Early growth response 1 mediates the systemic and hepatic inflammatory response initiated by hemorrhagic shock.
Hemorrhagic shock (HS) is a major cause of morbidity and mortality in trauma patients. The early growth response 1 (Egr-1) transcription factor is induced by a variety of cellular stresses, including hypoxia, and may function as a master switch to trigger the expression of numerous key inflammatory mediators. We hypothesized that HS would induce hepatic expression of Egr-1 and that Egr-1 upregulates the inflammatory response after HS. The Egr-1 mice and wild-type (WT) controls (n>or=5 for all groups) were subjected to HS alone or HS followed by resuscitation (HS/R). Other mice were subjected to a sham procedure which included general anesthesia and vessel cannulation but no shock (sham). After the HS, HS/R, or sham procedures, mice were euthanized for determination of serum concentrations of interleukin (IL) 6, IL-10, and alanine aminotransferase. Northern blot analysis was performed to evaluate Egr-1 messenger RNA (mRNA) expression. Liver whole cell lysates were evaluated for Egr-1 protein expression by Western blot analysis. Hepatic expression of IL-6, granulocyte colony-stimulating factor, and intracellular adhesion molecule 1 mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The Egr-1 DNA binding was assessed using the electrophoretic mobility shift assay. Hemorrhagic shock results in a rapid and transient hepatic expression of Egr-1 mRNA in WT mice by 1 h, whereas protein and DNA binding activity was evident by 2.5 h. The Egr-1 mRNA expression diminished after 4 h of resuscitation, whereas Egr-1 protein expression and DNA binding activity persisted through resuscitation. The Egr-1 mice exhibited decreased levels of hepatic inflammatory mediators compared with WT controls with a decrease in hepatic mRNA levels of IL-6 by 42%, granulocyte colony-stimulating factor by 39%, and intracellular adhesion molecule 1 by 43%. Similarly, Egr-1 mice demonstrated a decreased systemic inflammatory response and hepatic injury after HS/R compared with their WT counterparts. Early growth response 1 is rapidly upregulated in the liver during and after resuscitation from HS. Our results showing a blunted inflammatory response in Egr-1 mice provides evidence that Egr-1 functions as a proximal signal transduction mechanism responding to shock by amplifying the systemic inflammatory response.
Prince
Jose M
JM
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA, and Department of Hepatobiliary Surgery, General Hospital of Beijing Military District, Dongsi, Beijing, China.
Ming
Mei Jian
MJ
Levy
Ryan M
RM
Liu
Shubing
S
Pinsky
David J
DJ
Vodovotz
Yoram
Y
Billiar
Timothy R
TR
D000818:Animals; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012771:Shock, Hemorrhagic / Q000235:genetics / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018836:Inflammation Mediators; D012333:RNA, Messenger