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Hepatic Transcriptional Regulation & Mortality in Cecal Ligation and Puncture
Alan Sherburne, MD, Kendra Iskander, MD, Holly Sheldon, MD, Zhongyan Wang, MD, Suresh Agarwal, MD, Daniel Remick, MD, Peter Burke, MD
Boston University Medical Center, Boston, MA
Background: The hepatic acute phase response(APR) is an organ-specific response to multiple insults and is largely under control via liver-specific transcription factors. Hepatic nuclear factors(HNFs)-1? and 4? play important roles in maintenance of liver phenotype and function. Within a well-established murine sepsis model, cecal ligation and puncture(CLP), interleukin-6 levels have been previously used to predict mortality. The kinetics of HNF binding in relation to predicted mortality have not been defined within the CLP model.
Methods: ICR mice underwent CLP with peripheral blood collected at 6h and stratified into groups predicted to live or die(P-LIVE, P-DIE) based upon serum IL-6 levels. Liver tissue was harvested at 6h, 24h & 48h with immediate processing for nuclear extracts. HNF binding activity was assessed with gel shifts. Hepatic mRNA levels for fibrinogen-? and serum amyloid A(SAA)-3 were obtained through RT-PCR.
Results: Serum fibrinogen and SAA mRNA levels increased markedly after CLP and peaked at 24h. The binding activities of HNF-4? and HNF-1? were decreased at 24h with subsequent reconstitution. There was a significant difference found at 6h within HNF-4? binding with a similar trend within HNF-1? between P-LIVE and P-DIE.
Conclusion: CLP induced a robust APR response. HNF-4? and HNF-1? binding after CLP is similar to known kinetics of previous models. Mice predicted to die had significantly larger decreases in HNF-4? binding when compared to mice predicted to live. A similar trend was also present within HNF-1?. This data indicates that injury-induced alterations in mechanisms regulating liver phenotype are related to clinically significant outcomes.
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