Acute on chronic exposure to endotoxin in preterm fetal sheep

Abstract

Acute, high-dose exposure to endotoxin lipopolysaccharide (LPS) in preterm fetal sheep can trigger periventricular white matter lesions (PVL), in association with severe hypotension/hypoxemia and significant mortality. Intriguingly, however, chronic or repeated exposure to LPS can induce tachyphylaxis. We therefore tested the hypothesis that progressive, acute on chronic fetal infection would be associated with white matter injury with little fetal mortality. Chronically instrumented preterm (0.7 gestational age) fetal sheep were exposed to a continuous low-dose LPS infusion (100 ng over 24 h, followed by 250 ng/24 h for 96 h) or saline. Boluses of 1 μg LPS or saline were given at 48, 72, and 96 h; sheep were killed at day 10. Six of 11 fetal sheep exposed to saline infusion + LPS boluses died 4-7 h after the first bolus. In contrast, there was no fetal mortality after saline infusions alone (n = 9), low-dose LPS infusion + saline boluses (n = 5), or low-dose LPS + LPS boluses (n = 9). Low-dose LPS infusion + LPS boluses was associated with greater microglial induction than low-dose LPS + saline boluses but a similar area of periventricular white matter inflammation. One fetus developed severe focal white matter necrosis after LPS infusion + boluses. The acute cardiovascular compromise associated with high-dose, acute exposure to LPS is markedly attenuated by previous low-dose infusions, with limited apparent exacerbation of periventricular white matter injury compared with low-dose infusion alone.

Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep

“…Carotid vascular conductance was significantly increased in LPS-treated animals before occlusion consistent with our previous report (22) and previous studies that found increased carotid blood flow despite hypotension (10,25). Despite this marked central vasodilation, occlusion was associated with a rapid reduction in conductance that was not significantly different to saline-treated fetuses.…”

“…In part, the mechanisms are likely to include induction of self-tolerance to LPS, consistent with our previous report (22), with no fetal hypotension or tachycardia before occlusion despite administration of high-dose LPS just 6 h earlier. Nevertheless, it is not obvious how greater tolerance alone could mediate an enhanced response.…”

“…These data are difficult to interpret given that high-dose LPS by itself is associated with severe hypotension and a high risk of death over 4 to 7 h (7,8,10,22,25). Supporting a direct effect, there is evidence of impaired chemoreflex responses in adult patients with sepsis and multiple organ failure (29,30) and after acute LPS injection in anesthetized adult cats and neonatal piglets (11,23).…”

“…We recently reported that in 0.7 gestation fetal sheep, broadly equivalent to 28 -32 wk of human development (3), the acute hypotension and death associated with high-dose, acute exposure to LPS is markedly attenuated by previous low-dose infusion of LPS (22). We used this approach, which helps to reduce the confounding effects of acute LPS-induced hypotension, to test the hypothesis that acute on chronic exposure to LPS would impair fetal chemoreflex responses and hemodynamic adaptation to acute severe asphyxia induced by complete umbilical cord occlusion for 15 min.…”

“…LPS was administered as previously described (22). Briefly, at 102 Ϯ 0 days ga fetuses received a continuous infusion of either LPS (derived from Escherichia coli, serotype 055:B5, Sigma Aldrich, dissolved in normal saline; LPS-treated group, n ϭ 8), or the same volume of normal saline (saline-treated group, n ϭ 7) for 5 days.…”