Huayan Zhang

ABCA3 Is Critical for Lamellar Body Biogenesis in Vivo

Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3–/– knock-out mice died soon after birth, whereas most of the wild type, Abca3+/+, and heterozygous, Abca3+/–, neonates survived. The lungs from E18.5 and E19.5 Abca3–/– mice were less mature than wild type. Alveolar type 2 cells from Abca3–/– embryos contained no lamellar bodies, and expression of mature SP-B protein was disrupted when compared with the normal lung surfactant system of wild type embryos. Small structural and functional differences in the surfactant system were seen in adult Abca3+/– compared with Abca3+/+ mice. The heterozygotes had fewer lamellar bodies, and the incorporation of radiolabeled substrates into newly synthesized disaturated phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine in both lamellar bodies and surfactant was lower than in Abca3+/+ mouse lungs. In addition, since the fraction of near term Abca3–/– embryos was significantly lower than expected from Mendelian inheritance ABCA3 probably plays roles in development unrelated to surfactant. Collectively, these findings strongly suggest that ABCA3 is necessary for lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation.

Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia

Recommended Citation Abman, S. H., Collaco, J. M., Shepherd, E. G., Keszler, M., Cuevas-Guaman, M., Welty, S. E., Truog, W. E., McGrath-Morrow, S. A., Moore, P. E., Rhein, L. M., Kirpalani, H., Zhang, H., Gratny, L. L., Lynch, S. K., Curtiss, J., Stonestreet, B. S., McKinney, R. L., Dysart, K. C., Gien, J., Baker, C. D., Donohue, P. K., Austin, E., Fike, C., Nelin, L. D., . Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia. The Journal of pediatrics 181, 12-28 (2017).

Disrupted postnatal lung development in heme oxygenase-1 deficient mice

BackgroundHeme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin. The HO-1 isoform is both inducible and cyto-protective during oxidative stress, inflammation and lung injury. However, little is known about its precise role and function in lung development. We hypothesized that HO-1 is required for mouse postnatal lung alveolar development and that vascular expression of HO-1 is essential and protective during postnatal alveolar development.MethodsNeonatal lung development in wildtype and HO-1 mutant mice was evaluated by histological and molecular methods. Furthermore, these newborn mice were treated with postnatal dexamethasone (Dex) till postnatal 14 days, and evaluated for lung development.ResultsCompared to wildtype littermates, HO-1 mutant mice exhibited disrupted lung alveolar structure including simplification, disorganization and reduced secondary crest formation. These defects in alveolar development were more pronounced when these mice were challenged with Dex treatment. Expression levels of both vascular endothelial and alveolar epithelial markers were also further decreased in HO-1 mutants after Dex treatment.ConclusionsThese experiments demonstrate that HO-1 is required in normal lung development and that HO-1 disruption and dexamethasone exposure are additive in the disruption of postnatal lung growth. We speculate that HO-1 is involved in postnatal lung development through modulation of pulmonary vascular development.

The angiogenic factor midkine is regulated by dexamethasone and retinoic acid during alveolarization and in alveolar epithelial cells

BackgroundA precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The purpose of this study was to examine regulation of MK by GC and RA during postnatal alveolar formation in rats.MethodsNewborn rats were treated with dexamethasone (DEX) and/or all-trans-retinoic acid (RA) during the first two weeks of life. Lung morphology was assessed by light microscopy and radial alveolar counts. MK mRNA and protein expression in response to different treatment were determined by Northern and Western blots. In addition, MK protein expression in cultured human alveolar type 2-like cells treated with DEX and RA was also determined.ResultsLung histology confirmed that DEX treatment inhibited and RA treatment stimulated alveolar formation, whereas concurrent administration of RA with DEX prevented the DEX effects. During normal development, MK expression was maximal during the period of alveolarization from postnatal day 5 (PN5) to PN15. DEX treatment of rat pups decreased, and RA treatment increased lung MK expression, whereas concurrent DEX+RA treatment prevented the DEX-induced decrease in MK expression. Using human alveolar type 2 (AT2)-like cells differentiated in culture, we confirmed that DEX and cAMP decreased, and RA increased MK expression.ConclusionWe conclude that MK is expressed by AT2 cells, and is differentially regulated by corticosteroid and retinoid treatment in a manner consistent with hormonal effects on alveolarization during postnatal lung development.

Hormonal regulation of alveolarization: structure-function correlation

BackgroundDexamethasone (Dex) limits and all-trans-retinoic acid (RA) promotes alveolarization. While structural changes resulting from such hormonal exposures are known, their functional consequences are unclear.MethodsNeonatal rats were treated with Dex and/or RA during the first two weeks of life or were given RA after previous exposure to Dex. Morphology was assessed by light microscopy and radial alveolar counts. Function was evaluated by plethysmography at d13, pressure volume curves at d30, and exercise swim testing and arterial blood gases at both d15 and d30.ResultsDex-treated animals had simplified lung architecture without secondary septation. Animals given RA alone had smaller, more numerous alveoli. Concomitant treatment with Dex + RA prevented the Dex-induced changes in septation. While the results of exposure to Dex + RA were sustained, the effects of RA alone were reversed two weeks after treatment was stopped. At d13, Dex-treated animals had increased lung volume, respiratory rate, tidal volume, and minute ventilation. On d15, both RA- and Dex-treated animals had hypercarbia and low arterial pH. By d30, the RA-treated animals resolved this respiratory acidosis, but Dex-treated animals continued to demonstrate blood gas and lung volume abnormalities. Concomitant RA treatment improved respiratory acidosis, but failed to normalize Dex-induced changes in pulmonary function and lung volumes. No differences in exercise tolerance were noted at either d15 or d30. RA treatment after the period of alveolarization also corrected the effects of earlier Dex exposure, but the structural changes due to RA alone were again lost two weeks after treatment.ConclusionWe conclude that both RA- and corticosteroid-treatments are associated with respiratory acidosis at d15. While RA alone-induced changes in structure andrespiratory function are reversed, Dex-treated animals continue to demonstrate increased respiratory rate, minute ventilation, tidal and total lung volumes at d30. Concomitant treatment with Dex + RA prevents decreased septation induced by Dex alone and results in correction of hypercarbia. However, these animals continue to have abnormal pulmonary function and lung volumes. Increased septation as a result of RA treatment alone is reversed upon discontinuation of treatment. These data suggest that Dex + RA treatment results in improved gas exchange likely secondary to normalized septation.

Infertility, in vitro fertilization and congenital tuberculosis.

Congenital tuberculosis (CTB) due to maternal genitourinary (GU) TB infection is a rare occurrence, as infection of the genital tract in women generally leads to infertility. Increasing availability of assisted reproductive technology creates the potential for CTB to emerge as a significant problem. We describe five infants (two sets of twins and a singleton birth) conceived by in vitro fertilization who developed CTB. All five infants were born to mothers who had immigrated to the United States from India and none had GU TB diagnosed before the birth of their infected infants.

Tracheobronchomalacia Is Associated with Increased Morbidity in Bronchopulmonary Dysplasia

Rationale: Tracheobronchomalacia (TBM) is a common comorbidity in neonates with bronchopulmonary dysplasia (BPD). However, the effect of TBM on the clinical course of BPD is not well understood. Objectives: We sought to assess the impact of TBM on outcomes in neonates with BPD in a large, multicenter cohort. Methods: We performed a cohort study of 974 neonates with BPD admitted to 27 neonatal intensive care units participating in the Childrens Hospital Neonatal Database who had undergone bronchoscopy. In‐hospital morbidity for neonates with BPD and TBM (n = 353, 36.2%) was compared with those without TBM (n = 621, 63.8%) using mixed‐effects multivariate regression. Results: Neonates with TBM and BPD had more comorbidities, such as gastroesophageal reflux (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.23‐2.29; P = 0.001) and pneumonia (OR, 1.68; 95% CI, 1.21‐2.33; P = 0.002), and more commonly required surgeries, such as tracheostomy (OR, 1.55; 95% CI, 1.15‐2.11; P = 0.005) and gastrostomy (OR, 1.38; 95% CI: 1.03‐1.85; P = 0.03), than those without TBM. Neonates with TBM were hospitalized (118 ± 93 d vs. 105 ± 83 d; P = 0.02) and ventilated (83.1 ± 91.1 d vs. 67.2 ± 71.9 d; P = 0.003) longer than those without TBM. On discharge, neonates with TBM and BPD were more likely to be mechanically ventilated (OR, 1.37; 95% CI, 1.01‐1.87; P = 0.045) and possibly less likely to receive oral nutrition (OR, 0.69; 95% CI, 0.47‐1.01; P = 0.058). Conclusions: TBM is common in neonates with BPD who undergo bronchoscopy and is associated with longer and more complicated hospitalizations.

Determinants of Severe Metabolic Bone Disease in Very Low-Birth-Weight Infants with Severe Bronchopulmonary Dysplasia Admitted to a Tertiary Referral Center.

OBJECTIVE Nonrespiratory comorbidities are common among preterm infants with severe bronchopulmonary dysplasia (BPD) referred to tertiary perinatal centers. We evaluated the incidence, severity, and risk factors for metabolic bone disease (MBD) in this population. STUDY DESIGN We conducted a retrospective cohort study of all infants born ≤ 1,500 g who were diagnosed with severe BPD in our single, tertiary referral center between September 2010 and October 2012. MBD severity was classified by serial radiography. RESULTS Among the 83 infants diagnosed with severe BPD, 26 (31%) developed severe MBD (rickets). Male gender and lower gestational age and birth weight were associated with increased odds of severe MBD. After adjustment for these potential confounders, cytomegalovirus infection, postnatal growth restriction, surgical necrotizing enterocolitis, and blood culture confirmed sepsis were associated with increased odds of severe MBD. The cumulative duration of therapy with furosemide, hydrocortisone, and prednisolone each correlated with significantly greater probability of severe MBD. CONCLUSIONS Severe MBD was common in this referral-based cohort with severe BPD. The high incidence in this population is likely explained by the coexistence of multiple exposures and comorbidities associated with bone demineralization.

Anti-gastroesophageal reflux surgery in infants with severe bronchopulmonary dysplasia.

Gastroesophageal reflux may exacerbate lung disease in infants with bronchopulmonary dysplasia (BPD). Anti‐reflux surgery may therefore reduce the severity of this disease in some infants. We report a retrospective series of 22 infants with severe BPD who underwent anti‐reflux surgery. Our experience indicates that these procedures can be safely performed in this population and that early post‐operative initiation of gastric feeds is well tolerated. Modest post‐operative reductions in required oxygen and median respiratory rate were observed. Pediatr Pulmonol. 2015; 50:584–587.

The Impact of Pulmonary Hypertension in Preterm Infants with Severe Bronchopulmonary Dysplasia through 1 Year

Objectives To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. Study design This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation with severe bronchopulmonary dysplasia enrolled in the Childrens Hospital Neonatal Consortium with records linked to the Pediatric Health Information System. Results Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10‐4.73, P < .001), ventilator support at 36 weeks of postmenstrual age (60% vs 40%, P < .001), duration of ventilation (72 IQR 30‐124 vs 41 IQR 17‐74 days, P < .001), and higher respiratory severity score (3.6 IQR 0.4‐7.0 vs 0.8 IQR 0.3‐3.3, P < .001). At discharge, pulmonary hypertension was associated with tracheostomy (27% vs 9%, P < .001), supplemental oxygen use (84% vs 61%, P < .001), and tube feeds (80% vs 46%, P < .001). Through 1 year of corrected age, pulmonary hypertension was associated with increased frequency of readmission (incidence rate ratio [IRR] = 1.38, 95% CI 1.18‐1.63, P < .001). Conclusions Infants with severe bronchopulmonary dysplasia‐associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high‐risk population.