Epithelial-mesenchymal transitions in bronchopulmonary dysplasia of newborn rats

Yang, Haiping; Fu, Jianhua; Xue, Xindong; Yao, Li; Lin, Qiao; Hou, Ana; Jin, Linlin; Xing, Yujiao

doi:10.1002/ppul.22969

Cited by 35 publications

(40 citation statements)

References 40 publications

(55 reference statements)

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“…Moreover, hyperoxia may destruct both the endothelial and the epithelial barriers by downregulating tight junction proteins (20,21). We also observed deposition of extracellular matrix and retarded lung development, as reported in our preview study (22). …”

Section: Discussionsupporting

confidence: 89%

Vitamin D attenuates hyperoxia-induced lung injury through downregulation of Toll-like receptor 4

Yao

Shi

Zhao

et al. 2017

International Journal of Molecular Medicine

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With considerable morbidity and mortality, bron-chopulmonary dysplasia (BPD) is a focus of attention in neonatology. Hyperoxia-induced lung injury has long been used as a model of BPD. Among all the signaling pathways involved, Toll-like receptor 4 (TLR4) has been demonstrated to play an important role, and is known to be regulated by vitamin D. This study aimed at elucidating the effect of vitamin D on hyperoxia-induced lung injury and the role of TLR4 in the process. Vitamin D was administered to hyperoxia-treated neonatal rats to investigate changes in the morphology of lungs and expression of pro-inflammatory cytokines, apoptotic proteins and TLR4. Vitamin D attenuated hyperoxia-induced lung injury by protecting the integrity of the lung structure, decreasing extracellular matrix deposition and inhibiting inflammation. The upregulation of TLR4 by hyperoxia was ameliorated by vitamin D and apoptosis was reduced. Vitamin D administration antagonized the activation of TLR4 and therefore alleviated inflammation, reduced apoptosis and preserved lung structure.

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Section: Discussionsupporting

confidence: 89%

Vitamin D attenuates hyperoxia-induced lung injury through downregulation of Toll-like receptor 4

Yao

Shi

Zhao

et al. 2017

International Journal of Molecular Medicine

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“…in expression of both protein (P Ͻ 0.01) indicated that hyperoxia also stimulated EMT in cultured AEC II, in accordance with our previous in vivo study concerning EMT in the BPD model (59).…”

Section: Transdifferentiation Of Aec II Isolated From Newborn Rats Wasupporting

confidence: 76%

“…Alveolar epithelial EMT was observed after TGF-␤1 stimulation (35) and in adult idiopathic pulmonary fibrosis (56). Our preliminary study found EMT in lung tissue in a hyperoxiainduced BPD-like animal model (59). The present study has revealed that cultured AEC II also underwent EMT, in addition to transdifferentiation in response to hyperoxia stimulation, which means that AECs travel along several pathways in an hyperoxic environment.…”

Section: Discussionmentioning

confidence: 74%

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

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-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...

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“…Collectively, the changes in these biomarkers, accompanied by pulmonary morphological changes, are similar to the development of human BPD. The establishment and validation of the hyperoxia‐induced BPD rat model is consistent with previous studies …”

Section: Discussionsupporting

confidence: 88%

“…(7) Up‐down‐regulation (hyperoxia/normoxia): judges whether expression is unchanged, up or down according to the normalized expression. (8) p value: see our difference analysis method used in another study . FDR: corrected p ‐value…”

Section: Resultsmentioning

confidence: 99%

Insights into the expression profiles and functions of circRNAs in a newborn hyperoxia‐induced rat bronchopulmonary dysplasia model

Cheng

Wang

et al. 2020

The Journal of Gene Medicine

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Background: Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease in preterm infants. Circular RNAs (circRNAs) are key regulators of various biological processes. The present study aimed to explore the biological roles of circRNAs in BPD pathogenesis. Methods:A newborn BPD rat model was developed to construct a circRNA library;Illumina deep sequencing (Illumina, San Diego, CA, USA) was used to reveal differential expression of circRNAs in the hyperoxia-induced BPD rat models. Sanger sequencing and a reverse transcription-polymerase chain reaction were performed to confirm circRNAs that may be related to BPD. After miRNA binding-site prediction, we constructed a network diagram of circRNA-competing endogenous RNAs (ceRNAs) related to transforming growth factor (TGF)-β and p53 pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.Results: In total, 256 differentially expressed circRNAs were detected between the hyperoxia group and the normoxia group. Of these circRNAs, 195 were up-regulated and 61 were down-regulated. The differences of circRNA distribution between the two groups were analyzed and six circRNAs were validated in the tissue samples. GO analysis indicated that 6519 target genes were enriched in cell location and biological processes. KEGG pathway enrichment analysis showed that circRNAs involved in 242 KEGG pathways. A network diagram of circRNA-ceRNA related to TGF-β and p53 pathways was constructed.Conclusions: CircRNAs are differentially expressed between the BPD model and control group. Many target genes of circRNAs are involved in the developmental process, which suggests that BPD may be associated with pathways including extracellular matrix-receptor interaction, vascular endothelial growth factor signaling and vascular smooth muscle contraction. K E Y W O R D S bronchopulmonary dysplasia, ceRNA, circRNA, deep sequencing, p53, TGF-β Cheng and Wu contributed equally to this work.

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Epithelial-mesenchymal transitions in bronchopulmonary dysplasia of newborn rats

Abstract: EMT of AT2 cells occurred in the hyperoxia-induced newborn rat BPD model and resulted in attenuated alveolar development as a portion of the myofibroblasts accumulated in the lung originated from AT2 cells via EMT.

Cited by 35 publications

References 40 publications

Vitamin D attenuates hyperoxia-induced lung injury through downregulation of Toll-like receptor 4

Vitamin D attenuates hyperoxia-induced lung injury through downregulation of Toll-like receptor 4

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

Insights into the expression profiles and functions of circRNAs in a newborn hyperoxia‐induced rat bronchopulmonary dysplasia model

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