No abstract

Systemic maternal inflammation contributes to preterm birth and is associated with development of bronchopulmonary dysplasia (BPD). Infants with BPD exhibit decreased alveolarization, diffuse interstitial fibrosis with thickened alveolar septa, and impaired pulmonary function. We tested the hypothesis that systemic prenatal LPS administration to pregnant mice followed by postnatal hyperoxia exposure is associated with prolonged alterations in pulmonary structure and function after return to room air (RA) that are more severe than hyperoxia exposure alone. Timed-pregnant C3H/HeN mice were dosed with LPS (80 microg/kg) or saline on gestation day 16. Newborn pups were exposed to RA or 85% O2 for 14 days and then to RA for an additional 14 days. Data were collected and analyzed on postnatal days 14 and 28. The combination of prenatal LPS and postnatal hyperoxia exposure generated a phenotype with more inflammation (measured as no. of macrophages per high-power field) than either insult alone at day 28. The combined exposures were associated with a diffuse fibrotic response [measured as hydroxyproline content (microg)] but did not induce a more severe developmental arrest than hyperoxia alone. Pulmonary function tests indicated that hyperoxia, independent of maternal exposure, induced compliance decreases on day 14 that did not persist after RA recovery. Either treatment alone or combined induced an increase in resistance on day 14, but the increase persisted on day 28 only in pups receiving the combined treatment. In conclusion, the combination of systemic maternal inflammation and neonatal hyperoxia induced a prolonged phenotype of arrested alveolarization, diffuse fibrosis, and impaired lung mechanics that mimics human BPD. This new model should be useful in designing studies of specific mechanisms and interventions that could ultimately be utilized to define therapies to prevent BPD in premature infants.

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Dietary supplementation with (ω)-3 long chain fatty acids including docosahexaenoic acid (DHA) has increased in popularity in recent years and adequate DHA supplementation during pregnancy and early childhood is of clinical importance. Some evidence has been built for the neuro-cognitive benefits of supplementation with long chain polyunsaturated fatty acids (LCPUFA) such as DHA during pregnancy; however, recent data indicate that the anti-inflammatory properties may be of at least equal significance. Adequate DHA availability in the fetus/infant optimizes brain and retinal maturation in part by influencing neurotransmitter pathways. The anti-inflammatory properties of LCPUFA are largely mediated through modulation of signaling either directly through binding to receptors or through changes in lipid raft formation and receptor presentation. Our goal is to review the current findings on DHA supplementation, specifically in pregnancy and infant neurodevelopment, as a pharmacologic agent with both preventative and therapeutic value. Given the overall benefits of DHA, maternal and infant supplementation may improve neurological outcomes especially in vulernable populations. However, optimal composition of the supplement and dosing and treatment strategies still need to be determined to lend support for routine supplementation.

Objective:Premature infants, especially those born less than 1500 g, often exhibit slow overall growth after birth and lack of early nutritional support may be an important element. We tested the hypothesis that early administration of amino acids (within the first few hours of life) to infants born at less than 1500 g would be associated with fewer infants that were less than the 10th percentile at 36 weeks post-conceptual age than infants that received amino acids after the first 24 h of life.Study Design:A prospective intervention of early amino-acid (EAA) supplementation, began before 24 h of life, in preterm infants, <1500 g, was compared to a retrospective cohort of preterm infants receiving late amino-acid (LAA) supplementation, began after 24 h of life. The primary outcome variable was the proportion of infants at less than the 10th percentile at 36 weeks post-conceptual age.Result:Fewer infants fell below the 10th percentile (P<0.001) in the EAA group. Furthermore, infants in the EAA groups had significantly greater weight gains than did the LAA group (P<0.003) after adjusting for gestational age and time from birth to discharge. In addition, shorter duration of parenteral nutrition was associated with EAA supplementation (P<0.001).Conclusion:A prospective strategy of EAA in preterm infants <1500 g was associated with an improved weight gain, suggesting that nutrition that included amino acids may be critical during the first 24 h of life.

Aims: Pulmonary oxygen toxicity contributes to lung injury in newborn and adult humans. We previously reported that thioredoxin reductase (TrxR1) inhibition with aurothioglucose (ATG) attenuates hyperoxic lung injury in adult mice. The present studies tested the hypothesis that TrxR1 inhibition protects against the effects of hyperoxia via nuclear factor E2-related factor 2 (Nrf2)-dependent mechanisms. Results: Both pharmacologic and siRNA-mediated TrxR1 inhibition induced robust Nrf2 responses in murine-transformed Clara cells (mtCC). While TrxR1 inhibition did not alter the susceptibility of cells to the effects of hyperoxia, glutathione (GSH) depletion after TrxR1 inhibition markedly enhanced the hyperoxic susceptibility of cultured mtCCs. Finally, in vivo data revealed dose-dependent increases in the expression of the Nrf2 target gene NADPH:quinone oxidoreductase 1 (NQO1) in the lungs of ATGtreated adult mice. Innovation: TrxR1 inhibition activates Nrf2-dependent antioxidant responses in mtCCs in vitro and in adult murine lungs in vivo, providing a plausible mechanism for the protective effects of TrxR1 inhibition in vivo. Conclusion: GSH-dependent enzyme systems in mtCCs may be of greater importance for protection against hyperoxic exposure than are TrxR-dependent systems. The induction of Nrf2 activation via TrxR1 inhibition represents a novel therapeutic strategy that attenuates oxidant-mediated lung injury. Similar expression levels of TrxR1 in newborn and adult mouse or human lungs broaden the potential clinical applicability of the present findings to both neonatal and adult oxidant lung injury.

Maternal obesity induces chronic inflammatory responses that impact the fetus/neonate during the perinatal period. Inflammation, iron regulation, and myelination are closely interconnected and disruptions in these processes may have deleterious effects on neurodevelopment. Hepcidin levels are increased in response to inflammation causing subsequent decreases in ferroportin and available iron needed for myelination. Our current studies were designed to test the hypotheses that: 1) maternal high fat diet (HFD) prior to and during pregnancy is sufficient to induce inflammation and alter iron regulation in the brain of the offspring, and 2) HFD exposure is associated with altered myelination and neurobehavioral deficits in the offspring. Our data revealed modest increases in inflammatory cytokines in the serum of dams fed HFD prior to pregnancy compared to dams fed a control diet (CD). Early increases in IL-5 and decreases in IL-10 were observed in serum at PN7 while IL-5 remained elevated at PN21 in the HFDexposed pups. At PN0, most cytokine levels in whole brain homogenates were higher in the pups born to HFD-fed dams but were not different or were lower than in pups born to CD-fed dams at PN21. Conversely, the inflammation mediated transcription factor Nurr77 remained elevated at PN21. At birth, brain hepcidin, ferroportin, and l-ferritin levels were elevated in pups born to HFD-fed dams compared to pups born to CD-fed dams. Hepcidin levels remained elevated at PN7 and PN21 while ferroportin and l-ferritin levels were lower at PN7 and were not different at PN21. Decreases in myelination in the medial cortex were observed in male but not in female pups born to maternal HFD-fed dams at PN21. These structural changes correlated with changes in behavior (novel object recognition) in at 4 months in males only. Our data indicate that maternal obesity (HFD) results in disruption of iron regulation in the brains of the offspring with structural and neurobehavioral deficits in males.

Reduction of glutathione disulfide (GSSG) to glutathione (GSH) by glutathione reductase (GR) enhances the efficiency of GSH-dependent antioxidant activities. However, GR-deficient (a1Neu) mice are less susceptible to acute lung injury from continuous exposure to > 95% O(2) (96 h: 6.9 +/- 0.1 g right lung/kg body versus room air 3.6 +/- 0.3) than are C3H/HeN control mice (10.6 +/- 1.3 versus 4.2 +/- 0.3, P < 0.001). a1Neu mice have greater hepatic thioredoxin (Trx)1 and Trx2 levels than do C3H/HeN mice, suggesting compensation for the absence of GR. a1Neu mice exposed to hyperoxia for 96 hours showed lower levels of inflammatory infiltrates in lungs than did similarly exposed C3H/HeN mice. Pretreatment with aurothioglucose (ATG), a thioredoxin reductase (TrxR) inhibitor, exacerbated the effects of hyperoxia on lung injury in a1Neu mice (11.6 +/- 0.8, P < 0.001), but attenuated hyperoxic lung edema and inflammation in C3H/HeN mice (6.3 +/- 0.4, P < 0.001). No consistent alterations were observed in lung GSH contents or liver GSH or GSSG levels after ATG pretreatment. The data suggest that modulation of Trx/TrxR systems might provide therapeutically useful alterations of cellular resistance to oxidant stresses. The protective effects of ATG against hyperoxic lung injury could prove to be particularly useful therapeutically.