Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.

<h4>Background</h4>Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks' gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent...

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Autores principales:	Yuki Takahashi, Masatoshi Saito, Haruo Usuda, Tsukasa Takahashi, Shimpei Watanabe, Takushi Hanita, Shinichi Sato, Yusaku Kumagai, Shota Koshinami, Hideyuki Ikeda, Sean Carter, Erin L Fee, Lucy Furfaro, Sylvain Chemtob, Jeffrey Keelan, David Olson, Nobuo Yaegashi, John P Newnham, Alan H Jobe, Matthew W Kemp
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/44514cea9cfe466688f1f6cc5edf99b8
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spelling	oai:doaj.org-article:44514cea9cfe466688f1f6cc5edf99b82021-12-02T20:14:10ZDirect administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.1932-620310.1371/journal.pone.0257847https://doaj.org/article/44514cea9cfe466688f1f6cc5edf99b82021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257847https://doaj.org/toc/1932-6203<h4>Background</h4>Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks' 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.<h4>Methods</h4>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: i) 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); ii) 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); 3) 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.<h4>Results</h4>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-1β in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group.<h4>Conclusion</h4>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.Yuki TakahashiMasatoshi SaitoHaruo UsudaTsukasa TakahashiShimpei WatanabeTakushi HanitaShinichi SatoYusaku KumagaiShota KoshinamiHideyuki IkedaSean CarterErin L FeeLucy FurfaroSylvain ChemtobJeffrey KeelanDavid OlsonNobuo YaegashiJohn P NewnhamAlan H JobeMatthew W KempPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257847 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuki Takahashi Masatoshi Saito Haruo Usuda Tsukasa Takahashi Shimpei Watanabe Takushi Hanita Shinichi Sato Yusaku Kumagai Shota Koshinami Hideyuki Ikeda Sean Carter Erin L Fee Lucy Furfaro Sylvain Chemtob Jeffrey Keelan David Olson Nobuo Yaegashi John P Newnham Alan H Jobe Matthew W Kemp Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
description	<h4>Background</h4>Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks' 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.<h4>Methods</h4>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: i) 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); ii) 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); 3) 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.<h4>Results</h4>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-1β in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group.<h4>Conclusion</h4>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.
format	article
author	Yuki Takahashi Masatoshi Saito Haruo Usuda Tsukasa Takahashi Shimpei Watanabe Takushi Hanita Shinichi Sato Yusaku Kumagai Shota Koshinami Hideyuki Ikeda Sean Carter Erin L Fee Lucy Furfaro Sylvain Chemtob Jeffrey Keelan David Olson Nobuo Yaegashi John P Newnham Alan H Jobe Matthew W Kemp
author_facet	Yuki Takahashi Masatoshi Saito Haruo Usuda Tsukasa Takahashi Shimpei Watanabe Takushi Hanita Shinichi Sato Yusaku Kumagai Shota Koshinami Hideyuki Ikeda Sean Carter Erin L Fee Lucy Furfaro Sylvain Chemtob Jeffrey Keelan David Olson Nobuo Yaegashi John P Newnham Alan H Jobe Matthew W Kemp
author_sort	Yuki Takahashi
title	Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
title_short	Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
title_full	Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
title_fullStr	Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
title_full_unstemmed	Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
title_sort	direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/44514cea9cfe466688f1f6cc5edf99b8
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Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.

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