Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0257847
Title: Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis
Authors: Takahashi, Yuki
Saito, Masatoshi
Usuda, Haruo
Takahashi, Tsukasa
Watanabe, Shimpei
Hanita, Takushi
Sato, Shinichi
Kumagai, Yusaku
Koshinami, Shota
Ikeda, Hideyuki
Carter, Sean
Fee, Erin L.
Furfaro, Lucy
Chemtob, Sylvain
Keelan, Jeffrey
Olson, David
Yaegashi, Nobuo
Newnham, John P.
Jobe, Alan H.
Kemp, Matthew W. 
Issue Date: 24-Sep-2021
Publisher: Public Library of Science
Citation: Takahashi, Yuki, Saito, Masatoshi, Usuda, Haruo, Takahashi, Tsukasa, Watanabe, Shimpei, Hanita, Takushi, Sato, Shinichi, Kumagai, Yusaku, Koshinami, Shota, Ikeda, Hideyuki, Carter, Sean, Fee, Erin L., Furfaro, Lucy, Chemtob, Sylvain, Keelan, Jeffrey, Olson, David, Yaegashi, Nobuo, Newnham, John P., Jobe, Alan H., Kemp, Matthew W. (2021-09-24). Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis. PLoS ONE 16 (9-Sep) : e0257847. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0257847
Rights: Attribution 4.0 International
Abstract: Background 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 LPSinduced IA inflammation in amniotic fluid (AF) and fetal tissues. Methods 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, enzymelinked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis. Results 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? in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group. Conclusion 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. © 2021 Takahashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/233650
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0257847
Rights: Attribution 4.0 International
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