Edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia injury: heme oxygenase-1 and PI3K/Akt pathway may be involved

Cao, Haipeng; Feng, Yanjun; Ning, Yunye; Zhang, Zinan; Li, Weihao; Li, Qiang

doi:10.3109/01902148.2015.1054053

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…ZnPP has been reported to reduce HO-1 expression and suppress HO-1 activity [34,35,58,59], and has been widely used for HO-1-related research [35,58,59]. Our present study showed that the expression and activity of HO-1 was downregulated by ZnPP pretreatment of MSCs-HO-1.…”

Section: Discussionsupporting

confidence: 60%

“…These results suggested that enhanced endothelial HO-1 expression and activity also contributed to the beneficial effects of co-culture with MSCs-HO-1. Multiple kinase signaling pathways, such as phosphatidylinositol 3-kinase/p38 and extracellular-signal-regulated kinase/c-Jun N-terminal kinase pathways, have been reported to be involved in HO-1 inducible expression [35,39]. However, further investigations are still needed to reveal which kinase signaling pathways are involved the promotive effect of MSCs-HO-1 on endothelial HO-1 expression and activity following LPS-simulation.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-human-HO-1 (1: 1, 000), anti-human-β-actin primary antibodies (1: 1, 000), and corresponding horseradish peroxidase-labeled secondary antibody (1: 1, 000) were purchased from Beyotime Institute of Biotechnology. In addition, HO-1 activity in PVECs was determined as described previously [34,35]. PVECs were collected and homogenized in 4°C homogenization buffer (1 M Tris·Cl, 250 mM sucrose), then centrifuged at 12, 000 × g for 30 min at 4°C.…”

Section: Detection Of Ho-1 Protein Expression and Activity In Pvecsmentioning

confidence: 99%

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Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

Chen

Zhang

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has therapeutic effects on endothelial damage during acute lung injury (ALI). Heme oxygenase-1 (HO-1) can restore homeostasis and implement cytoprotective defense functions in many pathologic states. Therefore, we explored whether transduction of HO-1 into BM-MSCs (MSCs-HO-1) would have an increased beneficial effect on lipopolysaccharide (LPS)-induced inflammatory and oxidative damage in human pulmonary microvascular endothelial cells (PVECs). Methods: MSCs were isolated from rat bone marrow and transfected with the HO-1 gene by a lentivirus vector. The phenotype and multilineage differentiation of MSCs were assessed. MSCs or MSCs-HO-1 were co-cultured with PVECs using a transwell system, and LPS was added to induce PVEC injury. The production of reactive oxygen species (ROS), and the activities of lipid peroxide (LPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in PVECs were determined by flow cytometry and colorimetric assays, respectively. The levels of human PVEC-derived tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in the supernatants of the co-culture system, and the activity of nuclear transcription factor-κB and NF-E2-related factor 2 (Nrf2) in PVECs were examined by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of TNF-α, IL-1β and IL-6 in PVECs was detected by quantitative real-time polymerase chain reaction (qRT-PCR), HO-1 expression and enzymatic activity in PVECs and the influence of zinc protoporphyrin (ZnPP) or HO-1 small interfering RNA on the above inflammatory and oxidative stress markers were evaluated. In addition, the expression of rat MSC-derived hepatocyte growth factor (HGF) and IL-10 was determined by ELISA and qRT-PCR. Results: MSCs showed no significant changes in phenotype or multilineage differentiation after transduction. LPS strongly increased the production of inflammatory and oxidative stress indicators, as well as decreased the levels of antioxidant components and the activity of Nrf2 in PVECs. MSC co-cultivation ameliorated these detrimental effects in PVECs and MSCs-HO-1 further improved the damage to PVECs induced by LPS when compared with MSCs alone. The beneficial effects of MSCs-HO-1 were dependent on HO-1 overexpression and may be attributed to the enhanced paracrine production of HGF and IL-10. Conclusion: MSCs-HO-1 have an enhanced ability to improve LPS-induced inflammatory and oxidative damage in PVECs, and the mechanism may be partially associated with the enhanced paracrine function of the stem cells. These data encourage further testing of the beneficial effects of MSCs-HO-1 in ALI animal models.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Detection Of Ho-1 Protein Expression and Activity In Pvecsmentioning

confidence: 99%

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Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

Chen

Zhang

Wang

et al. 2018

Cell Physiol Biochem

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“…These results indicated that AEC II cells treated with hyperoxia had enhanced cell apoptosis, decreased MDA levels, and increased SOD activity. Therefore, we speculated that apoptosis of hyperoxia-treated cells is caused by increased oxidative stimuli in AEC II cells, which is consistent with a previous study [ 33 ]. However, interestingly, CGRP treatment inhibited hyperoxia-caused AEC II cells apoptosis and hyperoxia-triggered oxidative stress, including changes in MDA, SOD, and ROS.…”

Section: Discussionsupporting

confidence: 92%

Extrinsic Calcitonin Gene-Related Peptide Inhibits Hyperoxia-Induced Alveolar Epithelial Type II Cells Apoptosis, Oxidative Stress, and Reactive Oxygen Species (ROS) Production by Enhancing Notch 1 and Homocysteine-Induced Endoplasmic Reticulum Protein (HERP) Expression

et al. 2017

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BackgroundLung alveolar epithelial type II cells (AEC II) are the most important stem cells in lung tissues, which are critical for wound repair of bronchopulmonary dysplasia (BPD). This study investigated the effects of calcitonin gene-related peptide (CGRP) on AEC II cells exposed to hyperoxia.Material/MethodsNeonatal rat AEC II cells were isolated and identified by detecting surfactant protein C (SP-C). Three small interfering RNAs targeting Notch 1 were synthesized and transfected into AEC II. A hyperoxia-exposed AEC II cell injury model was established and was divided into 8 groups. MDA levels and SOD activity were examined using lipid peroxidation assay kits. Apoptosis and reactive oxygen species (ROS) production were evaluated using flow cytometry. Notch 1 mRNA expression was examined using RT-PCR. Homocysteine-induced endoplasmic reticulum protein (HERP) was examined using Western blot analysis.ResultsCGRP treatment significantly enhanced MDA levels and decreased SOD activity compared to hyperoxia-treated AEC II cells (P<0.05). CGRP treatment significantly inhibited hyperoxia-induced AEC II cell apoptosis, and significantly suppressed hyperoxia-induced ROS production compared to hyperoxia-treated AEC II cells (P<0.05) either undergoing γ secretase inhibitor or Notch RNA interference. CGRP significantly triggered Notch 1 mRNA expression and significantly enhanced HERP expression compared to hyperoxia-treated AEC II cells (P<0.05) either undergoing γ secretase inhibitor or Notch RNA interference.ConclusionsIn AEC II cells, extrinsic peptide CGRP suppressed hyperoxia-induced apoptosis, oxidative stress, and ROS production, which may be triggered by Notch 1 and HERP signaling pathway.

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“…These results demonstrated that the conditioned medium of hfPMSCs could activate the Nrf-2 signaling pathway and protect the cells from oxidative injury. Consequently, many signaling pathways, such as PI3/AKT/ERK pathways, have been reported to regulate HO-1 [37, 38]. Therefore, further studies still need to investigate signaling pathways playing key roles in preventing H 2 O 2 -induced oxidative injury in primary lung epithelial cells in vitro and animal models in vivo .…”

Section: Discussionmentioning

confidence: 99%

Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells

Yan

Jia

et al. 2019

Oxidative Medicine and Cellular Longevity

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The oxidative stresses are a major insult in pulmonary injury such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), two clinical manifestations of acute respiratory failure with substantially high morbidity and mortality. Mesenchymal stem cells (MSCs) hold a promise in treatments of many human diseases, mainly owing to their capacities of immunoregulation and antioxidative activity. The strong immunoregulatory role of human placental MSCs of fetal origin (hfPMSCs) has been previously demonstrated; their antioxidant activity, however, has yet been interrogated. In this report, we examined the antioxidative activity of hfPMSCs by accessing the ability to scavenge oxidants and radicals and to protect alveolar epithelial cells from antioxidative injury using both a cell coculture model and a conditioned culture medium (CM) of hfPMSCs. Results showed a comparable antioxidative capacity of the CM with 100 μM of vitamin C (VC) in terms of the total antioxidant capacity (T-AOC), scavenging abilities of free radicals DPPH, hydroxyl radical (·OH), and superoxide anion radical (O2-), as well as activities of antioxidant enzymes of SOD and GSH-PX. Importantly, both of the CM alone and cocultures of hfPMSCs displayed a protection of A549 alveolar epithelial cells from oxidative injury of 600 μM hydrogen peroxide (H2O2) exposure, as determined in monolayer and transwell coculture models, respectively. Mechanistically, hfPMSCs and their CM could significantly reduce the apoptotic cell fraction of alveolar epithelial A549 cells exposed to H2O2, accompanied with an increased expression of antiapoptotic proteins Bcl-2, Mcl-1, Nrf-2, and HO-1 and decreased proapoptotic proteins Bax, caspase 3, and Keap1, in comparison with naïve controls. Furthermore, hfPMSCs-CM (passage 3) collected from cultures exposed an inhibition of the Nrf2/Keap1/ARE signaling pathway which led to a significant reduction in caspase 3 expression in A549 cells, although the addition of Nrf2 inhibitor ML385 had no effect on the antioxidative activity of hfPMSCs-CM. These data clearly suggested that hfPMSCs protected the H2O2-induced cell oxidative injury at least in part by regulating the Nrf2-Keap1-ARE signaling-mediated cell apoptosis. Our study thus provided a new insight into the antioxidative mechanism and novel functions of hfPMSCs as antioxidants in disease treatments, which is warranted for further investigations.

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Edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia injury: heme oxygenase-1 and PI3K/Akt pathway may be involved

Abstract: This study indicates that edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia-induced injury and the antioxidant effect may be related to upregulation of HO-1, which is regulated by PI3K/Akt pathway.

Cited by 9 publications

References 49 publications

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

Extrinsic Calcitonin Gene-Related Peptide Inhibits Hyperoxia-Induced Alveolar Epithelial Type II Cells Apoptosis, Oxidative Stress, and Reactive Oxygen Species (ROS) Production by Enhancing Notch 1 and Homocysteine-Induced Endoplasmic Reticulum Protein (HERP) Expression

Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells

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