The effect of inhibition of a major cell signaling pathway following trauma hemorrhage on hepatic injury and interleukin 6 levels.
OBJECTIVE
Recent studies have shown that intracellular signaling pathways, such as the mitogen-activated protein kinases, play a pivotal role in the activation of the inflammatory response. We hypothesized that administration of a specific mitogen-activated protein kinase inhibitor, PD 98059, at the end of resuscitation following severe hemorrhagic shock can reduce the plasma levels of interleukin 6 (IL-6) and hepatocellular damage.


METHODS
Prospective controlled animal study.


METHODS
Medical school-affiliated university hospital.


METHODS
Male Sprague-Dawley (275-325 g) rats underwent laparotomy (ie, soft tissue trauma) and were then bled to a mean arterial pressure of 40 mm Hg for approximately 90 minutes. The animals were then resuscitated with 4 times the bleed-out volume using Ringer lactate solution for 60 minutes. PD 98059, an inhibitor of extracellular signal-regulated kinases (ERKs) 1 and 2 (750 mmol/L), or vehicle (dimethyl sulfoxide and isotonic sodium chloride solution) was administered intravenously as a bolus at the end of resuscitation.


METHODS
At 24 hours after resuscitation or sham operation, plasma levels of IL-6 and alpha-glutathione S-transferase were determined with enzyme-linked immunosorbent assay and enzyme immunoassay, respectively. Moreover liver sections were stained with monoclonal antibody against the phosphorylated form of ERKs.


RESULTS
At 24 hours following trauma hemorrhage and resuscitation, plasma levels of IL-6 and alpha-glutathione S-transferase were markedly elevated. Administration of PD 98059, however, reduced levels to sham values. Moreover, liver expression of phosphorylated ERKs was found in the cytosol and nuclear compartment of hepatocytes only following trauma hemorrhage.


CONCLUSIONS
Administration of PD 98059 (ie, inhibition of intracellular signaling pathways) may represent a feasible approach to blunt the inflammatory response and improve outcome following traumatic injuries and hemorrhagic shock.
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham 35294-0019, USA.
Doraid
D
Jarrar
Grace Y
GY
Song
Joachim F
JF
Kuebler
Loring W
LW
Rue
Kirby I
KI
Bland
Irshad H
IH
Chaudry
D000704:Analysis of Variance; D000818:Animals; D015232:Dinoprostone / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D007813:Laparotomy; D008099:Liver / Q000201:enzymology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D014947:Wounds and Injuries / Q000503:physiopathology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D015850:Interleukin-6; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one