Selenium Deficiency Exacerbates Hyperoxia-Induced Lung Injury in Newborn C3H/HeN Mice.

Extremely preterm infants are often treated with supraphysiological oxygen, which contributes to the development of bronchopulmonary dysplasia (BPD). These same infants exhibit compromised antioxidant capacities due in part to selenium (Se) deficiency. Se is essential for basal and inducible antioxidant responses. The present study utilized a perinatal Se deficiency (SeD) mouse model to identify the combined effects of newborn hyperoxia exposure and SeD on alveolarization and antioxidant responses, including the identification of affected developmental pathways. Se-sufficient (SeS) and SeD C3H/HeN breeding pairs were generated, and pups were exposed to room air or 85% O2 from birth to 14 d. Survival, antioxidant protein expression, and RNA seq analyses were performed. Greater than 40% mortality was observed in hyperoxia-exposed SeD pups. Surviving SeD pups had greater lung growth deficits than hyperoxia-exposed SeS pups. Gpx2 and 4 protein and Gpx activity were significantly decreased in SeD pups. Nrf2-regulated proteins, Nqo1 and Gclc were increased in SeD pups exposed to hyperoxia. RNA seq revealed significant decreases in the Wnt/ß-catenin and Notch pathways. Se is a biologically relevant modulator of perinatal lung development and antioxidant responses, especially in the context of hyperoxia exposure. The RNA seq analyses suggest pathways essential for normal lung development are dysregulated by Se deficiency.

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study.

Increasing evidence suggests that prolonged antibiotic therapy in preterm infants is associated with increased mortality and morbidities, such as necrotizing enterocolitis (NEC), a devastating gastrointestinal pathology characterized by intestinal inflammation and necrosis. While a clinical correlation exists between antibiotic use and the development of NEC, the potential causality of antibiotics in NEC development has not yet been demonstrated. Here, we tested the effects of systemic standard-of-care antibiotic therapy for ten days on intestinal development in neonatal mice. Systemic antibiotic treatment impaired the intestinal development by reducing intestinal cell proliferation, villi height, crypt depth, and goblet and Paneth cell numbers. Oral bacterial challenge in pups who received antibiotics resulted in NEC-like intestinal injury in more than half the pups, likely due to a reduction in mucous-producing cells affecting microbial-epithelial interactions. These data support a novel mechanism that could explain why preterm infants exposed to prolonged antibiotics after birth have a higher incidence of NEC and other gastrointestinal disorders.

Placental Neutrophil Infiltration Associated with Tobacco Exposure but Not Development of Bronchopulmonary Dysplasia.

Objective: In utero inflammation is associated with bronchopulmonary dysplasia (BPD) in preterm infants. We hypothesized that maternal tobacco exposure (TE) might induce placental neutrophil infiltration, increasing the risk for BPD. Study design: We compared the composite outcome of BPD and death in a prospective pilot study of TE and no-TE mothers and their infants born <32 weeks. Placental neutrophil infiltration was approximated by neutrophil gelatinase-associated lipocalin (NGAL) ELISA, and total RNA expression was analyzed via NanoString© (Seattle, WA, USA). Result: Of 39 enrolled patients, 44% were classified as tobacco exposure. No significant difference was noted in the infant's composite outcome of BPD or death based on maternal tobacco exposure. NGAL was higher in placentas of TE vs. non-TE mothers (p < 0.05). Placental RNA analysis identified the upregulation of key inflammatory genes associated with maternal tobacco exposure. Conclusion: Tobacco exposure during pregnancy was associated with increased placental neutrophil markers and upregulated inflammatory gene expression. These findings were not associated with BPD.

Clinical and Laboratory Predictors for the Development of Low Cardiac Output Syndrome in Infants Undergoing Cardiopulmonary Bypass: A Pilot Study.

Cardiac surgery employing cardiopulmonary bypass exposes infants to a high risk of morbidity and mortality. The objective of this study was to assess the utility of clinical and laboratory variables to predict the development of low cardiac output syndrome, a frequent complication following cardiac surgery in infants. We performed a prospective observational study in the pediatric cardiovascular ICU in an academic children's hospital. Thirty-one patients with congenital heart disease were included. Serum levels of nucleosomes and a panel of 20 cytokines were measured at six time points in the perioperative period. Cardiopulmonary bypass patients were characterized by increased levels of interleukin-10, -6, and -1α upon admission to the ICU compared to non-bypass cardiac patients. Patients developing low cardiac output syndrome endured longer aortic cross-clamp time and required greater inotropic support at 12 h postoperatively compared to bypass patients not developing the condition. Higher preoperative interleukin-10 levels and 24 h postoperative interleukin-8 levels were associated with low cardiac output syndrome. Receiver operating characteristic curve analysis demonstrated a moderate capability of aortic cross-clamp duration to predict low cardiac output syndrome but not IL-8. In conclusion, low cardiac output syndrome was best predicted in our patient population by the surgical metric of aortic cross-clamp duration.

The Protective Influence of Chondroitin Sulfate, a Component of Human Milk, on Intestinal Bacterial Invasion and Translocation.

BACKGROUND: Human milk is known to be protective against necrotizing enterocolitis, a devastating intestinal inflammatory disease affecting the preterm population. Although the pathogenesis of necrotizing enterocolitis is yet to be solidified, intestinal integrity dysfunction, bacterial invasion and/or translocation, and inflammation may play important roles. Glycosaminoglycans, compounds naturally prevalent in both human milk and the intestine, are thought to be anti-inflammatory and capable of altering bacterial interactions within the gut. RESEARCH AIM: In this study, we aimed to evaluate the potential of chondroitin sulfate, the most prominent class of glycosaminoglycans in human milk, to protect against bacterial infection in an intestinal in vitro model. METHODS: T84 cell monolayers were treated with chondroitin sulfate and cell viability was assessed across a number of doses. Monolayers were then pretreated with chondroitin sulfate and subsequently challenged with E. coli invasion and translocation to evaluate any protective role of the compound against infection. Tight junction barrier function was assessed by transepithelial electrical resistance, and cytokine levels were evaluated. RESULTS: Chondroitin sulfate at any dose up to 750 µg/ml was not associated with any statistically significant decrease in cell viability. Additionally, chondroitin sulfate at 750 µg/ml was associated with a 75% decrease in both bacterial invasion and translocation compared to control. CONCLUSIONS: These data suggest chondroitin sulfate may protect against bacterial infection through a reduction in both invasion and translocation, importantly without attendant reduction in cell viability.