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 κB (NF-κB) pathway. To further address the association between liver damage and NF-κB activation, we analyzed the H/R-induced activation of NF-κB using cis-NF-κB reporter gene mice. In these mice, the expression of green fluorescent protein (GFP) is linked to the activation of NF-κB, and therefore tracing of GFP colocalizes NF-κB 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-κB activation, using an in vivo approach and therefore might help to further analyze mechanisms of NF-κB activation after resuscitated blood loss.
Department of Trauma, Hand and Reconstructive Surgery, University Hospital of Goethe, University, Frankfurt am Main, Germany.
Sebastian
S
Korff
Reza
R
Falsafi
Christoph
C
Czerny
Christian
C
Jobin
Christoph
C
Nau
Heike
H
Jakob
Ingo
I
Marzi
Mark
M
Lehnert
D000293:Adolescent; D000328:Adult; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D018384:Oxidative Stress / Q000235:genetics; D012771:Shock, Hemorrhagic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
C556062:IL10 protein, mouse; D015850:Interleukin-6; D016328:NF-kappa B; D016753:Interleukin-10; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase