Intra-amniotic (IA)
lipopolysaccharide (LPS) induces intrauterine and fetal
lung inflammation and increases lung
surfactant and compliance in preterm sheep; however, the mechanisms are unknown.
Prostaglandins (PGs) are inflammatory mediators, and
PGE(2) has established roles in fetal lung
surfactant production. The aim of our first study was to determine
PGE(2) concentrations in response to IA LPS and pulmonary gene expression for PG
synthetic [prostaglandin H synthase-2 (PGHS-2) and
PGE synthase (PGES)] and PG-metabolizing [
prostaglandin dehydrogenase (PGDH)]
enzymes and
PGE(2) receptors. Our second study aimed to block LPS-induced increases in
PGE(2) with a
PGHS-2 inhibitor (
nimesulide) and determine
lung inflammation and
surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid
PGE(2) concentrations increased (P < 0.05) 12 h and 3-6 days after LPS. Fetal lung
PGHS-2 mRNA and PGES
mRNA increased 2 (P = 0.0084) and 7 (P = 0.014) days after LPS, respectively. In study 2, maternal intravenous
nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later.
Nimesulide inhibited LPS-induced increases in
PGE(2) and decreased fetal lung IL-1β and
IL-8 mRNA (P ≤ 0.002) without altering lung inflammatory cell infiltration.
Nimesulide decreased
surfactant protein (SP)-A (P = 0.05), -B (P = 0.05), and -D (P = 0.0015) but increased SP-C
mRNA (P = 0.023). Thus
PGHS-2 mediates, at least in part, fetal pulmonary responses to
inflammation.