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

Inosine is a naturally occurring purine formed from the breakdown of adenos ine. Here we have evaluated the effects of inosine in a murine model of pol ymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice subjec ted 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 a lpha, 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 neu trophil accumulation) and malondialdehyde (MDA, indicator of lipid peroxida tion), liver and lung chemokines (macrophage inflammatory protein 1 alpha [ MIP-1 alpha] and MIP-2), and ex vivo vascular reactivity in aortic rings we re 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 hepa tic NAD(+)/NADH ratio, decreased MPO activity in the lung, reduced MDA form ation in the gut and liver, and decreased MIP-1 alpha and MIP-2 in the lung and liver. Furthermore, inosine significantly improved endothelium-depende nt relaxant responses of aortic rings. These effects were associated with s ignificant improvement of the survival of CLP mice treated with inosine, an effect that was still observed when inosine treatment was delayed 1 h afte r CLP, especially when it was associated with appropriate antibiotic treatm ent. Thus, inosine reduced systemic inflammation, organ damage, tissue dyso xia, and vascular dysfunction, resulting in improved survival in septic sho ck.