[The mechanisms of extracellular-signal regulated protein kinase pathway in biopterin induction in rats with endotoxic shock].
OBJECTIVE
To observe the influence of treatment with the inhibitor of extracellular-signal regulated protein kinase (ERK) signal transduction pathway on the expression of biopterin/nitric oxide (NO) as well as the activation of nuclear factor-kappaB (NF-kappaB), and to clarify the potential cross-talk regulation mechanisms between ERK and NF-kappaB pathway in biopterin-mediated NO induction in rats with endotoxic shock.


METHODS
Using an endotoxic shock model, 60 male Wistar rats were randomly divided into normal controls (n = 8), endotoxic shock group (n = 32) and PD98059 treatment group (n = 20). At serial time points animals in each group were sacrificed, and tissue samples from liver, lungs as well as kidneys were harvested to detect NF-kappaB activity, guanosine triphosphate-cyclohydrolase (GTP-CHI) and inducible nitric oxide synthase (iNOS) mRNA expression. Biopterin and NO levels in plasma and tissues were also assayed.


RESULTS
It was found that after lipopolysaccharide (LPS) challenge, GTP-CHI mRNA expression and biopterin levels significantly elevated in liver, lungs and kidneys, keeping at high values up to 24 h, so did the values of iNOS mRNA expression and NO levels. NF-kappaB DNA binding activity was enhanced rapidly in various tissues, peaking at 2 h after LPS challenge. Treatment with PD98059, an inhibitor of ERK signal transduction pathway, could significantly inhibit GTP-CHI mRNA expression in kidneys, and GTP-CHI mRNA expression in liver and lungs showed certain down-regulation tendency. At the same time, biopterin level was significantly decreased in plasma, liver and kidneys at 12 h. Similarly, iNOS/NO induction at early stage markedly decreased in various tissues. In addition, treatment with PD98059 reduced NF-kappaB DNA binding activity in liver, lungs, as well as kidneys at 2-6 h, 2 h, 24 h and 24 h after LPS challenge, respectively.


CONCLUSIONS
Inhibition of ERK pathway could partially inhibit the production of biopterin/NO as well as the activation of NF-kappaB pathway, which indicated that cross-talk regulation seems to be existed between ERK and NF-kappaB pathway, and they might be involved in the regulatory process of biopterin-mediated nitric oxide induction in rats with endotoxic shock.
Xu
Cai-lin
CL
Burns Institute, 304th Hospital Affiliated to the People's Liberation Army General Hospital, Beijing 100037, China.
Yao
Yong-ming
YM
Yao
Feng-hua
FH
Yu
Yan
Y
Sheng
Zhi-yong
ZY
D000818:Animals; D001708:Biopterins / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology*; D015398:Signal Transduction
D016328:NF-kappa B; D001708:Biopterins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D006136:GTP Cyclohydrolase