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Subcutaneously administered adrenomedullin exerts a potent therapeutic effect in a murine model of ulcerative colitis

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Abstract

Adrenomedullin (AM) exerts a potent anti-inflammatory effect. Intrarectal or consecutive intravenous administrations of AM reduce pathological manifestations in rodent colitis models. However, in clinical applications, a safer administration route that provides stronger alleviation of patient burden is preferred. We investigated whether subcutaneously administered AM is effective against dextran sulfate sodium (DSS)-induced colitis. C57BL/6J mice were administered 1% DSS in drinking water and received AM at 8, 40 or 80 nmol/kg subcutaneously once a day for 7 consecutive days. Subcutaneously administered AM significantly and dose-dependently ameliorated body weight loss, diarrhea, and histological severity of colonic inflammation in DSS-treated mice. The AM therapeutic effect was associated with the upregulation of the production of autocrine AM, and expression of cAMP, c-fos, KLF4, and downregulation of STAT3 and NF-κB p65 phosphorylation, as well as a decrease in proinflammatory cytokine expression in the colon. Subcutaneous AM treatment potently attenuated DSS-induced colitis, which suggests that AM administered subcutaneously in ulcerative colitis (UC) patients may decrease diseases burden and improve quality of life.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (16K09316). We would like to thank all of members of the Division of Host Defense of the Prefectural University of Hiroshima for animal care support.

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Authors and Affiliations

  1. Division of Host Defense, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 5562, Nanatsuka, Shobara, Hiroshima, 727-0023, Japan

    Yuta Kinoshita, Seiya Arita, Haruka Murazoe & Kyoko Inagaki-Ohara

  2. First Department of Internal Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan

    Kazuo Kitamura & Shinya Ashizuka

Authors
  1. Yuta Kinoshita
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  2. Seiya Arita
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  3. Haruka Murazoe
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  4. Kazuo Kitamura
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  5. Shinya Ashizuka
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  6. Kyoko Inagaki-Ohara
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Corresponding author

Correspondence to Kyoko Inagaki-Ohara.

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Conflict of interest

Kazuo Kitamura holds the stock of Himuka AM Pharma Corp. Yuta Kinoshita, Seiya Arita, Haruka Murazoe, Shinya Ashizuka, and Kyoko Inagaki-Ohara have no conflicts of interest to declare.

Ethical approval

All animal experiments were conducted in accordance with the guidelines of the Animal Research Committee of the Prefectural University of Hiroshima Animal Care and Use Committee.

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Kinoshita, Y., Arita, S., Murazoe, H. et al. Subcutaneously administered adrenomedullin exerts a potent therapeutic effect in a murine model of ulcerative colitis. Human Cell 32, 12–21 (2019). https://doi.org/10.1007/s13577-018-0219-9

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  • DOI: https://doi.org/10.1007/s13577-018-0219-9

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