Background

Gastro-intestinal (GI) tract inflammation is as a result of inflammatory hypoxia which is also induced by long-standing group of disorders like inflammatory-bowel disease (IBD). Regulation of GI immune homeostasis by macrophage involves hypoxia-inducible factor (HIF). As inhibitor of HIF prolyl hydroxylase, roxadustat (ROX) increases the levels of HIF.

Methods

We induced experimental colitis (EC) model in mice via dextran-sulfate sodium (DSS) to evaluate ROX role in above-mentioned disease.

Results

ROX ameliorated EC in mice by blocking colonic length shorten and loss of body weight, thereby reducing scores of disease-activity index (DAI) and histopathology. ROX significantly reduced inflammatory cytokines levels, suppressed M1 and increased M2 macrophage polarization in colonic tissues. Besides, ROX blocked declining hematocrit (HCT) level in blood and increased HIF-1-α and HIF-2-α level in colonic tissues. The inhibitor of HIF-1- α, KC7F2 decreased body weight and colonic length in ROX-treated DSS mice. Meanwhile, DAI scores and histopathology in KC7F2 treated DSS mice were markedly higher than that of treatment with ROX alone. KC7F2 treatments also significantly increased inflammatory cytokines levels, respectively promoted and reduced polarization of M1 and M2 macrophages in colonic tissue from ROX treated mice. Further, KC7F2 treatments inhibited ROX induced HCT level increasing in blood and decreased HIF-1-α and HIF-2-α level in colonic tissue.

Conclusion

Collectively, we discovered that ROX ameliorated EC in mice by regulating macrophage polarization through promotion of HIF expression.

General significance

Taken together, we developed a new application of ROX, which provides new ideas and a scientific basis for IBD treatment.

中文翻译：

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Roxadustat 通过增加 HIF 水平调节巨噬细胞极化来改善小鼠实验性结肠炎

背景

胃肠道（GI）炎症是炎症性缺氧的结果，炎症性缺氧也是由炎症性肠病（IBD）等长期存在的疾病引起的。巨噬细胞对胃肠道免疫稳态的调节涉及缺氧诱导因子（HIF）。作为 HIF 脯氨酰羟化酶抑制剂，罗沙司他 (ROX) 会增加 HIF 水平。

方法

我们通过右旋糖酐硫酸钠 (DSS) 在小鼠中诱导实验性结肠炎 (EC) 模型，以评估 ROX 在上述疾病中的作用。

结果

ROX 通过阻止结肠长度缩短和体重减轻来改善小鼠 EC，从而降低疾病活动指数 (DAI) 和组织病理学评分。ROX 显着降低结肠组织中炎症细胞因子水平，抑制 M1 巨噬细胞极化并增加 M2 巨噬细胞极化。此外，ROX 还可阻止血液中血细胞比容 (HCT) 水平的下降，并增加结肠组织中 HIF-1-α 和 HIF-2-α 的水平。HIF-1-α 抑制剂 KC7F2 降低了 ROX 处理的 DSS 小鼠的体重和结肠长度。同时，KC7F2 治疗的 DSS 小鼠的 DAI 评分和组织病理学明显高于单独使用 ROX 治疗的小鼠。KC7F2 治疗还显着增加炎症细胞因子水平，分别促进和减少 ROX 治疗小鼠结肠组织中 M1 和 M2 巨噬细胞的极化。此外，KC7F2 治疗抑制 ROX 诱导的血液中 HCT 水平增加，并降低结肠组织中的 HIF-1-α 和 HIF-2-α 水平。

结论

总的来说，我们发现 ROX 通过促进 HIF 表达来调节巨噬细胞极化，从而改善小鼠的 EC。

一般意义

综上所述，我们开发了ROX的新应用，为IBD治疗提供了新思路和科学依据。