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  • Biliverdin and bilirubin sulfonate inhibit monosodium urate induced sterile inflammation in the rat

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    Embargoed until: 2021-09-12
    Author(s)
    Shiels, Ryan G
    Hewage, Wenu
    Pennell, Evan N
    Vidimce, Josif
    Grant, Gary
    Pearson, Andrew G
    Wagner, Karl-Heinz
    Morgan, Michael
    Bulmer, Andrew C
    Griffith University Author(s)
    Bulmer, Andrew C.
    Pearson, Andrew G.
    Pennell, Evan N.
    Vidimce, Josif
    Shiels, Ryan G.
    Hewage, Wenu
    Grant, Gary D.
    Year published
    2020
    Metadata
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    Abstract
    BACKGROUND: Biliverdin, a by-product of haem catabolism, possesses potent endogenous antioxidant and anti-inflammatory properties. Bilirubin-C10-sulfonate (BRS), an active metabolite formed after enteral administration of BV in the rat, also possess antioxidant properties. Therefore, we investigated the anti-inflammatory and antioxidant activity of BV and BRS in an in vivo model of monosodium urate induced sterile inflammation. METHODS: Subcutaneous air pouches were created on the dorsal flanks of Wistar rats (10-12 weeks of age). Prior to stimulation of the 6-day old pouch with monosodium urate (25 mg), groups were pre-treated ...
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    BACKGROUND: Biliverdin, a by-product of haem catabolism, possesses potent endogenous antioxidant and anti-inflammatory properties. Bilirubin-C10-sulfonate (BRS), an active metabolite formed after enteral administration of BV in the rat, also possess antioxidant properties. Therefore, we investigated the anti-inflammatory and antioxidant activity of BV and BRS in an in vivo model of monosodium urate induced sterile inflammation. METHODS: Subcutaneous air pouches were created on the dorsal flanks of Wistar rats (10-12 weeks of age). Prior to stimulation of the 6-day old pouch with monosodium urate (25 mg), groups were pre-treated with intraperitoneal BRS (27 mg/kg) and BV (27 mg/kg). Total and differential leukocyte counts were determined in pouch fluid aspirate at 1, 6, 12, 24 and 48 h after monosodium urate stimulation. Biliverdin (BV), BRS and unconjugated bilirubin (UCB) concentrations in the serum and pouch fluid were quantified using liquid chromatography-mass spectrometry. Pouch fluid cytokine concentrations (IL-1β, IL-1⍺, TNF-⍺, IL-17A, IL-12, GM-CSF, IL-33, IFN-γ, IL-18, IL-10, MCP-1, CXCL-1 and IL-6) were assessed after 6 h. In addition, 24 h protein carbonyl and chloramine concentrations were assessed in pouch fluid using ELISA and spectrophotometry, respectively. RESULTS: BRS and BV significantly (p < 0.05) inhibited leukocyte (total, neutrophil and macrophage) infiltration into the pouch fluid from 6 to 48 h. For example, after 6 h neutrophil counts decreased following BRS (0.32 ± 0.11 × 106 cells mL-1) and BV (0.17 ± 0.03 × 106 cells mL-1) compared to MSU only (3.51 ± 1.07 × 106 cells mL-1). Both BV and BRS significantly (p < 0.05) reduced pouch GM-CSF (BV: 5.8 ± 1.2 pg mL-1, BRS: 6.9 ± 1.5 pg mL-1 vs MSU only: 13.0 ±1.9 pg mL-1) and MCP-1 concentrations at 6 h (BV: 1804 ± 269 pg mL-1, BRS: 7927 ± 2668 pg mL-1vs MSU only: 17290 ± 4503 pg ml-1), whilst BV additionally inhibited IL-6 (4354 ± 977 pg mL-1 vs MSU only: 25070 ± 5178 pg mL-1) and IL-18 (17.6 ± 2.0 pg mL-1 vs MSU only: 81.5 ± 19.9 pg mL-1) concentrations at 6 h (p < 0.05). Despite these differences, no change in pouch chloramine or protein carbonyl concentrations occurred at 24 h (p > 0.05). Serum BV concentrations rapidly diminished over 6 h, however, BRS was readily detected in the serum over 48 h, and in pouch fluid over 12 h. CONCLUSIONS: This study is the first to elucidate anti-inflammatory activity of BRS and the efficacy of BV administration in a model of gouty inflammation. Reduced leukocyte infiltration and cytokine production in response to sterile inflammation further support the importance of these molecules in physiology and their therapeutic potential in sterile inflammation.
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    Journal Title
    European Journal of Pharmaceutical Sciences
    DOI
    https://doi.org/10.1016/j.ejps.2020.105546
    Copyright Statement
    © 2020 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/397887
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    • Journal articles

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