[Effects of extracellular signal-regulated kinase inhibition by AG126 on tissue tumor necrosis factor-alpha expression and multiple organ dysfunction in rats with postburn Staphylococcus aureus sepsis].
OBJECTIVE
To investigate the effects of extracellular signal-regulated kinase (ERKs) inhibition by AG126 on tissue tumor necrosis factor-alpha (TNF-alpha) expression and multiple organ dysfunction in rats with postburn Staphylococcus aureus sepsis and its potential signal regulating mechanism.


METHODS
To reproduce postburn sepsis model, male Wistar rats were inflicated with 20% total body surface area third-degree scald followed by Staphylococcus aureus challenge. 34 rats were randomly divided into four groups as follows: normal control group (n = 6), scald control group (n = 6), postburn sepsis group (n = 12), and AG126 treatment group (n = 10). Tissue samples from the liver, kidneys and lungs were collected to determine phosphorylated ERKs by Western blot analysis, and TNF-alpha mRNA expression as well as its protein levels.


RESULTS
It was revealed that phosphorylated ERKs in the liver, lungs, and kidneys from postburn septic animals were up-regulated rapidly at 0.5 - 2.0 hours, being 1.94-fold (P < 0.05), 2.86-fold (P < 0.01), and 1.41-fold at 2.0 hours compared to normal controls, respectively. Treatment with AG126 could significantly reduce phosphorylated ERKs in lung tissue by 70.6% (P < 0.01) at 2.0 hours postburn sepsis, and almost completely inhibited ERKs activation in the liver and kidneys at various time points. Meanwhile, both TNF-alpha mRNA and protein expressions in the liver, lungs, and kidneys were significantly decreased in AG126-treated group following septic challenge (P < 0.05 or 0.01). In addition, 2.0 hours after Staphylococcus aureus infection, treatment with AG126 markedly improved hepatic and renal function parameters, including serum ALT, AST, Cr, as well as BUN levels (P < 0.05 or 0.01), together with significant decrease in pulmonary myeloperoxidase activity, compared to those without AG126 treatment.


CONCLUSIONS
These data suggested that ERKs signal transduction might be involved in the pathogenesis of systemic inflammatory response and multiple organ dysfunction in postburn gram-positive bacterial sepsis. Early treatment with AG126 could significantly down-regulate TNF-alpha mRNA expression as well as protein levels in vital organs and attenuate multiple organ dysfunction induced by scald injury combined with Staphylococcus aureus challenge.
Yao
Yong-ming
YM
Burns Institute, 304th Hospital of People's Liberation Army, Beijing 100037, China.
Cheng
Ming-hua
MH
Yao
Sheng
S
Liang
Hua-ping
HP
Li
Hong-yun
HY
Dong
Ning
N
Yu
Yan
Y
Sheng
Zhi-yong
ZY
D000818:Animals; D015153:Blotting, Western; D002056:Burns / Q000150:complications; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009102:Multiple Organ Failure / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000209:etiology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C069028:AG 127; D020928:Mitogen-Activated Protein Kinases