Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction

A mouse model for fetal inflammatory response

Samuli Rounioja, Juha Rasanen, Virpi Glumoff, Marja Ojaniemi, Kaarin Mäkikallio, Mikko Hallman

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Objective: Intrauterine infection is associated with increased lipopolysaccharide (LPS) and proinflammatory cytokines in amniotic fluid. We hypothesized that intra-amniotic LPS launches a fetal inflammatory response leading to cardiac dysfunction. Methods: A mouse model was established. At 15-16 days of gestation, 52 fetuses of nine dams received LPS and 46 fetuses of nine dams vehicle intra-amniotically. Five dams underwent a sham operation. Echocardiography was performed before and 6 h after the injection to obtain inflow and outflow blood velocity waveforms. Outflow mean velocity (V mean) and the proportions of isovolumetric relaxation (IRT%) and contraction (ICT%) times of the cardiac cycle were calculated. Pulsatility indices (PI) were calculated from the umbilical and intracranial arteries and the descending aorta. Pulsatility indices for veins (PIV) were obtained from ductus venosus. Toll-like receptor-4 (TLR4) and several other inflammatory mediators were determined using ELISA, immunohistochemistry, or ribonuclease protection assay. Results: In the LPS group, outflow Vmean was significantly lower, and ICT% and IRT% longer than in the other groups. LPS increased PIs, except in the intracranial arteries, which showed a decrease in PIs. In ductus venosus, PIVs were increased after LPS. LPS increased interleukin (IL)-6 in amniotic fluid and induced the expression of proinflammatory cytokines in placenta and fetal membranes, but not in lung. In fetal myocardium, TLR4 was constitutional. LPS induced the expression of IL-1β and tumor necrosis factor (TNF)-α mRNA in myocardium, whereas inducible nitric oxide synthase (NOS2) protein and nitrotyrosine remained undetectable. Conclusions: As a response to endotoxin in amniotic fluid, fetal myocardium acutely generates cytokines and severe fetal cardiovascular compromise develops. These two may be linked through a mechanism that does not include NO.

Original languageEnglish (US)
Pages (from-to)156-164
Number of pages9
JournalCardiovascular Research
Volume60
Issue number1
DOIs
StatePublished - Nov 1 2003
Externally publishedYes

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Lipopolysaccharides
Amniotic Fluid
Myocardium
Toll-Like Receptor 4
Cytokines
Fetus
Extraembryonic Membranes
Umbilical Arteries
Nitric Oxide Synthase Type II
Ribonucleases
Thoracic Aorta
Interleukin-1
Endotoxins
Placenta
Echocardiography
Veins
Interleukin-6
Arteries
Tumor Necrosis Factor-alpha
Enzyme-Linked Immunosorbent Assay

Keywords

  • Contractile function
  • Cytokines
  • Endotoxins
  • Hemodynamics
  • Infection/ inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction : A mouse model for fetal inflammatory response. / Rounioja, Samuli; Rasanen, Juha; Glumoff, Virpi; Ojaniemi, Marja; Mäkikallio, Kaarin; Hallman, Mikko.

In: Cardiovascular Research, Vol. 60, No. 1, 01.11.2003, p. 156-164.

Research output: Contribution to journalArticle

Rounioja, Samuli ; Rasanen, Juha ; Glumoff, Virpi ; Ojaniemi, Marja ; Mäkikallio, Kaarin ; Hallman, Mikko. / Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction : A mouse model for fetal inflammatory response. In: Cardiovascular Research. 2003 ; Vol. 60, No. 1. pp. 156-164.
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abstract = "Objective: Intrauterine infection is associated with increased lipopolysaccharide (LPS) and proinflammatory cytokines in amniotic fluid. We hypothesized that intra-amniotic LPS launches a fetal inflammatory response leading to cardiac dysfunction. Methods: A mouse model was established. At 15-16 days of gestation, 52 fetuses of nine dams received LPS and 46 fetuses of nine dams vehicle intra-amniotically. Five dams underwent a sham operation. Echocardiography was performed before and 6 h after the injection to obtain inflow and outflow blood velocity waveforms. Outflow mean velocity (V mean) and the proportions of isovolumetric relaxation (IRT{\%}) and contraction (ICT{\%}) times of the cardiac cycle were calculated. Pulsatility indices (PI) were calculated from the umbilical and intracranial arteries and the descending aorta. Pulsatility indices for veins (PIV) were obtained from ductus venosus. Toll-like receptor-4 (TLR4) and several other inflammatory mediators were determined using ELISA, immunohistochemistry, or ribonuclease protection assay. Results: In the LPS group, outflow Vmean was significantly lower, and ICT{\%} and IRT{\%} longer than in the other groups. LPS increased PIs, except in the intracranial arteries, which showed a decrease in PIs. In ductus venosus, PIVs were increased after LPS. LPS increased interleukin (IL)-6 in amniotic fluid and induced the expression of proinflammatory cytokines in placenta and fetal membranes, but not in lung. In fetal myocardium, TLR4 was constitutional. LPS induced the expression of IL-1β and tumor necrosis factor (TNF)-α mRNA in myocardium, whereas inducible nitric oxide synthase (NOS2) protein and nitrotyrosine remained undetectable. Conclusions: As a response to endotoxin in amniotic fluid, fetal myocardium acutely generates cytokines and severe fetal cardiovascular compromise develops. These two may be linked through a mechanism that does not include NO.",
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T1 - Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction

T2 - A mouse model for fetal inflammatory response

AU - Rounioja, Samuli

AU - Rasanen, Juha

AU - Glumoff, Virpi

AU - Ojaniemi, Marja

AU - Mäkikallio, Kaarin

AU - Hallman, Mikko

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AB - Objective: Intrauterine infection is associated with increased lipopolysaccharide (LPS) and proinflammatory cytokines in amniotic fluid. We hypothesized that intra-amniotic LPS launches a fetal inflammatory response leading to cardiac dysfunction. Methods: A mouse model was established. At 15-16 days of gestation, 52 fetuses of nine dams received LPS and 46 fetuses of nine dams vehicle intra-amniotically. Five dams underwent a sham operation. Echocardiography was performed before and 6 h after the injection to obtain inflow and outflow blood velocity waveforms. Outflow mean velocity (V mean) and the proportions of isovolumetric relaxation (IRT%) and contraction (ICT%) times of the cardiac cycle were calculated. Pulsatility indices (PI) were calculated from the umbilical and intracranial arteries and the descending aorta. Pulsatility indices for veins (PIV) were obtained from ductus venosus. Toll-like receptor-4 (TLR4) and several other inflammatory mediators were determined using ELISA, immunohistochemistry, or ribonuclease protection assay. Results: In the LPS group, outflow Vmean was significantly lower, and ICT% and IRT% longer than in the other groups. LPS increased PIs, except in the intracranial arteries, which showed a decrease in PIs. In ductus venosus, PIVs were increased after LPS. LPS increased interleukin (IL)-6 in amniotic fluid and induced the expression of proinflammatory cytokines in placenta and fetal membranes, but not in lung. In fetal myocardium, TLR4 was constitutional. LPS induced the expression of IL-1β and tumor necrosis factor (TNF)-α mRNA in myocardium, whereas inducible nitric oxide synthase (NOS2) protein and nitrotyrosine remained undetectable. Conclusions: As a response to endotoxin in amniotic fluid, fetal myocardium acutely generates cytokines and severe fetal cardiovascular compromise develops. These two may be linked through a mechanism that does not include NO.

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KW - Hemodynamics

KW - Infection/ inflammation

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