Chronic Lung Disease in the Preterm Infant. Lessons Learned from Animal Models

Hilgendorff, Anne; Reiss, Irwin; Ehrhardt, Harald; Eickelberg, Oliver; Alvira, Cristina M.

doi:10.1165/rcmb.2013-0014tr

Cited by 127 publications

(122 citation statements)

References 197 publications

(200 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…These add to our proposition that, in the hyperoxia-induced BPD-like model, AECs do not decrease in number but undergo morphological and functional changes, resulting in air-blood barrier dysfunction and open tight junctions in the pulmonary epithelium. Furthermore, air-blood barrier damage may be a type of vascular endothelial cell injury, which has been previously validated (2,18,31), and production of increased AEC I attributable to transdifferentiation may be a compensatory effect for the reduction in vascular endothelial cells. However, such compensation is structurally and functionally incomplete.…”

Section: Discussionmentioning

confidence: 77%

Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats

Hou

Yang

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

-Supplemental oxygen treatment in preterm infants may cause bronchopulmonary dysplasia (BPD), which is characterized by alveolar simplification and vascular disorganization. Despite type II alveolar epithelial cell (AEC II) damage being reported previously, we found no decrease in the AEC II-specific marker, surfactant protein C (SP-C), in the BPD model in our previous study. We thus speculated that AEC II injury is not a unique mechanism of BPD-related pulmonary epithelial repair dysfunction and that abnormal transdifferentiation can exist. Newborn rats were randomly assigned to model (85% oxygen inhalation) and control groups (room air inhalation). Expressions of AEC I (aquaporin 5, T1␣) and AEC II markers (SP-C, SP-B) were detected at three levels: 1) in intact lung tissue, 2) in AEC II isolated from rats in the two groups, and 3) in AEC II isolated from newborn rats, which were further cultured under either hyperoxic or normoxic conditions. In the model group, increased AEC I was observed at both the tissue and cell level, and markedly increased transdifferentiation was observed by immunofluorescent double staining. Transmission electron microscopy revealed morphological changes in alveolar epithelium such as damaged AECs, a fused air-blood barrier structure, and opened tight junctions in the model group. These findings indicate that transdifferentiation of AECs is not suppressed but rather is increased under hyperoxic treatment by compensation; however, such repair during injury cannot offset pulmonary epithelial air exchange and barrier dysfunction caused by structural damage to AECs. transdifferentiation; alveolar epithelial cells; hyperoxia; bronchopulmonary dysplasia SUPPLEMENTAL OXYGEN TREATMENT, which is often necessary for preterm infants with respiratory failure, has become a major risk factor for bronchopulmonary dysplasia (BPD), one of the most common, serious complications in preterm infants (6,34). BPD is characterized by high morbidity in infants with very low birth weight (BW Ͻ 1,500 g) soon after birth and may induce multiple complications in respiratory and nervous systems during adolescence (4, 6). Despite several decades of research, the underlying pathophysiological foundation of BPD has not been completely clarified.Lung tissue consists of many different cell types, and a developmental disorder of alveolar epithelial cells (AEC) is likely a major cause of BPD (40). The alveolar area accounts for Ն99% of the internal surface area of the lungs (49). Mammals have two types of AECs that maintain normal air exchange function by mutual coordination. Type I AEC (AEC I) cover nearly 96% of alveolar spaces and closely adhere to adjacent capillaries. Such cells are the main epithelial constituents of the air-blood barrier (18, 53) and have air exchange functions. Recent studies have revealed that AEC I can also secrete transport proteins to maintain intrapulmonary fluid and electrolyte balance (9,19,22). Type II AEC (AEC II) are located at the corners of alveoli and are more abundant than AEC I bu...

show abstract

Section: Discussionmentioning

confidence: 77%

Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats

Hou

Yang

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…Although the pathogenesis of BPD is complex and multifactorial (15), preclinical studies have shown that early disruption of angiogenesis in the developing lung impairs alveolarization and causes sustained abnormalities of lung structure that mimic clinical BPD (16)(17)(18). Autopsy studies examining lung tissue from infants who died with severe BPD provide further evidence that BPD is characterized by disruption of angiogenic factor expression (19,20).…”

Section: At a Glance Commentarymentioning

confidence: 99%

Early Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia

Mourani¹,

Sontag

Younoszai

et al. 2015

Am J Respir Crit Care Med

375

473

View full text Add to dashboard Cite

Rationale: Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown.Objectives: To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA).Methods: Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. Measurements and Main Results:A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P , 0.05).Conclusions: Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.Keywords: bronchopulmonary dysplasia; pulmonary vascular disease; pulmonary hypertension; echocardiography; prematurity At a Glance CommentaryScientific Knowledge on the Subject: Preterm infants remain at high risk for late respiratory morbidity and mortality caused by the development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Early injury to the developing lung can impair angiogenesis and alveolarization and result in simplification of distal lung airspace and the clinical manifestations of BPD and PH. However, whether early signs of pulmonary vascular disease are indicative of the subsequent development of BPD or PH at 36 weeks postmenstrual age (PMA) has not been well established.What This Study Adds to the Field: This paper presents a longitudinal study identifying echocardiogram-derived risk factors at 7 days of age for the subsequent development of both BPD and PH. We also describe the incidence of PH at 36 weeks PMA and its relationship to BPD severity.

show abstract

“…Animal models to study the effects of noxious stimuli on lung development in BPD have focused on prenatal endotoxin exposure, postnatal hyperoxia or hypoxia, and mechanical ventilation (20,21,44). To the best of our knowledge, this is one of the first studies to examine the mechanisms underlying systemic sepsis-induced lung remodeling, which is observed in premature infants who develop " new BPD" without significant exposure to hyperoxia or ventilation (2).…”

Section: Original Researchmentioning

confidence: 99%

“…Traditionally, rodent models of BPD have used hyperoxia, antenatal endotoxin exposure, and mechanical ventilation to induce acute lung inflammation and alveolar remodeling in the immature lung (20,21). Although it is accepted that systemic sepsis in the premature infant is a major risk factor for the development of BPD, the mechanisms by which sepsis-induced acute lung inflammation contributes to alveolar simplification in BPD remain poorly understood (11,22,23).…”

mentioning

confidence: 99%

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Buonfiglio

Bagegni

Borcherding

et al. 2016

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsisinduced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2 1/1 and NOX2 2/2 mice were injected with intraperitoneal LPS to induce sepsis. Lung inflammation and canonical TLR signaling were assessed 24 hours after LPS. Alveolar development was examined in 15-day-old mice after LPS on Day 6. The in vivo efficacy of a NOX2 inhibitor (NOX2-I) on NOX2 complex assembly and sepsis-induced lung inflammation were examined. Lung cytokine expression and neutrophil influx induced with sepsis in NOX2 1/1 mice was decreased by .50% in NOX2 2/2 mice. LPS-induced TLR4 signaling evident by inhibitor of NF-kB kinase-b and mitogen-activated protein kinase phosphorylation, and nuclear factor-kB/AP-1 translocation were attenuated in NOX2 2/2 mice. LPS increased matrix metalloproteinase 9 while decreasing elastin and keratinocyte growth factor levels in NOX21/1 mice. An LPS-induced increase in matrix metalloproteinase 9 and decrease in fibroblast growth factor 7 and elastin were not evident in NOX22/2 mice. An LPS-induced reduction in radial alveolar counts and increased mean linear intercepts were attenuated in NOX2 2/2 mice. LPS-induced NOX2 assembly evident by p67phox/gp91phox coimmunoprecipitation was disrupted with NOX2-I. NOX2-I also mitigated LPS-induced cytokine expression, TLR pathway signaling, and alveolar simplification. In a mouse model of neonatal sepsis, NOX2 regulates proinflammatory TLR signaling and alveolar remodeling induced by a single dose of LPS. Our results provide mechanistic insight into the regulation of sepsis-induced alveolar remodeling in the developing lung.Keywords: nicotinamide adenine dinucleotide phosphate oxidase; sepsis; Toll-like receptor signaling; neonatal lung injury; bronchopulmonary dysplasia Postnatal inflammation and tissue injury in the developing lung contribute to the disrupted alveolar development observed in premature infants with bronchopulmonary dysplasia (BPD) (1, 2). Risk factors associated with BPD, such as hyperoxia, barotrauma, and sepsis, trigger the production of reactive oxygen species (ROS) in the premature lung, which contributes to lung inflammation and matrix degradation (3-5). Multiple investigators have shown that markers of oxidant-mediated lung injury, such as 8-Oxo-29-deoxyguanosine, oxidized surfactant phospholipids, F2-isoprostanes, and nitrotyrosine, are elevated in the bronchoalveolar lavage, serum, or urine of premature infants who subsequently develop BPD (4-7). Therapies to mitigate oxidant stress, such as recombinant superoxide dismutase and vitamin A, have been used in premature infants to decrease BPD, with limited succes...

show abstract

Chronic Lung Disease in the Preterm Infant. Lessons Learned from Animal Models

Cited by 127 publications

References 197 publications

Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats

Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats

Early Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Contact Info

Product

Resources

About