 Signaling Pathway","volume":"11","author":"X Li","year":"2021","journal-title":"Biomolecules"},{"key":"pone.0260719.ref012","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12890-015-0071-6","article-title":"Structural and functional correlations in a large animal model of bleomycin-induced pulmonary fibrosis","volume":"15","author":"L Organ","year":"2015","journal-title":"Bmc Pulm Med"},{"issue":"3","key":"pone.0260719.ref013","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3109\/01902148.2014.985806","article-title":"A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep","volume":"41","author":"L Organ","year":"2015","journal-title":"Exp Lung Res"},{"issue":"9\u201310","key":"pone.0260719.ref014","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1080\/01902148.2019.1695019","article-title":"The efficacy of pirfenidone in a sheep model of pulmonary fibrosis","volume":"45","author":"SNV Dewage","year":"2019","journal-title":"Exp Lung Res"},{"issue":"1","key":"pone.0260719.ref015","doi-asserted-by":"crossref","first-page":"19893","DOI":"10.1038\/s41598-019-56412-z","article-title":"KCa3.1 channel blockade attenuates microvascular remodelling in a large animal model of bleomycin-induced pulmonary fibrosis","volume":"9","author":"HB Derseh","year":"2019","journal-title":"Scientific reports"},{"issue":"4","key":"pone.0260719.ref016","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1165\/rcmb.2016-0092OC","article-title":"Inhibition of the KCa3.1 Channel Alleviates Established Pulmonary Fibrosis in a Large Animal Model","volume":"56","author":"L Organ","year":"2017","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"10082","key":"pone.0260719.ref017","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1016\/S0140-6736(17)30866-8","article-title":"Idiopathic pulmonary fibrosis","volume":"389","author":"L Richeldi","year":"2017","journal-title":"Lancet"},{"issue":"2","key":"pone.0260719.ref018","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1136\/thoraxjnl-2011-201398","article-title":"Hot off the breath: triple therapy for idiopathic pulmonary fibrosis\u2014hear the PANTHER roar","volume":"67","author":"EE McGrath","year":"2012","journal-title":"Thorax"},{"key":"pone.0260719.ref019","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.indcrop.2019.01.050","article-title":"Eucalyptus subgenus Eucalyptus (Myrtaceae) trees are abundant sources of medicinal pinocembrin and related methylated flavanones","volume":"131","author":"JQD Goodger","year":"2019","journal-title":"Ind Crops Prod"},{"key":"pone.0260719.ref020","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.intimp.2017.10.005","article-title":"Pinocembrin attenuates allergic airway inflammation via inhibition of NF-kappaB pathway in mice","volume":"53","author":"X Gu","year":"2017","journal-title":"International immunopharmacology"},{"issue":"3","key":"pone.0260719.ref021","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1152\/physrev.1975.55.3.418","article-title":"Posttranslational protein modifications, with special attention to collagen and elastin","volume":"55","author":"PM Gallop","year":"1975","journal-title":"Physiological reviews"},{"issue":"10","key":"pone.0260719.ref022","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1080\/01902148.2020.1834015","article-title":"Small airway remodeling in a sheep model of bleomycin-induced pulmonary fibrosis","volume":"46","author":"HB Derseh","year":"2020","journal-title":"Exp Lung Res"},{"issue":"2969","key":"pone.0260719.ref023","article-title":"Tetrathiomolybdate Treatment Attenuates Bleomycin-Induced Angiogenesis and Lung Pathology in a Sheep Model of Pulmonary Fibrosis","volume":"12","author":"HB Derseh","year":"2021","journal-title":"Frontiers in Pharmacology"},{"key":"pone.0260719.ref024","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.biopha.2017.06.052","article-title":"The efficacy of plant extract and bioactive compounds approaches in the treatment of pulmonary fibrosis: A systematic review","volume":"93","author":"S Bahri","year":"2017","journal-title":"Biomed Pharmacother"},{"issue":"6","key":"pone.0260719.ref025","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.01105-2019","article-title":"The importance of interventional timing in the bleomycin model of pulmonary fibrosis","volume":"55","author":"P Kolb","year":"2020","journal-title":"The European respiratory journal"},{"key":"pone.0260719.ref026","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jep.2015.03.041","article-title":"Pharmacokinetics, safety, and tolerability of single and multiple-doses of pinocembrin injection administered intravenously in healthy subjects","volume":"168","author":"G Cao","year":"2015","journal-title":"Journal of ethnopharmacology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260719","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T19:36:15Z","timestamp":1638473775000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260719"}},"subtitle":[],"editor":[{"given":"Christine M.","family":"Freeman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":26,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0260719","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}