Prolonged reductions in placental blood flow and cerebral oxygen delivery in preterm fetal sheep exposed to endotoxin: possible factors in white matter injury after acute infection

Abstract

Immature fetal sheep exposed to LPS had profound reductions in placental blood flow and cerebral O(2) delivery, which could contribute to fetal brain injury. Reduced O(2) delivery to white matter was similar to that in other brain regions. Mechanisms that enable fetal CBF to increase in hypoxemic conditions were apparently ineffective in the presence of LPS.

Acute on chronic exposure to endotoxin in preterm fetal sheep

“…Acute exposure to LPS, consistent with acute ascending E. coli infection, is associated with fetal hypotension, hypoxia, and metabolic acidosis in the fetal sheep (9,13,15), consistent with the present study. Although no mortality was reported by Duncan and colleagues in a slightly less mature cohort (0.65 of gestation) (13), others report acute loss of a third to over 40% of fetuses associated with terminal hypotension (9,15,31), similar to the deaths of 6/11 fetuses in our preliminary studies.…”

“…Mild fetal hypotension, tachycardia, and increased carotid blood flow with mixed respiratory and metabolic acidosis were seen after the first bolus of LPS. However, in contrast with the group that received saline preinfusion with the same LPS boluses, and previous studies using similar doses of LPS (9,15), there were no fetal deaths. Intriguingly, there was further attenuation of hypotension with successive LPS boluses, showing that the infusion did not induce complete or maximal insensitivity to LPS.…”

“…Although this is a well-recognized situation, subclinical infection followed by acute exacerbations is more common and associated with adverse outcomes (20,39). An important practical limitation of bolus administration of high-dose LPS is that it triggers hypotension and impaired placental flow, a decrease in oxygen delivery to the brain, and an increased risk of fetal death (9,18,31). Conversely, there is consistent evidence for tachyphylaxis with LPS, as shown by attenuation of cardiovascular responses with successive boluses of LPS (13), and reduced monocyte reactions after chronic LPS exposure (25,27).…”

Nitric Oxide and Fetal Organ Blood Flow During Normoxia and Hypoxemia in Endotoxin-Treated Fetal Sheep

“…Premature fetal sheep exposed to LPS endotoxin have been shown to have profound reductions in placental blood flow and cerebral oxygen delivery. 23 The regulation of umbilical and placental blood flow must depend on circulating or locally released vasoactive substances, 24,25 because these vessels lack autonomic innervation. 26 In fetal sheep, the microcirculation of the placenta is remarkably inert to many vasoconstrictors, whereas the umbilical artery and vein are more vasoactive.…”

Inhibition of Matrix Metalloproteinases-2/-9 Transiently Reduces Pre-Oligodendrocyte Loss during Lipopolysaccharide- but Not Tumour Necrosis Factor-alpha-Induced Inflammation in Fetal Ovine Glial Culture

“…The dose for TNF-α was chosen based on previously reported data [14,15,16]. The LPS dosage was selected because in vitro [14,17] and in vivo [9,18] it is associated with significant toxicity to oligodendrocytes. Sister cultures were pretreated with 1 µ M of the specific gelatinase inhibitor, SB-3CT (Biomol International), a dose greater than that reported to inhibit MMP-2 and MMP-9 (Ki ∼13.9 n M for MMP-2; Ki ∼600 n M for MMP-9) [19], 30 min before exposure to either TNF-α or LPS.…”