The Physiologic Significance of Early Urinary Intestinal Fatty Acid Binding Protein Levels in Preterm Infants: A Prospective Cohort Study.

Intestinal fatty acid binding protein (I-FABP) is released from mature enterocytes when cell membrane integrity is disrupted. This study aimed to prospectively investigate the physiologic significance of early urinary I-FABP and whether it might reflect intestinal compromise in preterm infants. We conducted a prospective cohort study of 100 preterm infants weighing <1250 g and collected serial urine samples at 12, 24, and 48 h after birth. The correlations between initial urinary I-FABP/urinary creatinine (creatinineu) levels and associated factors were analyzed. Among 100 patients, 15 were diagnosed with meconium obstruction of prematurity, and five were diagnosed with necrotizing enterocolitis during the hospital stay. Early urinary I-FABP/creatinineu levels were inversely correlated with both gestational age (Spearman's rank correlation coefficient (Rs) -0.381, p < 0.01) and birth weight ((Rs) -0.424, p < 0.01). Early urinary I-FABP/creatinineu levels were associated with cord pH ((Rs) -0.436, p < 0.01) and base excess ((Rs) -0.258, p = 0.021). There were significantly positive correlations between early urinary I-FABP/creatinineu levels and the time to full enteral feeding in preterm infants without specific intestinal morbidities. Therefore, a more premature gut with acute perinatal ischemia is expected to exhibit increased I-FABP levels shortly after birth. Because of small sample size, further large-scale studies are needed.

Differences in Comorbidities and Clinical Burden of Severe Bronchopulmonary Dysplasia Based on Disease Severity.

Background: The present study compared baseline characteristics, comorbidities and clinical burden of pre-term infants with type 1 and 2 severe bronchopulmonary dysplasia (BPD) Collaborative classification. Methods: This study was a prospective cohort study of pre-term (<32 weeks) very-low-birth-weight infants. Severe BPD was divided into type 1 severe BPD requiring of ≥30% oxygen and/or non-invasive ventilation at 36 weeks post-menstrual age (PMA), and type 2 severe BPD requiring invasive mechanical ventilation at 36 weeks PMA. Baseline characteristics, comorbidities, and clinical burden were compared between these two types of severe BPD. Results: Of the 1,328 infants included, 983 (74.0%) developed type 1 severe BPD, and 345 (26.0%) developed type 2 severe BPD. Lower birth weight, small for gestational age, lesser maternal pre-mature rupture of membrane, lower 5-min Apgar score, air leak, pulmonary hemorrhage, surgical ligation of patent ductus arteriosus, necrotizing enterocolitis, and late-onset sepsis were significantly associated with type 2 severe BPD. Compared with infants with type 1 severe BPD, infants with type 2 severe BPD had an increased risk of mortality (aOR 18.64, 95% CI 10.81-32.13), pulmonary hypertension (aOR 2.16, 95% CI 1.59-2.93), and tracheostomy (aOR 10.38, 95% CI 2.05-52.49). Conclusions: Our data highlight the substantially greater mortality and clinical burden in infants with type 2 severe BPD than infants with type 1 severe BPD. A comprehensive and multidisciplinary approach is needed for infants with type 2 severe BPD.

Thyroid dysfunction in preterm infants born before 32 gestational weeks.

BACKGROUND: Thyroid hormones are critical for growth and brain development during the newborn period and infancy. Because of delayed maturation of the hypothalamic-pituitary-thyroid axis in preterm infants, thyroid dysfunction is common, and thyroid stimulating hormone (TSH) elevation is often delayed in preterm infants. The objective of this study was to determine the incidence of thyroid dysfunction requiring levothyroxine treatment and to identify its risk factors in preterm infants. METHODS: A retrospective cohort study was performed on preterm infants who were born before 32 gestational weeks and admitted to a single tertiary academic center for more than 8 weeks between January 2008 and December 2014. In these infants, serial thyroid function tests (TFTs) measuring serum TSH and free thyroxine (fT4) were routinely performed at 1, 3, and 6 weeks of postnatal age. RESULTS: Of the 220 preterm infants enrolled, 180 infants underwent TFTs at 1, 3, and 6 weeks of postnatal age and were included in the study. Of the 180 infants, 35 infants (19.4%) were started on levothyroxine treatment based on the results of serial TFTs. Among the 35 infants who were treated with levothyroxine, 16 infants (45.7%) had normal results on the initial TFT. Three of these 16 infants continued to have normal results on the second TFT. Thyroid dysfunction requiring levothyroxine treatment was significantly associated with maternal pregnancy-induced hypertension (adjusted odds ratio 2.64, 95% confidence interval 1.02-6.81). CONCLUSIONS: Thyroid dysfunction requiring levothyroxine treatment occurred in nearly one-fifth of preterm infants born before 32 gestational weeks. Nearly half of the preterm infants who were treated with levothyroxine had normal TSH and fT4 levels at 1 week of postnatal age. The findings of the present study suggest that serial TFTs is important to find preterm infants who require levothyroxine treatment.

Retraction Note: Intra-amniotic LPS amplifies hyperoxia-induced airway hyperreactivity in neonatal rats.

This paper has been retracted at the request of the authors.

Correction to: Respiratory severity score as a predictive factor for severe bronchopulmonary dysplasia or death in extremely preterm infants.

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Length at birth z-score is inversely associated with an increased risk of bronchopulmonary dysplasia or death in preterm infants born before 32 gestational weeks: A nationwide cohort study.

OBJECTIVE: We investigated whether the extent of fetal growth restriction (FGR) in terms of not only birth weight but length and head circumference at birth is correlated with an increased risk of bronchopulmonary dysplasia (BPD) in preterm infants. STUDY DESIGN: A total of 4,940 very low birth weight (VLBW) infants born between 23 and 31 weeks of gestation from 2013 to 2015 who were registered in the Korean Neonatal Network (KNN) database were enrolled. Infants with major congenital malformations and those with incomplete data were excluded. Z-scores for weight, length, and head circumference at birth were calculated from the Fenton 2013 growth curve. Multivariable logistic regression analysis was performed to determine whether the z-score for length at birth was associated with BPD or death before 36 postmenstrual weeks. RESULTS: A total of 4,662 VLBW infants were analyzed: 518 infants died before 36 postmenstrual weeks; 1,388 infants developed BPD. Decreased length at birth z-scores were significantly associated with an increased risk of BPD or death when adjusted for covariates (odds ratio (OR) 1.25 per 1-point decrease of length at birth z-score, 95% confidence interval (CI) 1.14-1.37). The association was particularly evident in infants born earlier than 29 weeks of gestation (OR 1.57, 95% CI 1.31-1.89 in infants born at 23-25 weeks; OR 1.24, 95% CI 1.09-1.42 in infants born at 26-28 weeks). CONCLUSION: Length at birth was inversely associated with an increased risk of BPD or death in VLBW infants born earlier than 32 weeks of gestation.

Respiratory severity score as a predictive factor for severe bronchopulmonary dysplasia or death in extremely preterm infants.

BACKGROUND: Despite significant advances in neonatology, bronchopulmonary dysplasia (BPD) remains the most common cause of serious morbidity and mortality in premature infants. The aim of the present study was to determine associations between the respiratory severity score (RSS) with death or BPD in premature infants. METHODS: This was a retrospective study conducted between January 2010 and December 2014. We enrolled preterm infants with a gestational age of less than 28 weeks who were supported by mechanical ventilation for more than a week during the first 4 weeks of life. We collected the RSS scores on day of life 2, 7, 14, 21 and 28. The correlations between postnatal RSSs and death or severe BPD were analyzed using multivariate logistic regression. RESULTS: Of the 138 eligible infants, 66 infants (47.8%) either died or developed severe BPD. The RSS cut-off values for predicting severe BPD or death were 3.0 for postnatal day (PND) 14 with an odds ratio (OR) of 11.265 (p = 0.0006, 95% confidence interval (CI), 2.842 to 44.646), 3.6 for PND 21 with an OR of 15.162 (p = 0.0003, 95% CI, 3.467 to 66.316), and 3.24 for PND 28 with an OR of 10.713 (p = 0.0005, 95% CI, 2.825 to 40.630). CONCLUSION: Strong correlations were observed between the RSSs on PND 14, 21, and 28 and death or subsequent severe BPD. The RSS could provide a simple estimate of severe BPD or death., Further research with a larger study population is necessary to validate the usefulness of the RSS for predicting severe BPD or death.

Interstitial pneumonia pattern on day 7 chest radiograph predicts bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Early identification of infants at higher risk of developing bronchopulmonary dysplasia (BPD) may enable a targeted approach to reduce BPD. We aimed to evaluate the hypothesis that the interstitial pneumonia pattern on the day 7 chest radiograph predicts BPD or death before 36 weeks postmenstrual age (PMA). METHODS: A retrospective cohort study was performed on 336 preterm infants (birth weight < 1500 g and gestational age < 32 postmenstrual weeks) who were admitted to a single tertiary academic center between January 2008 and December 2014. Day 7 chest radiographs were independently reviewed by two pediatric radiologists who were unaware of the clinical information regarding each individual infant. RESULTS: Data from 304 infants who survived more than 7 days after birth were collected. The interstitial pneumonia pattern on the day 7 chest radiograph was independently associated with BPD or death before 36 weeks PMA (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.1-14.4). The interstitial pneumonia pattern on the day 7 chest radiograph predicted BPD or death with a specificity of 98%. Histologic chorioamnionitis was a preceding factor that was independently associated with the interstitial pneumonia pattern on the day 7 chest radiograph (OR 3.7, 95% CI 1.3-10.3). CONCLUSIONS: The interstitial pneumonia pattern on the day 7 chest radiograph has a high specificity for predicting BPD or death and can be utilized to select high-risk preterm infants who will benefit from potentially preventive interventions against BPD.

RNA-Seq for Gene Expression Profiling of Human Necrotizing Enterocolitis: a Pilot Study.

Necrotizing enterocolitis (NEC) characterized by inflammatory intestinal necrosis is a major cause of mortality and morbidity in newborns. Deep RNA sequencing (RNA-Seq) has recently emerged as a powerful technology enabling better quantification of gene expression than microarrays with a lower background signal. A total of 10 transcriptomes from 5 pairs of NEC lesions and adjacent normal tissues obtained from preterm infants with NEC were analyzed. As a result, a total of 65 genes (57 down-regulated and 8 up-regulated) revealed significantly different expression levels in the NEC lesion compared to the adjacent normal region, based on a significance at fold change ≥ 1.5 and P ≤ 0.05. The most significant gene, DPF3 (P < 0.001), has recently been reported to have differential expressions in colon segments. Our gene ontology analysis between NEC lesion and adjacent normal tissues showed that down-regulated genes were included in nervous system development with the most significance (P = 9.3 × 10⁻7; P(corr) = 0.0003). In further pathway analysis using Pathway Express based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, genes involved in thyroid cancer and axon guidance were predicted to be associated with different expression (P(corr) = 0.008 and 0.020, respectively). Although further replications using a larger sample size and functional evaluations are needed, our results suggest that altered gene expression and the genes' involved functional pathways and categories may provide insight into NEC development and aid in future research.

Coexistence of Ureaplasma and chorioamnionitis is associated with prolonged mechanical ventilation.

BACKGROUND: Both histologic chorioamnionitis (HCAM) and Ureaplasma infection are considered important contributors to perinatal lung injury. We tested the hypothesis that coexistence of maternal HCAM and perinatal Ureaplasma exposure increases the risk of prolonged mechanical ventilation in extremely low-birthweight (ELBW) infants. METHODS: A retrospective cohort study was carried out of all ELBW infants born between January 2008 and December 2013 at a single academic center. Placental pathology and gastric fluid Ureaplasma data were available for all infants. Culture and polymerase chain reaction were used to detect Ureaplasma in gastric fluid. Prolonged mechanical ventilation was defined as mechanical ventilation that began within 28 days after birth and continued. RESULTS: Of 111 ELBW infants enrolled, 84 survived beyond 36 weeks of postmenstrual age (PMA) and were included in the analysis. Eighteen infants (21.4%) had both HCAM and Ureaplasma exposure. Seven infants (8.3%) required mechanical ventilation beyond 36 weeks of PMA. Coexistence of HCAM and Ureaplasma in gastric fluid was significantly associated with prolonged mechanical ventilation after adjustment for gestational age, sex, mode of delivery, and use of macrolide antibiotics (OR, 8.7; 95%CI: 1.1-67.2). CONCLUSIONS: Coexistence of maternal HCAM and perinatal Ureaplasma exposure significantly increases the risk of prolonged mechanical ventilation in ELBW infants.

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants.

AIMS: The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. METHODS: Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2 h, 4 h or 6 h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. RESULTS: A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P < 0.001). Total, renal and nonrenal clearances of theophylline were 0.50 ± 0.29 ml kg-1  min-1 , 0.16 ± 0.06 ml kg-1  min-1 and 0.34 ± 0.28 ml kg-1  min-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CONCLUSIONS: CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants.

Comparison of the Mortality and In-Hospital Outcomes of Preterm Infants Treated with Ibuprofen for Patent Ductus Arteriosus with or without Clinical Symptoms Attributable to the Patent Ductus Arteriosus at the Time of Ibuprofen Treatment.

The aim of this study was to assess the differences in the mortality and in-hospital outcomes of preterm infants with < 28 weeks of gestation who received ibuprofen treatment according to the presence of clinical symptoms (any of oliguria, hypotension, or moderate to severe respiratory difficulty) attributable to hemodynamically-significant patent ductus arteriosus (hsPDA) at the time of first ibuprofen treatment. In total, 91 infants born from April 2010 to March 2015 were included. Fourteen infants (15.4%) received ibuprofen treatment when there were clinical symptoms due to hsPDA (clinical symptoms group). In clinical symptoms group, infants were younger (25 [23-27] vs. 26 [23-27] weeks; P = 0.012) and lighter (655 [500-930] vs. 880 [370-1,780] grams; P < 0.001). Also, the clinical risk index for babies (CRIB)-II scores were higher and more infants received invasive ventilator care ≤ 2 postnatal days. More infants received multiple courses of ibuprofen in clinical symptoms group. Although the frequency of secondary patent ductus arteriosus (PDA) ligation and the incidence of bronchopulmonary dysplasia (BPD) was higher in the clinical symptoms group in the univariate analysis, after multivariate logistic regression analysis adjusting for the CRIB-II score, birthweight, birth year, and the invasive ventilator care ≤ 2 postnatal days, there were no significant differences in mortality, frequency of secondary ligation and in-hospital outcomes including necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), BPD or death. Our data suggest that we can hold off on PDA treatment until the clinical symptoms become prominent.

Efficacy and safety of fluconazole prophylaxis in extremely low birth weight infants: multicenter pre-post cohort study.

BACKGROUND: There have been many studies supporting fluconazole prophylaxis in preterm infants for prevention of invasive fungal infections (IFIs). However, the routine use of fluconazole prophylaxis in neonatal intensive care units (NICUs) raises concerns with respect to resistance development, including the selection of resistant Candida species. We aimed to evaluate the efficacy and safety of fluconazole prophylaxis in extremely low birth weight (ELBW) infants. METHODS: An interventional pre-post cohort study at two tertiary NICUs was conducted. Data from two 5-year periods with and without fluconazole prophylaxis (Mar 2008-Feb 2013 and Mar 2003-Feb 2008) was compared. Prophylactic fluconazole was administered starting on the 3rd day at a dose of 3 mg/kg twice a week for 4 weeks during the prophylaxis period. RESULTS: The fluconazole prophylaxis group consisted of 264 infants, and the non-prophylaxis group consisted of 159 infants. IFI occurred in a total of 19 neonates (4.7 %) during the 10-year study period. Fluconazole prophylaxis lower the fungal colonization rate significantly (59.1 % vs. 33.9 %, P <0.001). However, the incidence of IFIs in ELBW infants was not reduced after fluconazole prophylaxis (4.4 % vs. 5.5 %, P = 0.80). Rather, although the increase did not reach statistical significance, fluconazole prophylaxis tended to increase the incidence of invasive infections involving fluconazole-resistant C. parapsilosis (0 % vs. 41.7 %, P = 0.11). CONCLUSIONS: Fluconazole prophylaxis was not efficacious in decreasing IFIs in ELBW infants. There is a need for targeting prophylaxis to greatest risk population and prospective studies to measure the long-term effect of fluconazole prophylaxis on the emergence of organisms with antifungal resistance.

Atypical acute respiratory disorder in late preterm and term newborn infants.

OBJECTIVE: We were to describe the clinical characteristics of late preterm and term newborn infants who needed invasive or non-invasive ventilation for respiratory distress but did not meet the diagnostic criteria of common neonatal respiratory disorders (atypical acute respiratory disorder; aRD). METHODS: We retrospectively reviewed electronic medical records of 242 late preterm and term newborn infants born who were admitted to the neonatal intensive care unit for acute respiratory distress developed within 24 h after birth. RESULTS: Newborn infants with aRD had significantly higher mean, maximum blood PCO2 levels and maximum FiO2 levels during the first 72 h after birth than infants with transient tachypnea of the newborn (TTN). Total periods of oxygen supplementation of the infants with aRD were significantly longer than those of infants with TTN, but shorter than those of the infants with meconium aspiration syndrome (MAS). CONCLUSIONS: Except for definite diagnosis, higher oxygen need and PCO2 level on blood gas analysis during the initial period of their respiratory illness may be able to predict aRD, and these interventions may be able to decrease neonatal respiratory morbidity.

Protective effect of chorioamnionitis on the development of bronchopulmonary dysplasia triggered by postnatal systemic inflammation in neonatal rats.

BACKGROUND: Prenatal or postnatal systemic inflammation can contribute to the development of bronchopulmonary dysplasia (BPD). We investigated whether prenatal intra-amniotic (i.a.) inflammation or early postnatal systemic inflammation can induce BPD in a rat model. METHODS: One microgram of lipopolysaccharide (LPS) or vehicle was injected into the amniotic sacs 2 d before delivery (E20). After birth, 0.25 mg/kg of LPS or vehicle was injected into the peritoneum of pups on postnatal day (P)1, P3, and P5. On P7 and P14, peripheral blood (PB), bronchoalveolar lavage fluid (BALF), and lung tissue were obtained and analyzed. RESULTS: Postnatal i.p. injections of LPS significantly increased neutrophil counts in PB and BALF on P7 and P14. Similarly, proinflammatory cytokine and angiogenic factor transcript levels were increased in the lung by i.p. LPS on P7. Alveolar and pulmonary vascular development was markedly disrupted by i.p. LPS on P14. However, pretreatment with i.a. LPS significantly negated the detrimental effects of postnatal i.p. LPS on PB and BALF neutrophil counts and on lung proinflammatory cytokine expression and histopathological changes. CONCLUSION: Exposure to early postnatal systemic LPS induces BPD, an arrest in alveolarization, in neonatal rats. Preceding exposure to i.a. LPS protects the lungs against BPD triggered by postnatal systemic inflammation.

Recent Changes in the Incidence of Bronchopulmonary Dysplasia among Very-Low-Birth-Weight Infants in Korea.

We investigated the incidence of bronchopulmonary dysplasia (BPD) in very-low-birth-weight (VLBW) infants in Korea using the Korean Neonatal Network (KNN) data. In total, 2,386 VLBW infants born from January 2013 to June 2014 were prospectively registered. BPD was defined as supplemental oxygen or positive pressure support at 36 weeks postmenstrual age (PMA). The overall incidence of BPD was 28.9%, and the overall mortality rate in the neonatal intensive care units (NICUs) was 11.9%. To investigate recent changes in the incidence of BPD among VLBW infants, we compared the BPD rate in the present study with the latest nationwide retrospective survey conducted between 2007 and 2008. For comparison, we selected infants (23-31 weeks of gestation) (n=1,990) to adjust for the same conditions with the previous survey in 2007-2008 (n=3,841). Among the limited data on VLBW infants (23-31 weeks of gestation), the incidence of BPD increased by 85% (from 17.8% to 33.0%) and the mortality rate in the NICU decreased by 31.4% (from 18.8% to 12.9%) compared to those in the study conducted in 2007-2008. The current trend of increase in the incidence of BPD among infants can be attributed to the increase in the survival rate of VLBW infants.

Neonatal Morbidities Associated with Histologic Chorioamnionitis Defined Based on the Site and Extent of Inflammation in Very Low Birth Weight Infants.

Conflicting results on the influences of histologic chorioamnionitis (HC) on neonatal morbidities might be partly originated from using different definition of HC. The aim of this study was to determine the relationship between HC and neonatal morbidities using definition of HC that reflects the site and extent of inflammation. This was a retrospective cohort study of 261 very low birth weight (VLBW) infants admitted at a tertiary academic center. Based on the site of inflammation, HC was categorized: any HC; amnionitis; funisitis; amnionitis+funisitis. The extent of inflammation in each site was reflected by sub-defining high grade (HG). The incidences of morbidities in infants with and without HC were compared. The bronchopulmonary dysplasia (BPD) rate was significantly higher in infants with amnionitis and the severe retinopathy of prematurity (ROP) rate was significantly higher in infants with any HC and funisitis. After adjustment for both gestational age and birth weight, the respiratory distress syndrome (RDS) rate was significantly lower in infants with all categories of HC except for HG amnionitis and HG funisitis, which are not associated with lower RDS rate. HG amnionitis was significantly associated with increased BPD rate but the association of HC with severe ROP disappeared. In conclusion, HC is significantly associated with decreased RDS and HG amnionitis with increased BPD while lacking association with other neonatal morbidities in VLBW infants. The association with HC and neonatal morbidities differs by the site and extent of chorioamnionitis.

The Impact of Atrial Left-to-Right Shunt on Pulmonary Hypertension in Preterm Infants with Moderate or Severe Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a well-known complication of prematurity; however, the additional impact of a left-to-right interatrial shunt on this condition remains poorly understood. The aim of the present study was to identify the significance of atrial left-to-right shunt lesions in PH infants with moderate or severe BPD. METHODS: The medical records of 383 preterm infants (gestational age of < 32 weeks) who were diagnosed with BPD between 2005 and 2013 were retrospectively reviewed. Baseline characteristics such as interatrial shunts and outcomes were compared between the infants who developed PH (n = 50) and infants who did not (n = 144). Infants with hemodynamically significant residual patent ductus arteriosus were excluded. Among the infants diagnosed with PH (n = 50), the outcomes were compared between the patients with (n = 21) and without atrial shunts (n = 29) at 36 weeks corrected postmenstrual age. RESULTS: Fifty (15%) preterm infants with BPD were diagnosed with PH. The number of infants with a history of atrial shunt lesions was significantly higher in the PH group than in the non-PH group (42% vs. 15.3%, respectively). The adjusted odds ratio for PH in the atrial shunt group was 3.8 (95% confidence interval, 1.8-8.0), compared to PH-BPD infants without an atrial shunt. CONCLUSION: The presence of an atrial left-to-right shunt was associated with PH in preterm infants with moderate or severe BPD. Close follow up is needed for infants with interatrial shunts, and a more tailored prognostic evaluation and treatment are recommended.

Deferoxamine Improves Alveolar and Pulmonary Vascular Development by Upregulating Hypoxia-inducible Factor-1α in a Rat Model of Bronchopulmonary Dysplasia.

Fetal lung development normally occurs in a hypoxic environment. Hypoxia-inducible factor (HIF)-1α is robustly induced under hypoxia and transactivates many genes that are essential for fetal development. Most preterm infants are prematurely exposed to hyperoxia, which can halt hypoxia-driven lung maturation. We were to investigate whether the HIF-1α inducer, deferoxamine (DFX) can improve alveolarization in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was produced by intra-amniotic lipopolysaccharide (LPS) administration and postnatal hyperoxia (85% for 7 days), and DFX (150 mg/kg/d) or vehicle was administered to rat pups intraperitoneally for 14 days. On day 14, the rat pups were sacrificed and their lungs were removed and examined. A parallel in vitro study was performed with a human small airway epithelial cell line to test whether DFX induces the expression of HIF-1α and its target genes. Alveolarization and pulmonary vascular development were impaired in rats with BPD. However, DFX significantly ameliorated these effects. Immunohistochemical analysis showed that HIF-1α was significantly upregulated in the lungs of BPD rats treated with DFX. DFX was also found to induce HIF-1α in human small airway epithelial cells and to promote the expression of HIF-1α target genes. Our data suggest that DFX induces and activates HIF-1α, thereby improving alveolarization and vascular distribution in the lungs of rats with BPD.