All-trans retinoic acid (RA) is a potent modulator of lung development. Chorioamnionitis, which is frequently associated with preterm birth, causes fetal lung inflammation and improves lung function but also results in alveolar simplification and microvascular injury. Endotoxin-mediated chorioamnionitis reduces RA concentration in the fetal lung to 16% of control values. We hypothesized that administration of RA to the fetus before induction of chorioamnionitis would preserve septation of the distal airspaces. Time-mated ewes with singletons were assigned to receive a fetal intramuscular treatment with 20,000 IU of RA in olive oil (or olive oil only) 3 hr prior to intra-amniotic injection of endotoxin (20 mg, E. coli 055:B5) or saline, at 124-day gestational age and 7 days after the fetal treatment. The right cranial lung lobe was processed for morphometric analysis. RA treatment did not affect chorioamnionitis-induced fetal and systemic inflammation or interleukin-8 concentrations in lung tissue. RA administration alone did not alter lung structure. Relative to control lungs (5 6 3 mL/kg), lung volume increased similarly with endotoxin (22 6 4 mL/kg) or RA plus endotoxin (20 6 3 mL/kg; P < 0.05). Alveolar wall thickness was 4.2 6 0.3 mm after endotoxin-induced chorioamnionitis, 6.0 6 0.4 mm in controls (P < 0.05 versus endotoxin) and 5.5 6 0.2 mm after RA and endotoxin (P < 0.05 versus control, n.s. versus endotoxin). The ratio of airspace versus tissue was 4.6 6 0.3 in endotoxin-induced chorioamnionitis, 2.1 6 0.3 in controls and 4.1 6 0.5 after RA and endotoxin. We conclude that fetal treatment with RA did not prevent inflammation-induced alveolar simplification.
Exposure of the fetus to antenatal inflammation can occur from chorioamnionitis, which may progress to a fetal inflammatory response syndrome (FIRS) and to fetal sepsis. We tested whether the fetal myocardium responded to systemic Gram-negative endotoxinaemia. We hypothesized that the myocardium would respond to inflammation by changes in hypoxia-inducible factor-␣ (HIF-1␣), inducible NO-synthase (iNOS), Toll-like receptors 2 and 4 (TLR2 and TLR4), IL-6, and phosphorylated signal transducer and activator of transcription-3 (pSTAT3). To model systemic endotoxinaemia, fetal sheep were exposed to Gram-negative endotoxin or saline i.v. 3 d before preterm delivery at 113 d of gestation (term ϭ 147 d). All endotoxin-exposed animals developed cardiac dysfunction within these 72 h. Cardiac mRNA and protein levels of HIF-1␣ and TLR2 and TLR4 mRNA increased, whereas STAT3 phosphorylation decreased significantly. IL-6 and iNOS mRNA remained unchanged. Fetal systemic endotoxinaemia induced myocardial inflammation by activating TLR2 and 4. The following cardiac dysfunction seems not to be mediated via cardiac iNOS. C ardiovascular dysfunction is a severe consequence of the systemic inflammatory response syndrome (SIRS) (1). A number of experiments in vivo and in vitro have been performed to study the mechanism of endotoxin-induced cardiac dysfunction in the adult (2). According to previous studies, it is mediated by proinflammatory cytokines as IL-6 (3,4) leading to excessive NO production, generated as a result of the induction of inducible NOS (iNOS) (5). These processes are controlled by signal transducer and activator of transcription-3 (STAT-3), which is activated on phosphorylation (6,7).Until now, this sequence has not been studied in the fetus. The proposed fetal counterpart to SIRS, the fetal inflammatory response syndrome (FIRS) results from an infection of the amniotic cavity called chorioamnionitis (8). FIRS is the precursor of neonatal early-onset sepsis and has been associated with fetal death, preterm premature rupture of membranes (PROM), and consequently spontaneous preterm labor, and cardiorespiratory failure, or hypoxic-ischemic brain damage at birth (9,10).Early onset neonatal sepsis remains an important cause of illness and death among very LBW preterm infants. More than one half of early infections caused by Gram-negative organisms (53%), with Escherichia coli the most common organism (41%) (11). Endotoxins from Gram-negative bacteria (lipopolysaccharide) bind to Toll-like receptors 2 and 4 (TLR2 and TLR4), which leads to the activation of nuclear factor (NF)-B, required for transcriptional activation of proinflammatory cytokines and several other inflammatory mediators (12). FIRS may launch a cytokine cascade similar to SIRS (8). Until now, it is not known whether the different fetal microenvironment with a relative lack of oxygen (13) and the more tolerant fetal immune system (14) allows the fetal heart to respond to systemic endotoxinaemia in the same way as the adult heart does. Therefore,...
The respiratory distress syndrome (RDS) contributes to perinatal morbidity and mortality associated with preterm birth. Surfactant protein B (SP-B) is decreased in RDS. Both maternal antenatal steroid administration and chorioamnionitis reduce the incidence and severity of RDS. An important mediator in chorioamnionitis is IL-6 using the JAK-STAT signaling pathway for signal transduction. We hypothesized that the steroids, betamethasone (BTM) and dexamethasone (DXM), and IL-6 had synergistic effects on SP-B gene expression and STAT3 phosphorylation in H441 cells. DXM and BTM increased SP-B mRNA levels by 16.5 (13.3)-fold and IL-6 alone by 2.3-fold. After 48-h exposure of cells to DXM or BTM, IL-6 caused a significantly greater increase in SP-B mRNA levels (28.1-fold) than IL-6 or glucocorticoids alone. Whereas IL-6 stimulated tyrosine phosphorylation of STAT3 in a time- and dose-dependent way, DXM and BTM had no effect on STAT3 phosphorylation. Both DXM and BTM could potentiate IL-6-induced phosphorylation of STAT3. The synergism of glucocorticoids and IL-6 on SP-B gene expression and the effect of glucocorticoids on IL-6-induced STAT3 phosphorylation could be blocked by a JAK inhibitor. Expression level analysis showed that glucocorticoids increased the expression of the IL-6-binding α-subunit receptor (IL-6R) on mRNA and protein level. Our findings could represent an example of a pulmonary regulation system in which one role of glucocorticoids is to increase the effect of a cytokine by upregulation of its receptor. The described in vitro interaction of IL-6 and glucocorticoids could help explain the clinical observation that prenatal inflammation in preterm babies with antenatal steroid administration can attenuate severity of RDS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.