Myocardial Response in Preterm Fetal Sheep Exposed to Systemic Endotoxinaemia

Abstract

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,...

Sex differences in cerebral blood flow following chorioamnionitis in healthy term infants

“…Cardiac dysfunction is a possible explanation for increases in CBF in the HC group, but our infants were asymptomatic, healthy term newborns without differences in heart rate between control and HC or sexes. 23, 29, 30, 31 …”

Propofol administration to the fetal–maternal unit reduces cardiac oxidative stress in preterm lambs subjected to prenatal asphyxia and cardiac arrest

“…Protein content in the supernatant was determined using the Micro BCA Protein Assay Kit (Thermo Fisher Scientific, Rockford, IL), with BSA as the standard. Western blots were performed as previously described (40). The following dilutions for antibodies were used: 1:1,000 for monoclonal anti-β-actin clone AC-1 (Sigma-Aldrich), anti-MLC antibody (Abcam, Cambridge, UK), anti-iNOS (BD Transduction Laboratories, Franklin Lakes, NJ), anti-TAK-1 (Cell Signaling Technology, Danvers, MA), and anti-phospho-p38 MAPK out of the PathScan Multiplex Western Cocktail II (Cell Signaling Technology).…”

Maternal inflammation, growth retardation, and preterm birth: Insights into adult cardiovascular disease

“…Conversely, changes in systolic and diastolic blood pressure and increased resting heart rates have been observed in adult rats after neonatal exposure to hyperoxia (Yzydorczyk et al, 2008). Most recently, Seehase et al (2011)reported that antenatal exposure of fetal sheep to endotoxinaemia resulted in cardiac inflammation and dysfunction within 3 days.…”