Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture

Lucas Liaudet, Jon G. Mabley, Francisco Garcia Soriano, Pál Pacher, Anita Marton, György Haskó, Csaba Szabò

    Research output: Contribution to journalArticle

    73 Scopus citations

    Abstract

    Inosine is a naturally occurring purine formed from the breakdown of adenosine. Here we have evaluated the effects of inosine in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice subjected to CLP were treated with either inosine (100 mg/kg, intraperitoneally) or vehicle 1 h before and 6 h after CLP. After 12 h tumor necrosis factor α, interleukin 6 (IL-6), and IL-10 were measured in plasma. Biochemical markers of organ damage, liver NAD+/NADH (indicator of the mitochondrial redox state), plasma nitrate, tissue myeloperoxidase (MPO, indicator of neutrophil accumulation) and malondialdehyde (MDA, indicator of lipid peroxidation), liver and lung chemokines (macrophage inflammatory protein 1α [MIP-1α] and MIP-2), and ex vivo vascular reactivity in aortic rings were also measured. Mice treated with inosine had significantly lower levels of circulating cytokines. Organ damage was significantly reduced by inosine treatment, which was associated at the tissue level with an increased hepatic NAD+/NADH ratio, decreased MPO activity in the lung, reduced MDA formation in the gut and liver, and decreased MIP-1α and MIP-2 in the lung and liver. Furthermore, inosine significantly improved endothelium-dependent relaxant responses of aortic rings. These effects were associated with significant improvement of the survival of CLP mice treated with inosine, an effect that was still observed when inosine treatment was delayed 1 h after CLP, especially when it was associated with appropriate antibiotic treatment. Thus, inosine reduced systemic inflammation, organ damage, tissue dysoxia, and vascular dysfunction, resulting in improved survival in septic shock.

    Original languageEnglish (US)
    Pages (from-to)1213-1220
    Number of pages8
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume164
    Issue number7
    DOIs
    StatePublished - Oct 1 2001

    Keywords

    • Endothelium
    • Organ failure
    • Purines
    • Shock
    • Vascular

    ASJC Scopus subject areas

    • Pulmonary and Respiratory Medicine
    • Critical Care and Intensive Care Medicine

    Fingerprint Dive into the research topics of 'Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture'. Together they form a unique fingerprint.

  • Cite this