Liao Wen-I, Wu Shu-Yu, Tsai Shih-Hung, Pao Hsin-Ping, Huang Kun-Lun, Chu Shi-Jye
The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Front Immunol. 2021 Mar 16;12:596376. doi: 10.3389/fimmu.2021.596376. eCollection 2021.
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. 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). , 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). 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). , 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. 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.
2-甲氧基雌二醇（2ME）是一种天然的17-β雌二醇代谢产物，是一种有效的抗炎剂，但其对缺血/再灌注（IR）诱导的急性肺炎症的影响尚不清楚。膜联蛋白A1（AnxA1）是一种糖皮质激素调节蛋白，通过结合甲酰肽受体（FPRs）有效抑制中性粒细胞跨内皮迁移。我们旨在研究2ME是否上调AnxA1的表达并预防IR诱导的肺损伤。在离体灌注大鼠肺模型中，通过缺血40分钟然后再灌注60分钟诱导IR介导的急性肺炎症。大鼠肺随机接受载体或2ME处理，并使用抗AnxA1抗体或BOC2（FPR的泛受体拮抗剂）确定AnxA1的功能相关性。人原代肺泡上皮细胞（HPAECs）和大鼠中性粒细胞用2ME和AnxA1 siRNA或抗AnxA1抗体预处理，然后进行缺氧-复氧（HR）。在IR诱导的急性肺炎症模型中，2ME显著降低了所有肺水肿参数、中性粒细胞浸润、氧化应激、促炎细胞因子产生、肺细胞凋亡、紧密连接蛋白破坏和肺组织损伤。2ME还增加了AnxA1 mRNA和蛋白的表达，并抑制了核因子-κB（NF-κB）的激活。此外，2ME减弱了HR触发的HPAECs中NF-κB的激活和白细胞介素-8的产生，减少了跨内皮迁移、肿瘤坏死因子-α的产生，并增加了暴露于HR的中性粒细胞的凋亡。2ME的这些保护作用被BOC2、抗AnxA1抗体或AnxA1 siRNA显著消除。2ME通过增加AnxA1表达改善IR诱导的急性肺炎症。基于这些结果，2ME可能是减轻IR诱导的肺损伤的有前景的药物。
