scholarly journals Nrf2 and STAT3 Alleviates Ferroptosis-Mediated IIR-ALI by Regulating SLC7A11

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Zhuanzhuan Qiang ◽  
Hui Dong ◽  
Yangyang Xia ◽  
Dongdong Chai ◽  
Rong Hu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Warning Signal ◽  
Antioxidant Stress ◽  
Intestinal Ischemia Reperfusion ◽  
Transcription 3

Acute lung injury (ALI) has gained increased attention in the field of critical illness research and is associated with a fatality rate of approximately 50%. Nuclear factor erythroid 2-related factor2 (Nrf2) is a key regulator of intracellular oxidation homeostasis and also functions as an antioxidant. It has been reported that Nrf2 associated antioxidant stress is closely related to ferroptosis inhibition. Signal transducer and activator of transcription 3 (STAT3) is activated into phosphorylated STAT3 (pSTAT3) in response to tissue damage and serves as a warning signal to enhance the inflammatory response. In this study, an intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI) model was established in C57BL/6 mice to investigate the role of Nrf2 in regulating IIR-ALI-associated ferroptosis. Compared with those in the IIR-ALI group, the injection of Fe (15 mg/kg) or ferrostatin-1 (5 mg/kg) (ferroptosis promoter and inhibitor, respectively) via the tail vein could aggravate or alleviate lung injury and pulmonary edema, respectively. Nrf2 was increased in IIR-ALI and promoted the phosphorylation of STAT3 to amplify downstream signals. An in vitro oxygen-glucose deprivation and reoxygenation (OGD-R) model was established in MLE12 cells to imitate the ischemia/reperfusion condition. The cells were transfected with lentiviruses to increase or downregulate the levels of STAT3. We found that Nrf2 and STAT3 played key roles in ferroptosis by regulating SLC7A11, which improved the pathological processes associated with ALI.

scholarly journals Corrigendum to: Acute Lung Injury in A Rat Model Of Intestinal Ischemia-Reperfusion: The Potential Time Depended Role Of Phospholipases

2021 ◽  
Vol 263 ◽  
pp. 291
Author(s):  
Georgia Kostopanagiotou ◽  
Efthimios Avgerinos ◽  
Konstantinos Kostopanagiotou ◽  
Nikolaos Arkadopoulos ◽  
Ioanna Andreadou ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Rat Model ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Intestinal Ischemia Reperfusion

scholarly journals Nrf2 Activation Induced by Sirt1 Ameliorates Acute Lung Injury After Intestinal Ischemia/Reperfusion Through NOX4-Mediated Gene Regulation

2018 ◽  
Vol 46 (2) ◽  
pp. 781-792 ◽  
Author(s):  
DongDong Chai ◽  
Lei Zhang ◽  
SiWei Xi ◽  
YanYong Cheng ◽  
Hong Jiang ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Vegf Expression ◽  
Intestinal Ischemia Reperfusion ◽  
Cd31 Expression

Background/Aims: Nuclear erythroid 2-related factor-2 (Nrf2) is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis. We investigated the effects of Nrf2 in regulating revascularization and modulating acute lung injury. Methods: The expression of Nrf2 and sirtuin1 (Sirt1) was assessed in lung tissue by western blotting and immunofluorescence staining after intestinal ischemia/reperfusion (IIR) in Nrf2–/– and wild-type (WT) mice. The involvement of Nrf2 in angiogenesis, cell viability, and migration was investigated in human pulmonary microvascular endothelial cells (PMVECs). Additionally, the influence of Nrf2 expression on NOX pathway activation was measured in PMVECs after oxygen–glucose deprivation/reoxygenation. Results: We found activation and nuclear accumulation of Nrf2 in lung tissue after IIR. Compared to IIR in WT mice, IIR in Nrf2–/– mice significantly enhanced leukocyte infiltration and collagen deposit, and inhibited endothelial cell marker CD31 expression. Nrf2 upregulation and translocation into the nucleus stimulated by Sirt1 overexpression exhibited remission of histopathologic changes and enhanced CD31 expression. Nrf2 knockdown repressed non-phagocytic cell oxidase 4 (NOX4), hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression after IIR. Nrf2 upregulation by Sirt1 enhances NOX4, HIF-1α and VEGF expression after IIR in WT mice. Furthermore, Nrf2 knockdown suppressed cell viability, capillary tube formation and cell migration in PMVECs after oxygen–glucose deprivation/reoxygenation and also inhibited NOX4, HIF-1 and VEGF expression. Moreover, NOX4 knockdown in PMVECs decreased the levels of VEGF, HIF-1α and angiogenesis. Conclusion: Nrf2 stimulation by Sirt1 plays an important role in sustaining angiogenic potential through NOX4-mediated gene regulation.

scholarly journals Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Jee Hyun Kim ◽  
Jihye Kim ◽  
Jaeyoung Chun ◽  
Changhyun Lee ◽  
Jong Pil Im ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Intestinal Ischemia Reperfusion

scholarly journals Author Correction: Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Jee Hyun Kim ◽  
Jihye Kim ◽  
Jaeyoung Chun ◽  
Changhyun Lee ◽  
Jong Pil Im ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Intestinal Ischemia Reperfusion

scholarly journals The protective role of Prolyl oligopeptidase (POP) inhibition in acute lung injury induced by intestinal ischemia-reperfusion

Oncotarget ◽  
2021 ◽  
Vol 12 (17) ◽  
pp. 1663-1676
Author(s):  
Giovanna Casili ◽  
Sarah Adriana Scuderi ◽  
Marika Lanza ◽  
Alessia Filippone ◽  
Rossella Basilotta ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Prolyl Oligopeptidase ◽  
Intestinal Ischemia Reperfusion

scholarly journals Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Hui Dong ◽  
Yangyang Xia ◽  
Shanliang Jin ◽  
Chaofan Xue ◽  
Yanjun Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Alveolar Epithelial Cells ◽  
Related Factor ◽  
Alveolar Epithelial ◽  
Scanning Transmission ◽  
Intestinal Ischemia Reperfusion

AbstractAcute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2−/− mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.

Acute Lung Injury in a Rat Model of Intestinal Ischemia-Reperfusion: The Potential Time Depended Role of Phospholipases A2

2008 ◽  
Vol 147 (1) ◽  
pp. 108-116 ◽  
Author(s):  
Georgia Kostopanagiotou ◽  
Efthimios Avgerinos ◽  
Constantinos Costopanagiotou ◽  
Nikolaos Arkadopoulos ◽  
Ioanna Andreadou ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Rat Model ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Phospholipases A2 ◽  
Intestinal Ischemia Reperfusion

scholarly journals Inhibition of p38 MAPK Mitigates Lung Ischemia Reperfusion Injury by Reducing Blood–Air Barrier Hyperpermeability

2020 ◽  
Vol 11 ◽  
Author(s):  
Tiantian Wang ◽  
Chunxia Liu ◽  
Ling-hui Pan ◽  
Zhen Liu ◽  
Chang-long Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
P38 Mapk ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Endothelial Barrier ◽  
Oxygen Glucose Deprivation

Background: Lung ischemia reperfusion injury (LIRI) is a complex pathophysiological process activated by lung transplantation and acute lung injury. The p38 mitogen-activated protein kinase (MAPK) is involved in breakdown of the endothelial barrier during LIRI, but the mechanism is still unclear. Therefore, we investigated the function of p38 MAPK in LIRI in vivo and in vitro.Methods: Sprague–Dawley rats were subjected to ischemia reperfusion with or without pretreatment with a p38 MAPK inhibitor. Lung injury was assessed using hematoxylin and eosin staining, and pulmonary blood–air barrier permeability was evaluated using Evans blue staining. A rat pulmonary microvascular endothelial cell line was infected with lentiviral expressing short hairpin (sh)RNA targeting p38 MAPK and then cells were subjected to oxygen/glucose deprivation and reoxygenation (OGD/R). Markers of endothelial destruction were measured by western blot and immunofluorescence.Results:In vivo LIRI models showed structural changes indicative of lung injury and hyperpermeability of the blood–air barrier. Inhibiting p38 MAPK mitigated these effects. Oxygen/glucose deprivation and reoxygenation promoted hyperpermeability of the endothelial barrier in vitro, but knockdown of p38 MAPK attenuated cell injury; maintained endothelial barrier integrity; and partially reversed injury-induced downregulation of permeability protein AQP1, endothelial protective protein eNOS, and junction proteins ZO-1 and VE-cadherin while downregulating ICAM-1, a protein involved in destroying the endothelial barrier, and ET-1, a protein involved in endothelial dysfunction.Conclusion: Inhibition of p38 MAPK alleviates LIRI by decreasing blood–air hyperpermeability. Blocking p38 MAPK may be an effective treatment against acute lung injury.

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