Wnt5a reverses the inhibitory effect of hyperoxia on transdifferentiation of alveolar epithelial type II cells to type I cells

Xu, Wei; Xu, Bo; Zhao, Ying; Yang, Ni; Liu, Chunfeng; Wen, Guangfu; Zhang, Binglun

doi:10.1007/s13105-015-0446-4

Cited by 12 publications

(14 citation statements)

References 53 publications

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“…AECII can decrease surface tension to prevent atelectasis and absorb fluid to prevent pulmonary edema. AECII help maintain normal air exchange function of the lung, and possess stem cell function in lung development and damage repair [5,6]. Because the biological characters of AECII are highly dependent on lung microenvironment, AECII would lose specific characteristics and differentiate into AECI after in vitro culture [22].…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal inflammatory response to cigarette smoke in the lung promotes COPD development [4]. Alveolar type II epithelial cells (AECII) play important role in the maintenance of normal lung structure and help the repair and recovery of the lung after biological and physical lung damages [5,6]. Cigarette smoking has been shown to cause the apoptosis of AECII [7].…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract

Tan

Jiang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cigarette smoking is a major risk factor of chronic obstructive pulmonary disease. This study aimed to examine the effects of cigarette smoke extract (CSE) on alveolar type II epithelial cells (AECII) and investigate the underlying mechanism. Methods: Primary AECII were isolated from rat lung tissues and exposed to CSE. Apoptosis was detected by flow cytometry. Protein expression was detected by Western blot analysis. Results: Primary rat AECII maintained morphological and physiological characteristic after 3 passages. CSE increased the expression of ER specific pro-apoptosis factors CHOP and caspase 12, and the phosphorylation of JNK in AECII. CSE activated ER stress signaling and increased the phosphorylation of PERK, eIF2α and IRE1. Furthermore, CSE induced the expression of Hrd1, a key factor of ER-associated degradation, in AECII. Knockdown of Hrd1 led to more than 2 fold increase of apoptosis, while overexpression of Hrd1 attenuated CSE induced apoptosis of AECII. Conclusions: Our results suggest that ER stress induces HRD1 to protect alveolar type II epithelial cells from apoptosis induced by CSE.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract

Tan

Jiang

et al. 2017

Cell Physiol Biochem

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“…Upon exposure to hyperoxia, type I cells are more susceptible to injury, and type II cells appear to increasingly proliferate and transdifferentiate into type I cells, which are resistant to oxidative damage ( 15 ). However, previous studies confirmed that hyperoxia inhibits activation of type II cells ( 16 , 17 ). A number of studies on the pathological foundation of BPD have focused on type II cell injury, with respect to proliferation, apoptosis and transdifferentiation into type I cells or mesenchymal cells (EMT).…”

Section: Discussionmentioning

confidence: 91%

SOX4 arrests lung development in rats with hyperoxia‑induced bronchopulmonary dysplasia by controlling EZH2 expression

et al. 2017

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Bronchopulmonary dysplasia (BPD) is currently the most common severe complication in premature infants and is characterized by the arrest of alveolar and vascular growth. Alveolar type II cells play an important role in the pathological foundation of BPD. An association of BPD with epithelial-to-mesenchymal transition (EMT) in type II cells exposed to hyperoxia was previously identified. SOX4, a transcription factor that is indispensable to embryogenesis, including lung development, participates in regulating EMT and cell survival, affecting tumorigenesis. The aim of the present study was to investigate the involvement of SOX4 in the occurrence of BPD, which, to the best of our knowledge, has not been previously determined. For this purpose, newborn rats were randomly divided into two treatment groups: The model group was exposed to hyperoxia (80–85% O2), while the control group was kept under normoxic conditions (21% O2). Lung tissues were collected on postnatal days 1, 3, 7, 14 and 21 and morphological changes in the lungs were examined by hematoxylin and eosin staining. The location of SOX4 in type II cells was detected by double immunofluorescence. The expression of SOX4 and enhancer of zeste homolog 2 (EZH2) in type II cells and lung tissues were detected by immunochemistry, western blotting and quantitative polymerase chain reaction analysis. The results demonstrated that, compared with the control group, the radial alveolar count decreased rapidly in the model group, accompanied by increased mean alveolar diameter and alveolar septal thickness. SOX4 and EZH2 were highly expressed in type II cells exposed to hyperoxia. However, in total lung tissues, SOX4 and EZH2 expression was profoundly decreased in the early stages and increased in the late stages following exposure to hyperoxia. The expression of the EZH2 protein was positively correlated with that of the SOX4 protein. In conclusion, at the alveolar stage, which is a critical period after birth for lung development, hyperoxia induced dysregulation of SOX4 and EZH2 in rat lungs, indicating that SOX4 may contribute to the disruption of lung development in BPD by regulating EZH2 expression.

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“…TGF-β1, produced by AECs, is secreted during the transdifferentiation of AEC IIs to AEC Is, and the autocrine production of TGF-β1 has been shown to promote the transdifferentiation of primary rat AEC IIs to AEC Is in vitro (11,12). An autocrine loop of TGF-β1 in mammary epithelium of pregnant mice has been shown to aid the differentiation process (29).…”

Section: Discussionmentioning

confidence: 99%

“…secretory, synthetic and remodeling reservoirs for the lung epithelium to host defense (9). The AEC IIs are the progenitors of AEC Is, and the progenitor function of AEC IIs may be activated when the lung epithelium encounters a variety of stimulators, including acute lung injury or bacteria, among others, to defend the alveolus from injury (10,11). However, whether the tumor cells metastasizing to the lung are able to stimulate AEC II transdifferentiation has not been examined in detail.…”

Section: Transdifferentiation Of Type II Alveolar Epithelial Cells Inmentioning

confidence: 99%

Transdifferentiation of type II alveolar epithelial cells induces reactivation of dormant tumor cells by enhancing TGF-β1/SNAI2 signaling

et al. 2018

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Dormant tumor cells (DTCs) serve a crucial role in the pathogenesis of metastasis and may compromise the efficacy of existing therapeutic modalities aimed at fully eradicating cancer. However, the mechanisms underlying the dormant-to-proliferating switch of DTCs remain largely unknown. The lung is one of the most common sites of metastatic recurrence. The transdifferentiation of alveolar epithelial cells II (AEC IIs) to AEC Is is a hallmark of alveolar epithelial stimulation. However, the role of AEC II transdifferentiation during the reactivation of DTCs has not been fully elucidated. In the present study, we found that tumor cells promoted the transdifferentiation of AEC IIs. Furthermore, the supernatant of the transdifferentiation of AEC IIs to AEC Is (Super-TDA) promoted the dormant-to-proliferating switch of DTCs via the autocrine effect of TGF-β1 on the 3D BME culture system in vitro. Monensin and LY2109761 blocked the dormant-to-proliferating switch of DTCs induced by Super-TDA. Although lipopolysaccharide did not directly stimulate the reactivation of DTCs, it promoted DTC reactivation by increasing the secretion of TGF-β1 in the Super-TDA. We further demonstrated that the upregulation of SNAI2 expression was required for Super-TDA facilitating the DTC dormant-to‑proliferating switch. Taken together, our findings demonstrated that tumor cells may promote AEC II transdifferentiation. Furthermore, the transdifferentiation of AEC IIs may, in turn, induce the reactivation of 3D-established DTCs by promoting TGF-β1/SNAI2 signaling. Targeting this process may provide novel therapeutic strategies for the inhibition of the dormant‑to-proliferating switch.

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Wnt5a reverses the inhibitory effect of hyperoxia on transdifferentiation of alveolar epithelial type II cells to type I cells

Cited by 12 publications

References 53 publications

Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract

Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract

SOX4 arrests lung development in rats with hyperoxia‑induced bronchopulmonary dysplasia by controlling EZH2 expression

Transdifferentiation of type II alveolar epithelial cells induces reactivation of dormant tumor cells by enhancing TGF-β1/SNAI2 signaling

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