{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:14:17Z","timestamp":1789996457066,"version":"4.0.1"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T00:00:00Z","timestamp":1632441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1145295"],"award-info":[{"award-number":["1145295"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001069","name":"Women and Infants Research Foundation","doi-asserted-by":"publisher","award":["MKEMP"],"award-info":[{"award-number":["MKEMP"]}],"id":[{"id":"10.13039\/501100001069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","award":["1145295"],"award-info":[{"award-number":["1145295"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","award":["1145295"],"award-info":[{"award-number":["1145295"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks\u2019 gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: <jats:bold>i)<\/jats:bold> IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7); <jats:bold>ii)<\/jats:bold> IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10); <jats:bold>3)<\/jats:bold> IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg\/fetal kg IA and 1 mg\/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF samples were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administration, the average MCP-1 concentrations in the AF were significantly lower in the LPS + rytvela Group relative to in the LPS Group. In delivery samples, the expression of IL-1\u03b2 in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>A single dose of rytvela was associated with partial, modest inhibition in the expression of a panel of cytokines\/chemokines in fetal tissues undergoing an active inflammatory response.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0257847","type":"journal-article","created":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T17:51:08Z","timestamp":1632505868000},"page":"e0257847","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis"],"prefix":"10.1371","volume":"16","author":[{"given":"Yuki","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruo","family":"Usuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsukasa","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimpei","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takushi","family":"Hanita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3253-9601","authenticated-orcid":true,"given":"Yusaku","family":"Kumagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Koshinami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L.","family":"Fee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Furfaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Chemtob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Keelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Olson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuo","family":"Yaegashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Newnham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H.","family":"Jobe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9662-5029","authenticated-orcid":true,"given":"Matthew W.","family":"Kemp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,24]]},"reference":[{"issue":"1","key":"pone.0257847.ref001","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ajog.2003.07.012","article-title":"A fetal response to chorioamnionitis is associated with early survival after preterm birth","volume":"190","author":"MM Lahra","year":"2004","journal-title":"Am J Obstet Gynecol"},{"issue":"10063","key":"pone.0257847.ref002","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1016\/S0140-6736(16)31593-8","article-title":"Global, regional, and national causes of under-5 mortality in 2000\u201315: an updated systematic analysis with implications for the Sustainable Development Goals","volume":"388","author":"L Liu","year":"2016","journal-title":"Lancet"},{"issue":"1","key":"pone.0257847.ref003","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1177\/1933719115618282","article-title":"Recent Progress in Therapeutics for Inflammation-Associated Preterm Birth","volume":"24","author":"A Taguchi","year":"2017","journal-title":"A Review. 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