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 Szabo

Research output: Contribution to journalArticle

72 Citations (Scopus)

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
StatePublished - Oct 1 2001
Externally publishedYes

Fingerprint

Inosine
Septic Shock
Punctures
Ligation
Inflammation
NAD
Liver
Macrophage Inflammatory Proteins
Lung
Blood Vessels
Malondialdehyde
Chemokines
Interleukin-10
Nitrates
Adenosine
Lipid Peroxidation
Peroxidase
Oxidation-Reduction
Endothelium
Interleukin-6

Keywords

  • Endothelium
  • Organ failure
  • Purines
  • Shock
  • Vascular

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. / Liaudet, Lucas; Mabley, Jon G.; Soriano, Francisco Garcia; Pacher, Pál; Marton, Anita; Haskó, György; Szabo, Csaba.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 164, No. 7, 01.10.2001, p. 1213-1220.

Research output: Contribution to journalArticle

Liaudet, Lucas ; Mabley, Jon G. ; Soriano, Francisco Garcia ; Pacher, Pál ; Marton, Anita ; Haskó, György ; Szabo, Csaba. / Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. In: American Journal of Respiratory and Critical Care Medicine. 2001 ; Vol. 164, No. 7. pp. 1213-1220.
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