Increase of tumor necrosis factor-alpha in the blood induces early activation of matrix metalloproteinase-9 in the brain.
Increases of cytokine in the blood play important roles in the pathogenesis of influenza-associated encephalopathy. TNF-alpha was administered intravenously to wild-type mice, after which blood, CSF and brain tissue were obtained, and changes in BBB permeability, the amounts of MMP-9 and TIMP-1, and the localization of activated MMP were assessed. There was a significant increase in BBB permeability after 6 and 12 hr. MMP-9 was increased after 3 hr in the brain and cerebrospinal fluid, which was earlier than in the serum. TIMP-1 protein in the brain increased significantly after MMP-9 had increased. Activation of MMP-9 was observed in neurons in the cerebral cortex and hippocampus, and in vascular endothelial cells. These findings suggest that an increase in blood TNF-alpha promotes activation of MMP-9 in the brain, and may also induce an increase in permeability of the BBB. Early activation of MMP-9 in the brain may contribute to an early onset of neurological disorders and brain edema prior to multiple organ failure in those inflammatory diseases associated with highly increased concentrations of TNF-alpha in the blood, such as sepsis, burns, trauma and influenza-associated encephalopathy.
Tsuge
Mitsuru
M
Department of Pediatrics, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Yasui
Kozo
K
Ichiyawa
Takashi
T
Saito
Yukie
Y
Nagaoka
Yoshiharu
Y
Yashiro
Masato
M
Yamashita
Nobuko
N
Morishima
Tsuneo
T
D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology; D001921:Brain / Q000201:enzymology*; D004789:Enzyme Activation; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9