Guiping Kong , Hu Hua , Yan Lu , Kunlong Yan , Yucan Zheng , Zhanjun Jia , Hongmei Guo , Mei Li , Yu Jin , Zhifeng Liu
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引用次数: 0
Abstract
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.
期刊介绍:
BBA General Subjects accepts for submission either original, hypothesis-driven studies or reviews covering subjects in biochemistry and biophysics that are considered to have general interest for a wide audience. Manuscripts with interdisciplinary approaches are especially encouraged.