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 alpha,
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 1alpha [MIP-1alpha] 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-1alpha 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.