Intraamniotic Endotoxin Increases Lung Antioxidant Enzyme Activity in Preterm Lambs

Abstract

Proinflammatory stimulation resulting from intraamniotic endotoxin improves lung function, increases surfactant protein mRNA expression and protein content, increases alveolar and lung saturated phosphatidylcholine pools, and accelerates lung morphometric maturation in fetal sheep. The mechanism for induction of lung maturation does not involve an increase in fetal cortisol. The effect of endotoxin on the maturation of a different lung system, the antioxidant enzyme (AOE) system, has not been examined. Therefore, we hypothesized that intraamniotic endotoxin would produce acceleration of AOE activity in fetal sheep at similar doses and schedule of administration to those producing lung functional and surfactant maturation. In a dose-response study, intraamniotic injections of 1, 4, 20, or 100 mg of Escherichia coli 055:␤5 endotoxin were administered 7 d before preterm delivery of sheep at 125 d gestation. In a study examining time interval of administration before delivery, 20 mg of endotoxin was injected at either 1-, 2-, 4-, 7-, or 15-d intervals before preterm delivery at 125 d. Doses of 1-100 mg of endotoxin produced significant increases in glutathione peroxidase activity; doses of 4 -100 mg significantly increased catalase activity, whereas doses of 20 -100 mg resulted in significant increases in total superoxide dismutase activity. Glutathione peroxidase activity was elevated within 2 d, whereas superoxide dismutase was increased by 4 d and catalase activity increased by 7 d after endotoxin. No AOE increases were sustained for 15 d. Endotoxin increased fetal lung AOE activity at similar dosing amounts and intervals to those producing maturation of lung function and surfactant. Thus, mechanisms involving proinflammatory stimulation, unrelated to glucocorticoid hormones, can induce maturation of the AOE system of the fetal lung. Chronic infection and chorioamnionitis are associated with a decreased incidence of hyaline membrane disease (1). The mechanism of this apparent acceleration in lung maturation may be related to an increase in endogenous glucocorticoid hormones or to the stimulatory effects of inflammatory cytokines on lung maturation (2, 3). Paradoxically, however, infants exposed to chorioamnionitis may have an increased likelihood of developing chronic lung damage, or bronchopulmonary dysplasia, thought to be related to the initiation and propagation of inflammation as a result of cytokine exposure (1).Antenatal exposure to the proinflammatory stimulation produced by intraamniotic endotoxin accelerated lung maturation in sheep. Specifically, antenatal exposure to intraamniotic endotoxin improved lung mechanics, increased saturated PC in lung tissue and alveolar pools, increased surfactant protein mRNA and surfactant proteins, and changed lung morphometry, resulting in fewer, larger alveoli with thinner walls and a decreased volume of interstitial tissue (4 -8). The lung maturational changes brought about by intraamniotic endotoxin appear not to be mediated by cortisol, as no increases were found i...

Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin

“…In contrast, neonatal hyperoxia in the ETX-naïve lung simply causes inflammatory injury proportional to the intensity (56) and duration (65) of hyperoxia exposure. Alternatively, fetal ETX exposure might upregulate lung antioxidant defense mechanisms, as previously reported in a sheep model of chorioamnionitis (58). This mechanism may attenuate the inflammatory response to subsequent hyperoxia exposure, but it is unclear how increased antioxidant defenses would further enhance lung structure during hyperoxia.…”

Chorioamnionitis Induced Hepatic Inflammation and Disturbed Lipid Metabolism in Fetal Sheep

“…Although the liver is one of the most important organs both in fetal and in adult life, studies concerning chorioamnionitisinduced FIRS are limited to lungs, brain, and gut (25)(26)(27). In previous studies, we already investigated the inflammatory response to chorioamnionitis in lungs, brain, and gut using the same fetal sheep model (10,28).…”

“…In previous studies, we already investigated the inflammatory response to chorioamnionitis in lungs, brain, and gut using the same fetal sheep model (10,28). We have shown that endotoxin evoked a pulmonary inflammatory response 2 d after injections (10), which is not mediated by cortisol (29) and induced oxidative stress in the fetal lung (27,30). The chorioamnionitis-induced inflammatory response in the brain was dose dependent and the most prominent in the animals that received endotoxin 2 wk before the deliv- Metabolic parameters of saline and endotoxin-exposed animals.…”

Oxidative Stress in Fetal Lambs Exposed to Intra-amniotic Endotoxin in a Chorioamnionitis Model

“…The fetal lung could be responding to oxidative stress in CAM, but this possibility has not been well studied. Intra-amniotic endotoxin does induce antioxidant enzymes in the lungs, suggestive of a host response to mitigate oxidative injury (11). Although intra-amniotic endotoxin increased the expression of heat shock protein 70 (HSP 70), the effect was brief and limited (8).…”