Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model.
Septic shock is a life-threatening disorder caused by lipopolysaccharide (LPS) and other bacterial products. Accumulating evidence indicates a role for vasoactive substances and cytokines in this disease process. In this study we examined the effect of LPS on the gene expression of endothelin-1 (ET-1) and adrenomedullin (AM), two major vasoactive peptides predominantly produced by vascular endothelial cells, to investigate their role in the pathophysiology of septic shock. LPS induced ET-1 and AM gene expression in the heart, lung, kidney, liver, and aorta within 6 h. In the liver, whereas basal ET-1 and AM mRNA were hardly detectable, ET-1 and AM gene expression and peptide production were markedly increased by LPS. This LPS-induced upregulation of ET-1 and AM expression is greatly potentiated by D-galactosamine (D-GalN), although D-GalN alone could not induce ET-1 and AM gene expression. These results, together with the previous findings that liver injury induced by LPS and D-GalN is mainly mediated by tumor necrosis factor-alpha (TNF-alpha), suggest that the LPS-cytokine pathway may cause upregulation of ET-1 and AM production, leading to dysregulation of systemic and regional vascular tone.
Shindo
T
T
Third Department of Internal Medicine, University of Tokyo, Japan.
Kurihara
H
H
Kurihara
Y
Y
Morita
H
H
Yazaki
Y
Y
D053607:Adrenomedullin; D000818:Animals; D015152:Blotting, Northern; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D004731:Endotoxins; D004797:Enzyme-Linked Immunosorbent Assay; D005688:Galactosamine / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000235:genetics*; D012313:RNA / Q000096:biosynthesis; D012772:Shock, Septic / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
D019332:Endothelin-1; D004731:Endotoxins; D008070:Lipopolysaccharides; D010455:Peptides; D053607:Adrenomedullin; D012313:RNA; C044101:endotoxin, Escherichia coli; D005688:Galactosamine