2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression
Background: 2-Methoxyestradiol (2ME), a natural 17-β estradiol metabolite, is a potent anti-inflammatory agent, but its effect on ischemia/reperfusion (IR)-induced acute lung inflammation remains unknown. Annexin A1 (AnxA1), a glucocorticoid-regulated protein, is effective at inhibiting neutrophil t...
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.596376/full |
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| author | Wen-I Liao Wen-I Liao Shu-Yu Wu Shih-Hung Tsai Shih-Hung Tsai Hsin-Ping Pao Kun-Lun Huang Kun-Lun Huang Shi-Jye Chu |
| author_facet | Wen-I Liao Wen-I Liao Shu-Yu Wu Shih-Hung Tsai Shih-Hung Tsai Hsin-Ping Pao Kun-Lun Huang Kun-Lun Huang Shi-Jye Chu |
| author_sort | Wen-I Liao |
| collection | DOAJ |
| description | Background: 2-Methoxyestradiol (2ME), a natural 17-β estradiol metabolite, is a potent anti-inflammatory agent, but its effect on ischemia/reperfusion (IR)-induced acute lung inflammation remains unknown. Annexin A1 (AnxA1), a glucocorticoid-regulated protein, is effective at inhibiting neutrophil transendothelial migration by binding the formyl peptide receptors (FPRs). We aimed to investigate whether 2ME upregulates the expression of AnxA1 and protects against IR-induced lung damage.Methods: IR-mediated acute lung inflammation was induced by ischemia for 40 min followed by reperfusion for 60 min in an isolated, perfused rat lung model. The rat lungs were randomly treated with vehicle or 2ME, and the functional relevance of AnxA1 was determined using an anti-AnxA1 antibody or BOC2 (a pan-receptor antagonist of the FPR). In vitro, human primary alveolar epithelial cells (HPAECs) and rat neutrophils were pretreated with 2ME and an AnxA1 siRNA or anti-AnxA1 antibody and subjected to hypoxia-reoxygenation (HR).Results: 2ME significantly decreased all lung edema parameters, neutrophil infiltration, oxidative stress, proinflammatory cytokine production, lung cell apoptosis, tight junction protein disruption, and lung tissue injury in the IR-induced acute lung inflammation model. 2ME also increased the expression of the AnxA1 mRNA and protein and suppressed the activation of nuclear factor-κB (NF-κB). In vitro, 2ME attenuated HR-triggered NF-κB activation and interleukin-8 production in HPAECs, decreased transendothelial migration, tumor necrosis factor-α production, and increased apoptosis in neutrophils exposed to HR. These protective effects of 2ME were significantly abrogated by BOC2, the anti-AnxA1 antibody, or AnxA1 siRNA.Conclusions: 2ME ameliorates IR-induced acute lung inflammation by increasing AnxA1 expression. Based on these results, 2ME may be a promising agent for attenuating IR-induced lung injury. |
| first_indexed | 2024-12-14T15:20:12Z |
| format | Article |
| id | doaj.art-d0713ab3775b465b8cb8fc13c9705d29 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T15:20:12Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d0713ab3775b465b8cb8fc13c9705d292022-12-21T22:56:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.5963765963762-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein ExpressionWen-I Liao0Wen-I Liao1Shu-Yu Wu2Shih-Hung Tsai3Shih-Hung Tsai4Hsin-Ping Pao5Kun-Lun Huang6Kun-Lun Huang7Shi-Jye Chu8The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanDepartment of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanInstitute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, TaiwanDepartment of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDepartment of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, TaiwanThe Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanThe Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanInstitute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, TaiwanDepartment of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanBackground: 2-Methoxyestradiol (2ME), a natural 17-β estradiol metabolite, is a potent anti-inflammatory agent, but its effect on ischemia/reperfusion (IR)-induced acute lung inflammation remains unknown. Annexin A1 (AnxA1), a glucocorticoid-regulated protein, is effective at inhibiting neutrophil transendothelial migration by binding the formyl peptide receptors (FPRs). We aimed to investigate whether 2ME upregulates the expression of AnxA1 and protects against IR-induced lung damage.Methods: IR-mediated acute lung inflammation was induced by ischemia for 40 min followed by reperfusion for 60 min in an isolated, perfused rat lung model. The rat lungs were randomly treated with vehicle or 2ME, and the functional relevance of AnxA1 was determined using an anti-AnxA1 antibody or BOC2 (a pan-receptor antagonist of the FPR). In vitro, human primary alveolar epithelial cells (HPAECs) and rat neutrophils were pretreated with 2ME and an AnxA1 siRNA or anti-AnxA1 antibody and subjected to hypoxia-reoxygenation (HR).Results: 2ME significantly decreased all lung edema parameters, neutrophil infiltration, oxidative stress, proinflammatory cytokine production, lung cell apoptosis, tight junction protein disruption, and lung tissue injury in the IR-induced acute lung inflammation model. 2ME also increased the expression of the AnxA1 mRNA and protein and suppressed the activation of nuclear factor-κB (NF-κB). In vitro, 2ME attenuated HR-triggered NF-κB activation and interleukin-8 production in HPAECs, decreased transendothelial migration, tumor necrosis factor-α production, and increased apoptosis in neutrophils exposed to HR. These protective effects of 2ME were significantly abrogated by BOC2, the anti-AnxA1 antibody, or AnxA1 siRNA.Conclusions: 2ME ameliorates IR-induced acute lung inflammation by increasing AnxA1 expression. Based on these results, 2ME may be a promising agent for attenuating IR-induced lung injury.https://www.frontiersin.org/articles/10.3389/fimmu.2021.596376/full2-methoxyestradiolacute lung injuryischemia and reperfusionepitheliumannexin A1 |
| spellingShingle | Wen-I Liao Wen-I Liao Shu-Yu Wu Shih-Hung Tsai Shih-Hung Tsai Hsin-Ping Pao Kun-Lun Huang Kun-Lun Huang Shi-Jye Chu 2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression Frontiers in Immunology 2-methoxyestradiol acute lung injury ischemia and reperfusion epithelium annexin A1 |
| title | 2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression |
| title_full | 2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression |
| title_fullStr | 2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression |
| title_full_unstemmed | 2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression |
| title_short | 2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression |
| title_sort | 2 methoxyestradiol protects against lung ischemia reperfusion injury by upregulating annexin a1 protein expression |
| topic | 2-methoxyestradiol acute lung injury ischemia and reperfusion epithelium annexin A1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.596376/full |
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