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https://hdl.handle.net/2440/123888
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Type: | Journal article |
Title: | Toll-like receptor-4 antagonist (+)-naltrexone protects against carbamyl-platelet activating factor (Cpaf)-induced preterm labor in mice |
Author: | Wahid, H.H. Chin, P.Y. Sharkey, D.J. Diener, K.R. Hutchinson, M.R. Rice, K.C. Moldenhauer, L.M. Robertson, S.A. |
Citation: | American Journal of Pathology, 2020; 190(5):1030-1045 |
Publisher: | Elsevier |
Issue Date: | 2020 |
ISSN: | 0002-9440 1525-2191 |
Statement of Responsibility: | Hanan H. Wahid, Peck Yin Chin, David J. Sharkey, Kerrilyn R. Diener, Mark R. Hutchinson, Kenner C. Rice, Lachlan M. Moldenhauer, and Sarah A. Robertson |
Abstract: | Spontaneous preterm labor is frequently caused by an inflammatory response in the gestational tissues elicited by either infectious or sterile agents. In sterile preterm labor, the key regulators of inflammation are not identified, but platelet activating factor (PAF) is implicated as a potential rate-limiting effector agent. Since toll-like receptor 4 (TLR4) can amplify PAF signaling, we evaluated whether TLR4 contributes to inflammation and fetal loss in a mouse model of PAF-induced sterile preterm labor, and whether a small molecule TLR4 inhibitor (+)-naltrexone can mitigate adverse PAF-induced effects. Administration of carbamyl-PAF (cPAF) caused preterm labor and fetal loss in wild-type mice but not in TLR4-deficient (Tlr4-/-) mice. Treatment with (+)-naltrexone prevented preterm delivery and alleviated fetal demise in utero elicited after cPAF administered by intraperitoneal or intrauterine routes. Pups born after cPAF and (+)-naltrexone treatment exhibited comparable rates of postnatal survival and growth to carrier-treated controls. (+)-Naltrexone suppressed the cPAF-induced expression of inflammatory cytokine genes, Il1b, Il6, and Il10 in the decidua, Il6, Il12b, and Il10 in the myometrium, and Il1b and Il6 in the placenta. These data demonstrate that TLR4 antagonist (+)-naltrexoneinhibits the inflammatory cascade induced by cPAF, preventing preterm birth and perinatal death. Inhibition of TLR4 signaling warrants further investigation as a candidate strategy for fetal protection and delaying preterm birth elicited by sterile stimuli. |
Keywords: | Animals Mice, Inbred BALB C Mice Naltrexone Platelet Activating Factor Narcotic Antagonists Pregnancy Female Obstetric Labor, Premature Toll-Like Receptor 4 |
Rights: | © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
DOI: | 10.1016/j.ajpath.2020.01.008 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1140916 |
Published version: | http://dx.doi.org/10.1016/j.ajpath.2020.01.008 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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