Arrest In Lung Development Research Articles

Lung epithelial-endothelial-mesenchymal signaling network with hepatocyte growth factor as a hub is involved in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal.

Loss of microRNA-30a and sex-specific effects on the neonatal hyperoxic lung injury

BackgroundBronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.MethodsWild-type and miR-30a−/− neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a−/− mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a−/− male and female lung transcriptome data.ResultsSignificantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a−/− mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a−/− female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand–receptor interaction. Gene expression signature in the miR-30a−/− female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.ConclusionsmiR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.

Cerebral Myelination in a Bronchopulmonary Dysplasia Murine Model.

Bronchopulmonary dysplasia (BPD) is a devastating disease in preterm infants concurrent with neurodevelopmental disorders. Chronic hyperoxia exposure might also cause brain injury, but the evidence was insufficient. Neonatal C57BL/6J mice were exposed to hyperoxia from P0 to induce a BPD disease model. Lung histopathological morphology analyses were performed at P10, P15, and P20. Cerebral myelination was assessed using MBP (myelin basic protein, a major myelin protein), NfH (neurofilament heavy chain, a biomarker of neurofilament heavy chain), and GFAP (glial fibrillary acidic protein, a marker of astrocytes) as biomarkers by western blot and immunofluorescence. Mice exposed to hyperoxia exhibited reduced and enlarged alveoli in lungs. During hyperoxia exposure, MBP declined at P10, but then increased to a comparable level to the air group at P15 and P20. Meanwhile, GFAP elevated significantly at P10, and the elevation sustained to P15 and P20. Neonatal hyperoxia exposure caused an arrest of lung development, as well as an obstacle of myelination process in white matter of the immature brain, with a decline of MBP in the generation period of myelin and persistent astrogliosis.

Endothelial progenitor cells derived from embryonic stem cells prevent alveolar simplification in a murine model of bronchopulmonary dysplasia.

Introduction: Vascular remodeling and compromised alveolar development are hallmarks of chronic pulmonary diseases such as bronchopulmonary dysplasia (BPD). Despite advances in neonatal healthcare the number of BPD cases worldwide continues to increase. One approach to overcoming the premature arrest in lung development seen in BPD is to stimulate neonatal angiogenesis via delivery and engraftment of endothelial progenitor cells (EPCs). One such population is resident to the pulmonary microvasculature and expresses both FOXF1 and c-KIT. Previous studies have shown that c-KIT+FOXF1+ EPCs are highly sensitive to elevated levels of oxygen (hyperoxia) and are decreased in premature infants with BPD and hyperoxia-induced BPD mouse models. We hypothesize that restoring EPCs through transplantation of c-KIT+FOXF1+ EPCs derived in vitro from pluripotent embryonic stem cells (ESCs), will stimulate neonatal angiogenesis and alveolarization in mice with hyperoxia-induced lung injury. Methods: Utilizing a novel ESC line with a FOXF1:GFP reporter, we generated ESC-derived c-KIT+FOXF1+ EPCs in vitro. Using a second ESC line which contains FOXF1:GFP and tdTomato transgenes, we differentiated ESCs towards c-KIT+FOXF1+ EPCs and tracked them in vivo after injection into the neonatal circulation of hyperoxia-injured mice. After a recovery period in room air conditions, we analyzed c-KIT+FOXF1+ EPC engraftment and quantified the number of resident and circulating endothelial cells, the size of alveolar spaces, and the capillary density after EPC transplantations. Results and conclusion: Herein, we demonstrate that addition of BMP9 to the directed endothelial differentiation protocol results in very efficient generation of c-KIT+FOXF1+ EPCs from pluripotent ESCs. ESC-derived c-KIT+FOXF1+ EPCs effectively engraft into the pulmonary microvasculature of hyperoxia-injured mice, promote vascular remodeling in alveoli, increase the number of resident and circulating endothelial cells, and improve alveolarization. Altogether, these results provide a proof-of-principle that cell therapy with ESC-derived c-KIT+FOXF1+ EPCs can prevent alveolar simplification in a hyperoxia-induced BPD mouse model.

Rad1 attenuates DNA double-strand breaks and cell cycle arrest in type II alveolar epithelial cells of rats with bronchopulmonary dysplasia

BackgroundBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease in preterm infants with pathological characteristics of arrested lung development. DNA double-strand breaks (DSBs) are a serious manifestation of oxidative stress damage, but little is known about the role of DSBs in BPD. The current study set out to detect DSB accumulation and cell cycle arrest in BPD and study the expression of genes related to DNA damage and repair in BPD through DNA damage signaling pathway-based PCR array to determine a suitable target to improve arrested lung development associated with BPD.MethodsDSB accumulation and cell cycle arrest were detected in a BPD animal model and primary cells, then a DNA damage signaling pathway-based PCR array was used to identify the target of DSB repair in BPD.ResultsDSB accumulation and cell cycle arrest were shown in BPD animal model, primary type II alveolar epithelial cells (AECII) and cultured cells after exposure to hyperoxia. Of the 84 genes in the DNA damage-signaling pathway PCR array, eight genes were overexpressed and 11 genes were repressed. Rad1, an important protein for DSB repair, was repressed in the model group. Real-time PCR and western blots were used to verify the microarray results. Next, we confirmed that silencing Rad1 expression aggravated the accumulation of DSBs and cell cycle arrest in AECII cells, whereas its overexpression alleviated DSB accumulation and cell cycle arrest.ConclusionsThe accumulation of DSBs in AECII might be an important cause of alveolar growth arrest associated with BPD. Rad1 could be an effective target for intervention to improve this arrest in lung development associated with BPD.

Big Data for Tiny Patients: A Precision Medicine Approach to Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of extreme prematurity. Despite more than 50 years of research, current treatments are ineffective, and clinicians are largely unable to accurately predict which neonates the condition will develop in. A deeper understanding of the molecular mechanisms underlying the characteristic arrest in lung development are warranted. Integrating high-fidelity technology from precision medicine approaches may fill this gap and provide the tools necessary to identify biomarkers and targetable pathways. In this review, we describe insights garnered from current studies using omics for BPD prediction and stratification. We conclude by describing novel programs that will integrate multi-omics in efforts to better understand and treat the pathogenesis of BPD. [Pediatr Ann. 2022;51(10):e396-e404.].

Autophagy is required for lung development and morphogenesis.

Bronchopulmonary dysplasia (BPD) remains a major respiratory illness in extremely premature infants. The biological mechanisms leading to BPD are not fully understood, although an arrest in lung development has been implicated. The current study aimed to investigate the occurrence of autophagy in the developing mouse lung and its regulatory role in airway branching and terminal sacculi formation. We found 2 windows of epithelial autophagy activation in the developing mouse lung, both resulting from AMPK activation. Inhibition of AMPK-mediated autophagy led to reduced lung branching in vitro. Conditional deletion of beclin 1 (Becn1) in mouse lung epithelial cells (Becn1Epi-KO), either at early (E10.5) or late (E16.5) gestation, resulted in lethal respiratory distress at birth or shortly after. E10.5 Becn1Epi-KO lungs displayed reduced airway branching and sacculi formation accompanied by impaired vascularization, excessive epithelial cell death, reduced mesenchymal thinning of the interstitial walls, and delayed epithelial maturation. E16.5 Becn1Epi-KO lungs had reduced terminal air sac formation and vascularization and delayed distal epithelial differentiation, a pathology similar to that seen in infants with BPD. Taken together, our findings demonstrate that intrinsic autophagy is an important regulator of lung development and morphogenesis and may contribute to the BPD phenotype when impaired.

HIF‐1 alpha Mediates Sex‐specific miR‐30a Expression in Neonatal Hyperoxic Lung Injury: Implications for Bronchopulmonary Dysplasia

BackgroundBronchopulmonary Dysplasia (BPD) is characterized by an arrest in lung development with severe impairment of alveolar septation and vascular development. Premature male neonates are at a greater risk of developing bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. Neonatal female mice have improved alveolarization and pulmonary vascular development compared to male littermates in a murine model of BPD. Analysis of the pulmonary transcriptome suggests that miR‐30a, may modulate these sex‐specific differences in gene expression. HIF‐1α plays an important role in post‐natal lung development, especially in recovery from hyperoxic injury and acute lung injury. We hypothesized that differential sex‐specific expression of miR‐30a is mediated through HIF‐1α.MethodsMale and female neonatal WT (C57BL6) mice were exposed to hyperoxia (P1–P5; saccular stage of lung development) and euthanized on P7 or P21 after recovery in normoxia. Human pulmonary microvascular endothelial cells (HPMECs; from 18–24 weeks gestation donors; 3 male and 3 female) were obtained from ScienCell (Carlsbad, California). They were cultured in endothelial cell media per protocol. Cells from passage from 3 to 6 were used for experiments. For hyperoxic exposure, cells were incubated in 95% O2 and 5% CO2 at 37 °C for upto 72 hours. Cells in normoxia were maintained in air and 5% CO2. miR‐30a and Dll4 (miR‐30a target) expression was measured. Hif‐1α binding to its targets genes (by ChIP‐qPCR) and expression was measured in vivo. To further establish potential regulation of miR‐30a by Hif‐1α, miR‐30a expression after Hif‐1α inhibition was measured in neonatal HPMECs.ResultsExpression of miR‐30a was increased and Dll4 decreased on PND21 in hyperoxia‐exposed neonatal female mice compared to males. On PND21, hyperoxia‐ exposed female mice showed a significant increase in Hif‐1α binding to target genes compared to room air controls and hyperoxia‐exposed male mice. In contrast to male mice, females did not show a decrease in Hif‐1α expression at PND21 after early hyperoxia exposure and this was accompanied by a significant decrease in Phd2 expression in female mice, which metabolizes Hif‐1α. Motif analysis revealed a hypoxia response element (HRE) [AG]CGTG site 428 base pairs upstream of miR‐30a. siRNA mediated loss of Hif‐1α expression in human pulmonary microvascular endothelial cells decreased miR‐30a and increased Dll4 mRNA and protein expression.ConclusionsHif‐1α mediated differential sex‐specific miR‐30a expression may contribute to protection from hyperoxic lung injury in female neonatal mice and contribute to the sex‐specific differences seen in BPD.Support or Funding InformationK08 HL‐127103R03 HL‐141572This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Congenital Cystic Adenomatoid Malformation: A Tertiary Care Hospital Experience.

Congenital Cystic Adenomatoid Malformation (CCAM) is an uncommon developmental deformity affecting the terminal respiratory structures. It is characterized by broncho pulmonary foregut malformations. The reason behind it is an arrest in lung development between 4th and 7th week of fetal life. The present study was conducted to assess the clinical and radiological profile and also to study the role of surgical intervention in patients with CCAM. All patients with clinical suspicion or provisional diagnosis of CCAM were included in the study. A clinical questionnaire was prepared to collect data. Computed Tomography (CT) chest with High Resolution Computed Tomography (HRCT) was done for all the patients. Patients were assessed by paediatric surgeon and eligible patients were operated. The procedure conducted was usually open thoracotomy under general anaesthesia. The affected lobes were removed and specimens were sent for histopathological analysis. All included patients were followed up prospectively to find out about their current level of health. Via telephonic interview they were asked about their overall growth, quality of life, activity, rate of respiratory infections and requirement of hospital admission. Total 15 patients with diagnosis of CCAM were included in the study. Of them, 8 (53.3%) were male. The commonest presentation was cough 13(86%), breathing difficulty 11(73%), fever 9(60%), recurrent pneumonia 4(26%), hypoxia requiring oxygen supplementation 6(40%), others 2(12%). Thirteen patients required surgical intervention and underwent lobectomy. There were 2 cases of type I, one each of type II and III, 3 case of type IV while 5 were intermediate type. There was no procedure related mortality. The median duration of hospital stay and all were successfully discharged with median duration of stay 11±16 days. The study concludes that if recognized early, surgical removal of affected lung prevents the complications like recurrent pulmonary infections. The surgery is well tolerated without any post-operative mortality or morbidity.

Next generation sequence analysis of the transcriptional response to neonatal hyperoxia

Results 248 genes were identified as differentially expressed between hyperoxia and control samples by both SAM (median FDR = 0) and CuffDiff2 (p<0.05) and had a foldchange ≤ 2. We successfully validated 17 of 24 genes by qPCR. Canonical pathways significantly dysregulated in hyperoxia lungs included Nrf2-mediated oxidative stress signaling, p53 signaling, hepatic fibrosis and sildenafil pathways. Interestingly most genes significantly affected following hyperoxia exposure (~70%) showed a pattern of expression consistent with an arrest in lung development. A subset of the genes dysregulated in hyperoxic neonatal mouse lungs, were also differentially expressed in human BPD lung tissue. Conclusions We have identified genes dysregulated in mouse of BPD-like pathology. Further analysis of these data will enhance our current knowledge of BPD, and may be useful for developing novel therapeutic strategies.

Epidermal growth factor receptor (EGFR) contributes to fetal lung fibroblast injury induced by mechanical stretch

Context: Epidermal growth factor receptor (EGFR) is critical for normal fetal lung development. However, the role of this receptor in lung injury induced by mechanical ventilation is controversial. Objective: To investigate in vitro whether EGFR plays a protective role or contributes to stretch-induced lung injury. Methods: Fetal lung fibroblasts were isolated from wild-type and EGFR knockout mice and exposed to physiologic stretch (2.5% elongation) or injurious stretch (20% distention). Cells were evaluated for necrosis, apoptosis, proliferation and inflammation. Results: Injurious stretch increased lactate dehydrogenase (LDH) release to similar degree in wild-type and knockout cells. In contrast, 20% stretch increased cleaved caspase-3 and decreased proliferating cell nuclear antigen (PCNA) only in wild-type cells. Furthermore, 20% stretch increased macrophage inflammatory protein-2 (MIP-2) and monocyte chemotactic protein-1 (MCP-1) by 3–5 fold in wild-type cells. In contrast, in knockout cells MIP-2 decreased by 50% and MCP-1 only increased by 60% when compared to physiologic stretch. Conclusion: Our data show a decrease of apoptosis and inflammation and absence of decreased proliferation after injurious stretch of fetal fibroblasts lacking EGFR. These data suggest that EGFR contributes to lung injury mediated by stretch. We speculate that EGFR may contribute to the arrest of lung development observed after mechanical ventilation by decreasing the population of lung fibroblasts.

Développement pulmonaire et cellules souches mésenchymateuses

The survival of extremely premature newborns has increased because of improvements in perinatal care. These infants however, are at high risk for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD). BPD, the most common complication in infants born before 28 weeks of gestation, is a multifactorial disease characterized by an arrest in alveolar development. Current preventive and curative therapies show limited efficacy. Cell-based therapies hold tremendous promise in regenerative medicine. Recent evidence suggests the therapeutic benefit of mesenchymal stem (or stromal) cells (MSC) in various diseases, including among others neurodegenerative, cardiovascular and respiratory disorders. Moreover, in an oxygen-induced BPD model, we and others recently demonstrated that bone marrow (BM) derived-MSCs efficiently prevent the arrest in lung development. In this review, we summarize the current knowledge regarding the therapeutic properties and mechanisms of action, specifically paracrine, of MSCs.

Early Alterations of Growth Factor Patterns in Bronchoalveolar Lavage Fluid From Preterm Infants Developing Bronchopulmonary Dysplasia

Chronic lung disease of prematurity (bronchopulmonary dysplasia; BPD) is characterized by an arrest in lung development. We hypothesized that early alterations in pulmonary expression of growth factors important for normal lung development would precede development of BPD. Bronchoalveolar lavage fluid (BALF) was obtained from ventilated preterm infants (n = 62) on postnatal d 0, 1, 3, and 7 and analyzed for total phospholipids (PL), VEGF, PDGF-BB, TGF-alpha and -beta1, granulocyte macrophage colony stimulating factor (GM-CSF), and keratinocyte growth factor (KGF). Levels (Ln transformed) were compared between infants developing BPD and BPD-free survivors, adjusted for potential confounders. BPD was associated with higher overall GM-CSF (beta (95% CI) = 0.69 (0.13;1.25); p < 0.05), lower overall latent TGF-beta1 (beta (95% CI) = -1.19 (-1.87, -0.39); p < 0.01) and total PL (beta (95% CI) = -0.64 (-1.23, -0.05); p < 0.05), and lower d 0 and 3 levels of VEGF (mean difference (95% CI) = -1.75 (-2.72, -0.77), p < 0.001; and -1.18 (-2.30, -0.06), p < 0.05, respectively) and TGF-alpha (mean difference (95% CI) = -0.73 (-1.42, -0.04), p < 0.05; and -1.01 (-1.64, -0.38), p < 0.01, respectively). Day 0 VEGF levels had the highest predictive value for BPD (area under receiver operating characteristic curve = 0.87; p < 0.01). In conclusion, substantial alterations in BALF growth factor levels are present in infants developing BPD. An early imbalance in pulmonary growth factors may contribute to the developmental arrest of the lung seen in BPD. :

Congenital Cystic Adenomatoid Malformation

Congenital cystic adenomatoid malformation (CCAM) is a rare lung lesion that may be diagnosed antenatally by ultrasonography. It is believed to result from an arrest in lung development. The differential diagnosis of a mass in the fetal thorax includes CCAM, congenital diaphragmatic hernia, and pulmonary sequestration. This brief review discusses classifications of CCAM with images of each type, sonographic findings, factors that affect the prognosis, and important aspects of management once the diagnosis is made.

Bronchopulmonary Dysplasia: A Genetic Disease

Survival of low birth weight infants continues to improve because of marked advances in perinatal care,1 yet significant late pulmonary and neurocognitive impairments persist. Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major clinical problem, occurring in an estimated 10000 to 15000 infants each year in the United States alone. As initially described by Northway et al2 more than 40 years ago, BPD was originally characterized as resulting from severe acute lung injury in modestly premature newborns caused by the adverse effects of hyperoxia, inflammation, mechanical ventilation, and infection. These mechanisms are still recognized as major contributors to the pathogenesis of BPD, along with chorioamnionitis, maternal smoking and drug use, and delivery room management.3,4 Over the past decades, however, changes in care, including antenatal steroid therapy, surfactant use, novel ventilator modalities and strategies, aggressive treatment of patent ductus arteriosus (PDA), and other factors, have altered the nature of BPD. Infants now surviving with BPD have been born at far earlier gestational ages than in the past. The “new BPD” is believed to represent less of the effects of severe lung injury and its repair and more of a disruption or arrest of lung development.5 This is … Address correspondence to Steven H. Abman, MD, Children's Hospital, Pulmonary Medicine, B395, 13123 E Sixteenth Ave, Aurora, CO 80045. E-mail: steven.abman{at}uchsc.edu

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

Antenatal inflammation in utero may be associated with lung injury and subsequent aberrant lung development resulting in bronchopulmonary dysplasia (BPD). BPD has become a developmental disease with a uniform arrest in lung development. The role of antenatal inflammation in the induction of lung injury was explored in a sheep model suitable for the study of lung development with respect to human development. Chorioamnionitis was induced by a single injection of endotoxin into the amniotic cavity under ultrasound guidance. Endotoxin-induced chorioamnionitis caused a cascade of lung injury, pulmonary inflammation and remodeling in the fetal lung similar to lung injury previously described in adult animal models. The structural changes in the fetal lung after chorioamnionitis showed little to no fibrosis and alveolar/microvascular simplification similar to new BPD. The identified cytokine networks and regulators may explain the absence of fibrosis and lung simplification after strictly intra-uterine inflammation. The mechanisms of antenatal inflammation in the fetal lung were multifactorial and could be antenatally modulated. Fetal pulmonary inflammation was temporarily suppressed by maternal glucocorticoid therapy. However, pulmonary inflammation could be augmented postnatally by resuscitation, oxygen toxicity, mechanical ventilation and pulmonary and systemic infection, which opens a broad window of clinical options.

Chronic lung disease in newborns

Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) occurs in preterm infants who require respiratory support in the first few days of birth. Apart from prematurity, oxygen therapy and assisted ventilation, factors like intrauterine/postnatal infections, patent ductus arteriosus, and genetic polymorphisms also contribute to its pathogenesis. The severe form of BPD with extensive inflammatory changes is rarely seen nowadays; instead, a milder form characterized by decreased alveolar septation due to arrest in lung development is more common. A multitude of strategies, mainly pharmacological and ventilatory, have been employed for prevention and treatment of BPD. Unfortunately, most of them have not been proved to be beneficial. A comprehensive protocol for management of BPD based on the current evidence is discussed here.

Postnatal glucocorticoids in very preterm infants: "the good, the bad, and the ugly"?

Premature births represent 7% to 10% of all births, but account for >85% of all perinatal complications and death. Survival of extremely premature newborns (<28 weeks' gestation) has increased because of the widespread use of surfactant treatment for respiratory distress syndrome, together with antenatal glucocorticoids and new ventilator strategies.1 However, these infants are at high risk for long-term injury of both the lungs and the brain. Bronchopulmonary dysplasia (BPD) is one of the most frequent sequelae in extremely premature infants and results in increased health care costs, prolonged hospital stays with frequent rehospitalizations, and deleterious effects on subsequent growth and neurodevelopment.2 Periventricular leukomalacia, the most severe form of white matter brain damage, is a frequent cause of cerebral palsy in children surviving preterm birth, with lifelong consequences.3 Recent data suggest that a common treatment for one, dexamethasone for BPD, may have deleterious effects on both sequelae. Northway et al4 first described BPD as severe lung injury resulting from mechanical ventilation and oxygen exposure. With improved prenatal and postnatal care, preterm infants developing BPD now are generally very immature, and have antenatal and postnatal histories that differ from those of preterm infants in previous eras. The “new BPD,” as described by Jobe,5 is characterized by an arrest of lung development and interference with alveolarization. This more complex view of the pathogenesis of BPD includes prenatal lung inflammation in response to proinflammatory cytokine exposure in utero, together with postnatal exposure to proinflammatory stimuli, such as ventilation and oxygen. Jobe5 postulates that these stimuli, together with glucocorticoid exposure and inadequate nutrition, can result in inhibition of alveolar and vascular development. Therein lies the irony: the postnatal dexamethasone (DXM) widely used for the treatment or prevention of BPD may suppress inflammation, but also may impair alveolarization and interfere …

Lung development and function in preterm infants in the surfactant treatment era.

Mortality of infants of < 1-kg birth weight has decreased because of surfactant treatments, antenatal glucocorticoid treatments, and new ventilation strategies. However, many of these infants develop a chronic lung disease characterized by an arrest of lung development and interference with alveolarization. Antenatal glucocorticoids can induce early lung maturation clinically, but new information from transgenic and other experimental models indicates that traditional explanations for glucocorticoid effects on the developing lung are inadequate. These very preterm infants have lungs with small lung gas volumes and delicate lung tissue that are susceptible to injury with the initiation of ventilation and subsequent ventilation. Antenatal proinflammatory exposures are frequent in very preterm infants, and postnatal injury is associated with elevations of proinflammatory cytokines in the lungs. One hypothesis is that proinflammatory cytokines can promote or interfere with lung development as well as promote lung injury. Mechanisms of lung injury being characterized in the adult lung may have unique characteristics in the developing lung.

The new BPD: an arrest of lung development.

The new BPD: an arrest of lung development.