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      Angiotensin-converting enzyme 2 attenuates inflammatory response and oxidative stress in hyperoxic lung injury by regulating NF-κB and Nrf2 pathways

      1 , 2 , 3
      QJM: An International Journal of Medicine
      Oxford University Press (OUP)

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          Summary

          Objective

          To investigate the role of angiotensin-converting enzyme 2 (ACE2) in hyperoxic lung injury.

          Methods

          Adult mice were exposed to 95% O2 for 72 h to induce hyperoxic lung injury, and simultaneously treated with ACE2 agonist diminazene aceturate (DIZE) or inhibitor MLN-4760. ACE2 expression/activity in lung tissue and angiotensin (Ang)-(1–7)/Ang II in bronchoalveolar lavage fluid (BALF), and the severity of hyperoxic lung injury were evaluated. The levels of inflammatory factors in BALF and lung tissue and the expression levels of phospho-p65, p65 and IkBα were measured. Oxidative parameter and antioxidant enzyme levels in lung tissue were measured to assess oxidative stress. Finally, the expression levels of nuclear factor-erythroid-2-related factor (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were measured using Western blotting.

          Results

          Hyperoxia treatment significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1–7) ratio, while co-treatment with hyperoxia and DIZE significantly increased lung ACE2 expression/activity and decreased the Ang II/Ang-(1–7) ratio. By contrast, co-treatment with hyperoxia and MLN-4760 significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1–7) ratio. Hyperoxia treatment induced significant lung injury, inflammatory response and oxidative stress, which were attenuated by DIZE but aggravated by MLN-4760. The NF-κB pathways were activated by hyperoxia and MLN-4760 but inhibited by DIZE. The Nrf2 pathway and its downstream proteins NQO1 and HO-1 were activated by DIZE but inhibited by MLN-4760.

          Conclusion

          Activation of ACE2 can reduce the severity of hyperoxic lung injury by inhibiting inflammatory response and oxidative stress. ACE2 can inhibit the NF-κB pathway and activate the Nrf2/HO-1/NQO1 pathway, which may be involved in the underlying mechanism.

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          Most cited references19

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          Biomarkers in acute lung injury.

          Acute respiratory distress syndrome (ARDS) and its milder form acute lung injury (ALI) may result from various diseases and situations including sepsis, pneumonia, trauma, acute pancreatitis, aspiration of gastric contents, near-drowning etc. ALI/ARDS is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation, and surfactant dysfunction. Clinically, ALI/ARDS is manifested by decreased lung compliance, severe hypoxemia, and bilateral pulmonary infiltrates. Severity and further characteristics of ALI/ARDS may be detected by biomarkers in the plasma and bronchoalveolar lavage fluid (or tracheal aspirate) of patients. Changed concentrations of individual markers may suggest injury or activation of the specific types of lung cells-epithelial or endothelial cells, neutrophils, macrophages, etc.), and thereby help in diagnostics and in evaluation of the patient's clinical status and the treatment efficacy. This chapter reviews various biomarkers of acute lung injury and evaluates their usefulness in diagnostics and prognostication of ALI/ARDS.
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            Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways

            Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine. ACE2 has been shown to protect against lung injury. However, the mechanisms of its protective effects on ARDS are largely unknown. Here, we report that ACE2 prevents LPS-induced ARDS by inhibiting MAPKs and NF-κB signaling pathway. Lentiviral packaged Ace2 cDNA or Ace2 shRNA was intratracheally administrated into the lungs of male SD rats. Two weeks after gene transfer, animals received LPS (7.5 mg/Kg) injection alone or in combination with Mas receptor antagonist A779 (10 μg/Kg) or ACE2 inhibitor MLN-4760 (1 mg/Kg) pretreatment. LPS-induced lung injury and inflammatory response were significantly prevented by ACE2 overexpression and deteriorated by Ace2 shRNA. A779 or MLN-4760 pretreatment abolished the protective effects of ACE2. Moreover, overexpression of ACE2 significantly reduced the Ang II/Ang-(1-7) ratio in BALF and up-regulated Mas mRNA expression in lung, which was reversed by A779. Importantly, the blockade of ACE2 on LPS-induced phosphorylation of ERK1/2, p38 and p50/p65 was also abolished by A779. Whereas, only the ERK1/2 inhibitor significantly attenuated lung injury in ACE2 overexpressing rats pretreated with A779. Our observation suggests that AEC2 attenuates LPS-induced ARDS via the Ang-(1-7)/Mas pathway by inhibiting ERK/NF-κB activation.
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              The Keap1-Nrf2 system as an in vivo sensor for electrophiles.

              The Keap1-Nrf2 regulatory system plays a central role in cytoprotection from electrophilic and oxidative stress. In unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3-Keap1 ubiquitin E3 ligase complex and is degraded in the proteasome. Upon the exposure to electrophilic and oxidative stress, reactive cysteine residues in Keap1 are covalently modified, which abrogates the E3 ligase activity of the Cul3-Keap1 complex. Consequently Nrf2 is stabilized and induces the transcription of various cytoprotective genes. Structural analyses have revealed the overall structure of the Keap1 homodimer as well as structural features of the association between Keap1 and Nrf2, which has greatly enhanced our understanding of the molecular mechanisms involved in the regulation of the Keap1-Nrf2 system. Recently nitric oxide signaling has been shown to activate Nrf2, suggesting that Nrf2 is a mediator of the cytoprotective effect of nitric oxide. Analyses of Nrf2-null mice have revealed a critical contribution of Nrf2 to the protection from various diseases caused by electrophilic and oxidative stress. In contrast, constitutive activation of Nrf2 has been found in many cancers, resulting in resistance against chemotherapy and radiotherapy in cancer cells. Thus, Nrf2 is a promising target for drug development. The development of Nrf2 inducers and inhibitors is an important challenge for enhancing therapies for stress-induced diseases and cancers, respectively. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                QJM: An International Journal of Medicine
                Oxford University Press (OUP)
                1460-2725
                1460-2393
                December 2019
                December 01 2019
                August 08 2019
                December 2019
                December 01 2019
                August 08 2019
                : 112
                : 12
                : 914-924
                Affiliations
                [1 ]Department of Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University, 85 WuJin Road, Shanghai, China
                [2 ]Department of Respiratory Medicine, Shanghai Construction Group Hospital, No. 666, Zhongshan North 1st Road, Shanghai, China
                [3 ]Department of Pulmonary and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, 85 WuJing Road, Shanghai, China
                Article
                10.1093/qjmed/hcz206
                31393582
                88af7457-72eb-49ee-9bfd-1438b03db735
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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