Time dependency and topography of hepatic nuclear factor κB activation after hemorrhagic shock and resuscitation in mice.

The leading causes of death in people aged 1 to 44 years are unintentional injuries with associated hemorrhagic shock. Hemorrhagic shock followed by resuscitation (H/R) activates the nuclear factor NF-kappa B (NF-kappa B) pathway. To further address the association between liver damage and NF-kappa B activation, we analyzed the H/R-induced activation of NF-kappa B using cis-NF-kappa B-egfp reporter gene mice. In these mice, the expression of green fluorescent protein (GFP) is linked to the activation of NF-kappa B, and therefore tracing of GFP colocalizes NF-kappa B activation. Mice were hemorrhaged to a mean arterial blood pressure of 30mmHg for 90 min, followed by resuscitation. Six, 14, or 24 h after resuscitation, mice were killed. Compared with sham-operated mice, H/R led to a profound hepatic and cellular damage as measured by aspartate aminotransferase, creatine kinase, and lactate dehydrogenase levels, which was accompanied by an elevation in interleukin 6 levels and hepatic leukocyte infiltration. Interleukin 10 levels in plasma were elevated 6 h after H/R. Using serial liver sections, we found an association between necrotic areas, oxidative stress, and enhanced GFP-positive cells. Furthermore, enhanced GFP-positive cells surrounded areas of necrotic liver tissue, predominantly in a penumbra-like-shape pericentrally. These results elucidate spatial relationship between oxidative stress, liver necrosis, and NF-kappa B activation, using an in vivo approach and therefore might help to further analyze mechanisms of NF-kappa B activation after resuscitated blood loss.