Chronic ethanol consumption increases vascular oxidative stress and the mortality induced by sub-lethal sepsis: Potential role of iNOS.

We hypothesized that long-term ethanol consumption would increase the mortality and aggravate the deleterious effects of sub-lethal cecal ligation and puncture (SL-CLP) in the vasculature by inducing the expression of inducible nitric oxide (NO) synthase (iNOS). Male C57BL/6J wild-type (WT) or iNOS-deficient mice (iNOS-/-) were treated with ethanol (20% v/v) for 12 weeks and then subjected to SL-CLP. Mice were killed 24 h post-operatively or followed six days for survival. Septic ethanol-treated mice showed a higher mortality than septic WT mice. However, septic iNOS-deficient mice treated with ethanol showed a decreased mortality rate when compared to ethanol-treated WT mice. Ethanol and SL-CLP augmented superoxide anion (O2-) generation in the mesenteric arterial bed (MAB) of both WT and iNOS-deficient mice. Treatment with ethanol and SL-CLP enhanced lipoperoxidation in the MAB of WT, but not iNOS-deficient mice. SL-CLP enhanced nitrate/nitrite (NOx) concentrations in the MAB of WT, but not iNOS-deficient mice. Both, ethanol and SL-CLP increased TNF-α and IL-6 levels in the MAB. Treatment with ethanol as well as SL-CLP up-regulated the expression of iNOS in the MAB of WT mice. The major finding of our study is that chronic ethanol consumption increases the mortality induced by SL-CLP and that iNOS plays a role in such response. Although ethanol led to vascular alterations, it did not aggravate the vascular injury induced by SL-CLP. Finally, iNOS mediated the increase in oxidative stress and pro-inflammatory cytokines induced by SL-CLP in the vasculature.