Inflammation In Preterm Infants Research Articles

IL-17a-producing γδT cells and NKG2D signaling mediate bacterial endotoxin-induced neonatal lung injury: implications for bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm birth survivors characterized by inflammation, impaired alveolarization and dysmorphic vasculature. Activated IL-17A+ lymphocytes are key drivers of inflammation in preterm infants. We have shown that in immature mice chronic airway exposure to lipopolysaccharide (LPS) induces pulmonary inflammation, increased IL-17a expression, and hypoalveolarization, a BPD-like phenotype. The source of IL-17a and contribution to lung pathology is unknown. The natural-killer group 2, member D (NKG2D) receptor mediates activation and IL-17a production in γδ T cells by binding to stress molecules. LPS induces NKG2D ligand expression, including Rae-1 and MULT1. We hypothesized that IL-17a+ γδ T cells and NKG2D signaling mediate neonatal LPS-induced lung injury. Immature C57BL/6J (wild type), Nkg2d-/- or Tcrd-/- (lacking γδ T cells) mice were inoculated with 3ug/10ul of LPS from E. coli O26:B6 or 10ul of PBS intranasally on day of life 3, 5, 7, and 10. Selected mice were treated with neutralizing antibodies against IL-17a, or NKG2D intraperitoneally. Lung immune cells were assessed by flow cytometry and gene expression was analyzed by qPCR. Alveolar growth was assessed by lung morphometry. We established that anti-IL-17a antibody treatment attenuated LPS-induced hypoalveolarization. We found that LPS induced the fraction of IL-17a+NKG2D+ γδ T cells, a major source of IL-17a in the neonatal lung. LPS also induced lung mRNA expression of NKG2D, Rae-1, MULT1, and the DNA damage regulator p53. Anti-NKG2D treatment attenuated the effect of LPS on γδ T cell IL-17a expression, immune cell infiltration and hypoalveolarization. LPS-induced hypoalveolarization was also attenuated in Nkg2d-/- and Tcrd-/- mice. In tracheal aspirates of preterm infants IL-17A and its upstream regulator IL-23 were higher in infants who later developed BPD. Also, human ligands of NKG2D, MICA and MICB were present in the aspirates and MICA correlated with median FiO2. Our novel findings demonstrate a central role for activated IL-17a+ γδ T cells and NKG2D signaling in neonatal LPS-induced lung injury. Future studies will determine the role of NKG2D ligands and effectors, other NKG2D+ cells in early-life endotoxin-induced lung injury and inflammation with a long-term goal to understand how inflammation contributes to BPD pathogenesis.

Essential Fatty Acid Supplementation and Early Inflammation in Preterm Infants: Secondary Analysis of a Randomized Clinical Trial

Introduction: Postnatal inflammation is associated with increased mortality and adverse outcomes in preterm infants. The essential fatty acids arachidonic acid (ARA) and docosahexaenoic acid (DHA) are precursors of lipid mediators with a key role in resolving inflammation. Our aim was to investigate the effect of ARA and DHA supplementation on systemic inflammation in very preterm infants and to identify clinical factors associated with early inflammation. Methods: Secondary analysis of data from a randomized clinical trial (ImNuT study). Infants with gestational age (GA) less than 29 weeks were randomized to receive a daily enteral supplement with ARA 100 mg/kg and DHA 50 mg/kg (ARA:DHA group) or MCT oil (control group) from the second day of life to 36 weeks postmenstrual age. ARA, DHA, and four proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) were analyzed in repeated dried blood samples from birth to day 28 and the area under the curve (AUC) for each variable was calculated. Results: The intention to treat population included 120 infants with mean (SD) GA 26.4 (1.7). The ARA:DHA group had significantly lower IL-6 levels from day 3 to day 28 compared to the control group, mean difference AUC log₁₀ (95% CI): 0.16 (0.03–0.30) pg/mL, p = 0.018. There was no correlation between ARA or DHA blood concentrations and cytokine levels. Having a low gestational age was independently associated with increased levels of all cytokines during the first 4 weeks of life. Conclusions: Enhanced supplementation with ARA and DHA may modulate inflammation in very preterm infants.

Fecal calprotectin, lactoferrin and morbidity associated with immature digestive tract in preterm infants

Introduction. Excessive intestinal inflammation in preterm infants is one of the key factors in the development of necrotizing enterocolitis (NEC), early- (EOS) and late-onset neonatal sepsis (LOS). Purpose - to evaluate the connection between fecal calprotectin (FC), enteral use of lactoferrin (LF), and the occurrence of NEC, EOS, and LOS in preterm infants. Materials and methods. FC was measured in 26 newborns with gestational age (GA) ≤32 weeks and birth weight ≤1500 g. Feces were collected twice: in the first 7 days of life and at the postmenstrual age (PMA) of 36 weeks. The main group included 15 infants with either EOS, LOS or NEC. The remaining 11 infants formed the comparison group. Eleven infants received LF (4 in the main group and 7 in the comparison group), which was randomly administered in the first 3 days of life. Results. FC in the first 7 days of life was higher in the main group (р>0.05). At the PMA of 36 weeks, FC decreased in the main group and increased in the comparison group (p>0.05). FC in the first week of life was higher in infants with EOS compared to newborns without the diseases (p=0.03), followed by a decrease at the PMA of 36 weeks (p=0.04). There was no significant difference in FC levels depending on the development of LOS or NEC. FC levels increased in all infants who received LF and decreased in babies who did not receive LF (p>0.05). Conclusions. The occurrence of EOS is associated with a significant increase in FC which subsequently decrease by the PMA of 36 weeks. FC in the first week of life are not associated with the development of NEC or LOS. Enteral use of LF at a dose of 100 mg/day is associated with an increase in FC levels (p>0.05). The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Factors associated with adverse neurodevelopment outcome using Bayley III scale at 3 to 6 month follow-up

Introduction: As the survival rate of preterm infants has increased, the management of long-term complications, especially neurodevelopmental impairment, becomes important. Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. Preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment. Objective: To assess the factors associated with adverse neurodevelopment outcome using bayley iii scale at 3 to 6 month follow-up. Materials and methods: This prospective cohort study was conducted in Department of Paediatrics, Mugda Medical College Hospital, Dhaka, Bangladesh from July 2021 to December 2021. After taking informed written consent (annexure-III) from parents of the selected premature infants to participate in the study, a total of 82 neonates were enrolled. Hospitalized inborn and out born babies were included consecutively. Results: A total 54 patients were analyzed in 1st follow up visit by using Bayley scale III. Mean cognitive score were 81.67±7.58 and 73.50±10.16 in ACS exposed and ACS unexposed group (p-0.001).Mean language score were 85.33±6.73 vs. 77.88±9.98, (p- 0.002). Mean motor score were 84.50±9.83 vs. 76.83±12.03 in ACS exposed and ACS unexposed group (p- 0.013). Though all scores were below normal in both groups, ACS exposed group had relatively better score than ACS unexposed group at 3 months of age. During 2nd follow up 47 infants were assessed at 6 months of age, mean cognitive score in ACS group was 84.88±12.32 and in ACS unexposed group was 75.71±15.67.which was statistically significant(p- .030).Motor and language composite scores were higher at 6 months in ACS group but no difference between two groups were statistically significant. Conclusion: Our prospective cohort study showed that systemic inflammation induced by clinical infection and NEC is associated with poor neurodevelopment in preterm infants. These results may help estimate the neurodevelopmental risk of individual patients who have inflammatory illness and narrow down the target population of neuroprotection in the future.

Factors associated with neurodevelopment in preterm infants with systematic inflammation

BackgroundSeveral studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment.MethodsThis prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months.ResultsThe I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months.ConclusionsSystemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.

Lipid Composition, Digestion, and Absorption Differences among Neonatal Feeding Strategies: Potential Implications for Intestinal Inflammation in Preterm Infants.

Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality in the neonatal population. Formula feeding is among the many risk factors for developing the condition, a practice often required in the cohort most often afflicted with NEC, preterm infants. While the virtues of many bioactive components of breast milk have been extolled, the ability to digest and assimilate the nutritional components of breast milk is often overlooked. The structure of formula differs from that of breast milk, both in lipid composition and chemical configuration. In addition, formula lacks a critical digestive enzyme produced by the mammary gland, bile salt-stimulated lipase (BSSL). The gastrointestinal system of premature infants is often incapable of secreting sufficient pancreatic enzymes for fat digestion, and pasteurization of donor milk (DM) has been shown to inactivate BSSL, among other important compounds. Incompletely digested lipids may oxidize and accumulate in the distal gut. These lipid fragments are thought to induce intestinal inflammation in the neonate, potentially hastening the development of diseases such as NEC. In this review, differences in breast milk, pasteurized DM, and formula lipids are highlighted, with a focus on the ability of those lipids to be digested and subsequently absorbed by neonates, especially those born prematurely and at risk for NEC.

Elevated Intestinal Inflammation in Preterm Infants With Signs and Symptoms of Gastroesophageal Reflux Disease.

Reflux is common in infancy; however, persistent signs and symptoms of gastrointestinal distress are often attributed to gastroesophageal reflux disease (GERD). In this pilot study, we aimed to characterize associations between signs and symptoms of suspected GERD and noninvasive markers of intestinal inflammation in preterm infants. We reviewed Electronic Medical Record (EMR) data to identify clinical signs and symptoms among case patients (n = 16). Controls (n = 16) were matched on gestational age. Univariate and multivariate regression analyses were used to compare fecal calprotectin and urinary intestinal fatty acid binding protein (I-FABP) levels between cases and controls. We found no differences in baseline characteristics between cases and controls. In the multivariate regression analysis controlling for the proportion of mother's milk, cases had higher fecal calprotectin levels than controls, with no differences in I-FABP levels between cases and controls. Our findings suggest that preterm infants with signs and symptoms of GERD have higher levels of intestinal inflammation as indicated by fecal calprotectin compared to their controls. Further studies are needed to evaluate the role of intestinal inflammation in signs and symptoms of gastrointestinal distress and whether fecal calprotectin might have predictive value in diagnosing GERD.

Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide.

BackgroundChorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS).MethodsLambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared.ResultsCompared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h.ConclusionsIn preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation.Impact The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS.Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation.IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide.The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis.

Does Human Milk Fortifier Affect Intestinal Inflammation in Preterm Infants?

Background: Fecal calprotectin, a recognized marker of intestinal inflammation, is derived from neutrophil migration to a site of inflammation. Introduction of bovine-based human milk fortifier containing intact protein in preterm infants is associated with an increase in fecal calprotectin suggestive of intestinal inflammation. Newer fortifiers contain protein hydrolysates in place of intact protein. Objective: To measure fecal calprotectin in human milk-fed preterm infants before and after human milk fortification using a fortifier containing hydrolyzed protein. Methods: Serial stool samples were collected from 24 infants beginning at the first week to 60 days postnatal age. To compare the effect of human milk fortification, samples collected before and after fortification were compared. Infant demographics, diet, postnatal morbidities, and maternal characteristics were recorded. Results: A total of 401 stool samples were collected from 24 study infants who had a birth weight of 993 ± 277 g (mean ± standard deviation), gestational age 27.5 ± 2.8 weeks, and fortifier initiation at 14 days. Median fecal calprotectin before and after fortification were similar. Calprotectin levels were not correlated with birth weight or gestational age but were inversely correlated with postnatal age (p = 0.005), use of fortifier (p < 0.001), receipt of antibiotics antenatally (p = 0.007) and postnatally (p = 0.008). After adjusting for postnatal age, calprotectin levels were significantly lower following receipt of fortifier (p < 0.001) and postnatal antibiotics (p < 0.001). Conclusions: The feeding of protein hydrolysate-containing human milk fortifiers does not appear to be associated with increases in a marker of intestinal inflammation.

Expression of S100A Alarmins in Cord Blood Monocytes Is Highly Associated With Chorioamnionitis and Fetal Inflammation in Preterm Infants.

Background: Preterm infants exposed to chorioamnionitis and with a fetal inflammatory response are at risk for neonatal morbidity and adverse outcome. Alarmins S100A8, S100A9, and S100A12 are expressed by myeloid cells and have been associated with inflammatory activation and monocyte modulation.Aim: To study S100A alarmin expression in cord blood monocytes from term healthy and preterm infants and relate results to clinical findings, inflammatory biomarkers and alarmin protein levels, as well as pathways identified by differentially regulated monocyte genes.Methods: Cord blood CD14+ monocytes were isolated from healthy term (n = 10) and preterm infants (<30 weeks gestational age, n = 33) by MACS technology. Monocyte RNA was sequenced and gene expression was analyzed by Principal Component Analysis and hierarchical clustering. Pathways were identified by Ingenuity Pathway Analysis. Inflammatory proteins were measured by Multiplex ELISA, and plasma S100A proteins by mass spectrometry. Histological chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) were diagnosed by placenta histological examination.Results: S100A8, S100A9, and S100A12 gene expression was significantly increased and with a wider range in preterm vs. term infants. High S100A8 and S100A9 gene expression (n = 17) within the preterm group was strongly associated with spontaneous onset of delivery, HCA, FIRS and elevated inflammatory proteins in cord blood, while low expression (n = 16) was associated with impaired fetal growth and physician-initiated delivery. S100A8 and S100A9 protein levels were significantly lower in preterm vs. term infants, but within the preterm group high S100A gene expression, spontaneous onset of labor, HCA and FIRS were associated with elevated protein levels. One thousand nine hundred genes were differentially expressed in preterm infants with high vs. low S100A alarmin expression. Analysis of 124 genes differentially expressed in S100A high as well as FIRS and HCA groups identified 18 common pathways and S100A alarmins represented major hubs in network analyses.Conclusion: High expression of S100A alarmins in cord blood monocytes identifies a distinct clinical risk group of preterm infants exposed to chorioamnionitis and with a fetal inflammatory response. Gene and pathway analyses suggest that high S100A alarmin expression also affects monocyte function. The connection with monocyte phenotype and inflammation-stimulated S100A expression in other cell types (e.g., neutrophils) warrants further investigation.

Comparative study of preterm infants fed new and existing human milk fortifiers showed favourable markers of gastrointestinal status.

AimThis study examined the influence of different human milk fortifiers on biomarkers of gastrointestinal immaturity and inflammation in preterm infants.MethodsWe report secondary outcomes from a controlled, double‐blind, randomised, parallel group study conducted from 2011 to 2014 in neonatal intensive care units at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland and Italy. Preterm infants born at up to 32 weeks or weighing up to 1500 g were randomised to a new powdered human milk fortifier (n = 77) or a control fortifier (n = 76) for a minimum of 21 days. We analysed faecal markers of gut inflammation, namely alpha‐1 antitrypsin and calprotectin, and maturity, namely elastase‐1.ResultsFaecal alpha‐1 antitrypsin was slightly lower in the new than control fortifier group after 21 days of full enteral feeding, with a geometric mean and standard deviation of 1.52 ± 1.32 vs 1.82 ± 1.44 mg/g stools (P = .01). There was no significant difference in faecal calprotectin (median [Q1‐Q3] of 296 [136‐565] μg/g stools in both groups combined at study day 21). Faecal elastase‐1 was lower in the new fortifier than control fortifier group (202.5 ± 1.6 vs 257.7 ± 1.5 μg/g stools, P = .016).ConclusionMean values for each parameter were within the ranges in healthy term infants, indicating favourable markers of gastrointestinal status in both groups. In addition, for faecal calprotectin, the relatively high concentration observed in preterm infants fed fortified human milk suggests that the threshold level for detecting necrotising enterocolitis should be revised.

Inflammatory mediators of stress exposure and neurodevelopment in very preterm infants: Protocol for the stress neuro-immune study.

(a) Determine relationships among stress exposure, inflammation, and neurodevelopment in very preterm infants and determine the mediated effect of inflammation on the relationship between stress exposure and neurodevelopment; (b) describe cytokine trajectories following birth and determine the effect of stress exposure on these trajectories; and (c) examine relationships between stress exposure and chronic stress responses in very preterm infants. Non-experimental, repeated measures. Very preterm infants born 28-31weeks post menstrual age will be enrolled. Cumulative stress exposure over the first 14days of life will be measured using the Neonatal Infant Stressor Scale. Blood will be collected weekly for the quantification of cytokines. Neurodevelopment will be assessed using the Neurobehavioral Assessment of the Preterm Infant and hair for quantification of hair cortisol will be collected at 35weeks post menstrual age. Multiple linear regression and conditional process analysis will be used to analyse the relationships among stress exposure, inflammation and neurodevelopment. Linear mixed models will be used to determine inflammatory trajectories over time. IRB approval for the study was received May 2017, and funding from the National Institute of Nursing Research was awarded July 2017. This study will determine the extent to which inflammation mediates the relationship between stress exposure and neurodevelopment. Interventions to attenuate inflammation in preterm infants may improve outcomes. Determining the potentially modifiable mediators of stress exposure and neurodevelopment in preterm infants is critical to improving long-term outcomes.

Perinatal Ureaplasma Exposure Is Associated With Increased Risk of Late Onset Sepsis and Imbalanced Inflammation in Preterm Infants and May Add to Lung Injury.

Background: Controversy remains concerning the impact of Ureaplasma on preterm neonatal morbidity.Methods: Prospective single-center study in very low birth weight infants <30 weeks' gestation. Cord blood and initial nasopharyngeal swabs were screened for Ureaplasma parvum and U. urealyticum using culture technique and polymerase chain reaction. Neonatal outcomes were followed until death or discharge. Multi-analyte immunoassay provided cord blood levels of inflammatory markers. Using multivariate regression analyses, perinatal Ureaplasma exposure was evaluated as risk factor for the development of bronchopulmonary dysplasia (BPD), other neonatal morbidities until discharge and systemic inflammation at admission.Results: 40/103 (39%) infants were positive for Ureaplasma in one or both specimens, with U. parvum being the predominant species. While exposure to Ureaplasma alone was not associated with BPD, we found an increased risk of BPD in Ureaplasma-positive infants ventilated ≥5 days (OR 1.64; 95% CI 0.12–22.98; p = 0.009). Presence of Ureaplasma was associated with a 7-fold risk of late onset sepsis (LOS) (95% CI 1.80–27.39; p = 0.014). Moreover, Ureaplasma-positive infants had higher I/T ratios (b 0.39; 95% CI 0.08–0.71; p = 0.014), increased levels of interleukin (IL)-17 (b 0.16; 95% CI 0.02–0.30; p = 0.025) and matrix metalloproteinase 8 (b 0.77; 95% CI 0.10–1.44; p = 0.020), decreased levels of IL-10 (b −0.77; 95% CI −1.58 to −0.01; p = 0.043) and increased ratios of Tumor necrosis factor-α, IL-8, and IL-17 to anti-inflammatory IL-10 (p = 0.003, p = 0.012, p < 0.001).Conclusions: Positive Ureaplasma screening was not associated with BPD. However, exposure contributed to BPD in infants ventilated ≥5 days and conferred an increased risk of LOS and imbalanced inflammatory cytokine responses.

Neuroinflammation in preterm babies and autism spectrum disorders.

Genetic anomalies have a role in autism spectrum disorders (ASD). Each genetic factor is responsible for a small fraction of cases. Environment factors, like preterm delivery, have an important role in ASD. Preterm infants have a 10-fold higher risk of developing ASD. Preterm birth is often associated with maternal/fetal inflammation, leading to a fetal/neonatal inflammatory syndrome. There are demonstrated experimental links between fetal inflammation and the later development of behavioral symptoms consistent with ASD. Preterm infants have deficits in connectivity. Most ASD genes encode synaptic proteins, suggesting that ASD are connectivity pathologies. Microglia are essential for normal synaptogenesis. Microglia are diverted from homeostatic functions towards inflammatory phenotypes during perinatal inflammation, impairing synaptogenesis. Preterm infants with ASD have a different phenotype from term born peers. Our original hypothesis is that exposure to inflammation in preterm infants, combined with at risk genetic background, deregulates brain development leading to ASD.

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory κB kinase β transactivated) mice that conditionally express an activator of the NF-κB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-κB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase like-1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory κB kinase β transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-κB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.

Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease.

BackgroundThe etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD) is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation.ObjectivesTo investigate airway innate immune cellular phenotypes in preterm infants with respiratory distress syndrome (RDS) or CLD.MethodsBronchoalveolar lavage (BAL) fluid was obtained from term and preterm infants requiring mechanical ventilation. BAL cells were phenotyped by flow cytometry.ResultsPreterm birth was associated with an increase in the proportion of non-classical CD14+/CD16+ monocytes on the day of delivery (58.9±5.8% of total mononuclear cells in preterm vs 33.0±6.1% in term infants, p = 0.02). Infants with RDS were born with significantly more CD36+ macrophages compared with the CLD group (70.3±5.3% in RDS vs 37.6±8.9% in control, p = 0.02). At day 3, infants born at a low gestational age are more likely to have greater numbers of CD14+ mononuclear phagocytes in the airway (p = 0.03), but fewer of these cells are functionally polarized as assessed by HLA-DR (p = 0.05) or CD36 (p = 0.05) positivity, suggesting increased recruitment of monocytes or a failure to mature these cells in the lung.ConclusionsThese findings suggest that macrophage polarization may be affected by gestational maturity, that more immature macrophage phenotypes may be associated with the progression of RDS to CLD and that phenotyping mononuclear cells in BAL could predict disease outcome.

Cyclooxygenase-2 in newborn hyperoxic lung injury

Supraphysiological O2 concentrations, mechanical ventilation, and inflammation significantly contribute to the development of bronchopulmonary dysplasia (BPD).Exposure of newborn mice to hyperoxia causes inflammation and impaired alveolarization similar to that seen in infants with BPD.Previously, we demonstrated that pulmonary cyclooxygenase-2 (COX-2) protein expression is increased in hyperoxia-exposed newborn mice.The present studies were designed to define the role of COX-2 in newborn hyperoxic lung injury.We tested the hypothesis that attenuation of COX-2 activity would reduce hyperoxia-induced inflammation and improve alveolarization.Newborn C3H/HeN micewere injected daily with vehicle, aspirin (nonselective COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor) for the first 7 days of life.Additional studies utilized wild-type (C57Bl/6, COX-2+/+), heterozygous (COX-2+/-), and homozygous (COX-2-/-) transgenic mice.Micewere exposed to room air (21% O2) or hyperoxia (85% O2) for 14 days.Aspirin-injected and COX-2-/- pups had reduced levels of monocyte chemoattractant protein (MCP-1) in bronchoalveolar lavage fluid (BAL).Both aspirin and celecoxib treatment reduced macrophage numbers in the alveolar walls and air spaces.Aspirin and celecoxib treatment attenuated hyperoxia-induced COX activity, including altered levels of prostaglandin (PG)D2 metabolites.Decreased COX activity, however, did not prevent hyperoxia-induced lung developmental deficits.Our data suggest thatincreased COX-2 activity may contribute to proinflammatory responses, including macrophage chemotaxis, during exposure to hyperoxia.Modulation of COX-2 activity may be a useful therapeutic target to limit hyperoxia-induced inflammation in preterm infants at risk of developing BPD.

Association with Ductus Arteriosus Closure by Ibuprofen and Intrauterine Inflammation in Very Low Birth Weight Infants

Purpose : Ibuprofen is an inhibitor of prostaglandin synthesis and used to close a patent ductus arteriosus (PDA) of preterm infants. This study investigated the association between the response to ibuprofen treatment for PDA and maternal intrauterine inflammation in preterm infants. Methods : We retrospectively reviewed the medical records of very low birth weight (VLBW) infants diagnosed with PDA, who are admitted immediately after birth in the neonatal intensive care unit at Dongguk University Ilsan Hospital between March 2010 and May 2013. After the first cycle of ibuprofen therapy, infants whose ductus arteriosus was closed and not closed were classified as Responders and Non-responders I, respectively. After the second cycle of ibuprofen therapy, infants with persistent PDA were classified as Non-responders II. We performed multiple logistic regression analysis to determine the most important factor associated with persistent PDA. Results : After the first cycle of ibuprofen therapy, the numbers of Responders and Non-responders I were 40 and 14, respectively. Rate of cesarean section was significantly lower in Non-responders I than that of Re sponders (P=0.023). In addition, Rate of maternal amnionitis in Non-responder I was significantly higher than that of Responders (P=0.016). By multiple logistic regression analysis, maternal amnionitis was found to be a significant risk factor of the failure of ductus arteriosus closure after the first cycle of ibuprofen treatment ( P=0.039). Conclusion : The present study shows that maternal amnionitis is an independent risk factor for the treatment failure after the first cycle of ibuprofen therapy in VLBW infants with PDA.

The Role of Glucocorticoid Receptors in Dexamethasone-Induced Apoptosis of Neuroprogenitor Cells in the Hippocampus of Rat Pups

Background. Dexamethasone (Dex) has been used to reduce inflammation in preterm infants with assistive ventilation and to prevent chronic lung diseases. However, Dex treatment results in adverse effects on the brain. Since the hippocampus contains a high density of glucocorticoid receptors (GCRs), we hypothesized that Dex affects neurogenesis in the hippocampus through inflammatory mediators. Methods. Albino Wistar rat pups first received a single dose of Dex (0.5 mg/kg) on postnatal day 1 (P1) and were sacrificed on P2, P3, P5, and P7. One group of Dex-treated pups (Dex-treated D1D2) was given mifepristone (RU486, a GCR antagonist) on P1 and sacrificed on P2. Hippocampi were isolated for western blot analysis, TUNEL, cleaved-caspase 3 staining for cell counts, and morphological assessment. Control pups received normal saline (NS). Results. Dex reduced the developmental gain in body weight, but had no effect on brain weight. In the Dex-treated D1D2 group, apoptotic cells increased in number based on TUNEL and cleaved-caspase 3 staining. Most of the apoptotic cells expressed the neural progenitor cell marker nestin. Dex-induced apoptosis in P1 pups was markedly reduced (60%) by pretreatment with RU486, indicating the involvement of GCRs. Conclusion. Early administration of Dex results in apoptosis of neural progenitor cells in the hippocampus and this is mediated through GCRs.

Elevated midtrimester α-fetoprotein and delivery markers of inflammation in a preterm population

Objective: Determine whether elevated second trimester maternal serum α-fetoprotein (AFP) is associated with clinical and histopathologic markers of inflammation at preterm delivery. Methods: 105 women <32 weeks’ gestation were included. AFP levels were dichotomized at 2.0 multiples of the median (MoM). Rates of neonatal morbidities, clinical chorioamnionitis, cord blood IL-6 level, and placental inflammatory findings were compared. Results: Thirteen (12.4%) had elevated AFP. Fewer women with AFP ≥2 MoM had histologic placental or membrane rupture site inflammation, funisitis, or placental culture positive for Mycoplasma and Ureaplasma species, compared to those with normal AFP. Neonatal death was increased in the elevated AFP group (23.1% vs. 2.27%, RR 10.6). Elevated AFP was associated with a nonsignificant increase in indicated birth (54% vs. 35%; p = 0.225). Virtually all inflammatory findings were confined to the spontaneous delivery group. Conclusion: Elevated midtrimester AFP conveyed significant risk of neonatal death, but was negatively associated with clinical or histopathologic inflammation in preterm infants.