Repeated exposure to intra-amniotic LPS partially protects against adverse effects of intravenous LPS in preterm lambs

Abstract

Histologic chorioamnionitis, frequently associated with preterm births and adverse outcomes, results in prolonged exposure of preterm fetuses to infectious agents and pro-inflammatory mediators, such as LPS. Endotoxin tolerance-type effects were demonstrated in fetal sheep following repetitive systemic or intra-amniotic (i.a.) exposures to LPS, suggesting that i.a. LPS exposure would cause endotoxin tolerance to a postnatal systemic dose of LPS in preterm sheep. In this study, randomized pregnant ewes received either two i.a. injections of LPS or saline prior to preterm delivery. Following operative delivery, the lambs were treated with surfactant, ventilated, and randomized to receive either i.v. LPS or saline at 30 min of age. Physiologic variables and indicators of systemic and lung inflammation were measured. Intravenous LPS decreased blood neutrophils and platelets values following i.a. saline compared to that after i.a. LPS. Intra-amniotic LPS prevented blood pressure from decreasing following the i.v. LPS, but also caused an increased oxygen index. Intra-amniotic LPS did not cause endotoxin tolerance as assessed by cytokine expression in the liver, lung or plasma, but increased myeloperoxidase-positive cells in the lung. The different compartments of exposure to LPS (i.a. vs i.v.) are unique to the fetal to newborn transition. Intra-amniotic LPS incompletely tolerized fetal lambs to postnatal i.v. LPS.

Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis

“…This is in contrast with previous studies, which differed in methodology using cord blood instead of peripheral blood . In fetal AIS sheep models, it was shown that the number of T regs in the fetal gut, thymus and lymph nodes is decreased due to intra‐amniotic IL‐1a . In the same models, these studies demonstrated that chorioamnionitis causes inflammatory changes in many organ systems after birth.…”

Fetal inflammation associated with minimal acute morbidity in moderate/late preterm infants

“…Immunostaining for inflammatory cells was performed as previously reported on sections of placenta, fetal membranes and umbilical cords from a subset of subjects in each group that were matched for sex, race and gestational age 30 31. Blind scoring for positive cells used a system to account for the heterogeneous nature of the tissue.…”

Fetal Immune Response to Chorioamnionitis

“…Compared with control lambs exposed to IA saline, the lambs exposed to IA LPS had less hypotension suggesting a systemic tolerance for cardiovascular effects of LPS. 66 However, no fetal tolerance was seen for cytokine production in multiple fetal organs. 66 Other curious interactions between prenatal and postnatal exposure have also been reported.…”