The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice†

Abstract

Sepsis is the leading cause of direct maternal mortality, but there are no data directly comparing the response to sepsis in pregnant and nonpregnant (NP) individuals. This study uses a mouse model of sepsis to test the hypothesis that the cardiovascular response to sepsis is more marked during pregnancy. Female CD1 mice had radiotelemetry probes implanted and were time mated. NP and day 16 pregnant CD-1 mice received intraperitoneal lipopolysaccharide (LPS; 10 μg, serotype 0111: B4). In a separate study, tissue and serum (for RNA, protein and flow cytometry studies), aorta and uterine vessels (for wire myography) were collected after LPS or vehicle control administration. Administration of LPS resulted in a greater fall in blood pressure in pregnant mice compared to NP mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors, and circulating leukocytes, but with a greater monocyte and lesser neutrophil margination in the lungs of pregnant mice. Baseline markers of cardiac dysfunction and apoptosis as well as cytokine expression were higher in pregnant mice, but the response to LPS was similar in both groups as was the ex vivo assessment of vascular function. In pregnant mice, nonfatal sepsis is associated with a more marked hypotensive response but not a greater immune response. We conclude that endotoxemia induces a more marked hypotensive response in pregnant compared to NP mice. These changes were not associated with a more marked systemic inflammatory response in pregnant mice, although monocyte lung margination was greater. The more marked hypotensive response to LPS may explain the greater vulnerability to some infections exhibited by pregnant women. Pregnancy enhances LPS-induced hypotension, 2017, Vol. 97, No. 2 Summary SentenceIn pregnant mice, nonfatal sepsis is associated with a more marked hypotensive response but not a greater immune response.

Short‐term LPS induces aortic valve thickening in ApoE*3Leiden mice

“…Moreover, noninflammatory effects of LPS‐induced systemic inflammation could be further explored. For instance, hemodynamic disturbances—as observed in several mice models upon LPS administration—might affect valve pathology . However, whether this leads to direct valve thickening remains to be established.…”

LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation

“…This may relate to pregnancy-induced changes in the cardiovascular system or to an excessive response of the innate immune system to infection. Previously, we reported that the administration of the bacterial wall component, lipopolysaccharide (LPS), to pregnant mice resulted in marked hypotension, but had no effect in non-pregnant mice [3]. We extended these findings using caecal ligation and puncture (CLP), showing that pregnant mice had a more marked hypotensive response and a higher mortality [4].…”

“…However, since P4 alters both the maternal immune and cardiovascular systems, it is possible that it could change the maternal response to infection, potentially making women more susceptible to sepsis. In an earlier study, we reported that LPS administration induced a greater hypotensive response in pregnant compared to non-pregnant mice [3]. In this study, we have tested the hypothesis that P4 supplementation exacerbates this hypotensive response in pregnant mice and investigated potential causative mechanisms, studying aspects of the innate immune and the cardiac responses to LPS.…”

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

“…The immune system of the mother during pregnancy is tightly regulated to prevent an unwanted immune response against the paternal antigens present in the developing conceptus (Racicot et al, 2014 ; Groen et al, 2015 ; Zöllner et al, 2017 ). As gestation progresses, there is suppression of the pro-inflammatory Th1 type of immunity and a shift toward a more anti-inflammatory, Th2 immune state in the mother (Saito et al, 2010 ), which supports fetal growth and maternal well-being (Mor and Cardenas, 2010 ).…”