Deletion of the c-Rel subunit of NF-κB shows a significantly attenuated response to ischemia/reperfusion injury Academic Article uri icon

Overview

MeSH Major

  • Biomedical Research
  • General Surgery

abstract

  • Introduction: Ischemia/reperfusion (I/R) initiates a proinflammatory response that results in neutrophil infiltration and tissue injury. Serum levels of proinflammatory cytokines are elevated after liver I/R and are correlated to liver I/R related injuries. Transcription factor NF-κB is important for cytokine-inducible gene expression. Once the cell is stimulated, Ikappa B is degraded allowing the release of NF-κB which translocates to the nucleus and activates transcription of responsive genes. It has been shown that NF-κB is activated prior to any increase in proinflammatory cytokine production, suggesting that NF-κB activation may represent an initial event in the proinflammatory sequence induced by I/R injury. In this study, a liver I/R model was established in mice deficient in the c-Rel subunit of NF-κB in order to determine the importance of c-Rel during I/R injury. Methods: Mice deficient in the c-Rel subunit of NF-κB or wild-type control mice (n = 10/group) underwent midline laparotomy and 80% hepatic ischemia for 30 minutes followed by reperfusion for 60 minutes before sacrifice. Serum was assayed for IL-6 (ELISA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Liver and lung histology was examined through conventional section and HE staining. Hepatic myeloperoxidase activity (MPO), a major indicator of neutrophil sequestration, was assayed. Pulmonary inflammatory cell infiltration in the lung was graded from normal (0) to severe (4). Results: Liver I/R in wild-type mice resulted in more severe hepatic and pulmonary injuries manifested by elevated hepatic mean MPO (37±8 mOD/min/g), serum AST (368±123 U/ml) and ALT (987±344 U/ml), when compared to NF-κB/c-Rel knockout mice with hepatic mean MPO (14±11, p<0.05 vs wild-type), serum AST (120±97) and ALT (460±200, p<0.05 vs wild-type). Histologic evidence of pulmonary neutrophil infiltration at 60 minutes of reperfusion was more severe in the wild-type vs. knockout mice (2.6±1.6 vs 1.5±1.4). These injuries were associated with increased mean serum IL-6 in the wild type compared to the c-Rel deficient mice (450±167 vs 103±95 pg/ml, p<0.05). Conclusions: The results suggest that in a liver I/R model, the c-Rel subunit of NF-κB appears to play a major role in the activation or regulation of the proinflammatory response associated with this injury.

publication date

  • December 1999

Research

keywords

  • Academic Article

Additional Document Info

start page

  • A56

volume

  • 27

number

  • 1 SUPPL.