Endotoxemia produces coma and brain swelling in bile duct ligated rats.
This study explores the hypothesis that the inflammatory response induced by administration of lipopolysaccharide (LPS) exacerbates brain edema in cirrhotic rats; and if so whether this is associated with altered brain metabolism of ammonia or anatomical disturbance of the blood-brain barrier. Adult Sprague-Dawley rats 4 weeks after bile duct ligation (BDL)/Sham-operation, or naïve rats fed a hyperammonemic diet (HD), were injected with LPS (0.5 mg/kg, intraperitoneally) or saline, and killed 3 hours later. LPS administration increased brain water in HD, BDL, and sham-operated groups significantly (P < 0.05), but this was associated with progression to pre-coma stages only in BDL rats. LPS induced cytotoxic brain swelling and maintained anatomical integrity of the blood-brain barrier. Plasma/brain ammonia levels were higher in HD and BDL rats than in sham-operated controls and did not change with LPS administration. Brain glutamine/myoinositol ratio was increased in the HD group but reduced in the BDL animals. There was a background pro-inflammatory cytokine response in the brains of cirrhotic rats, and plasma/brain tumor necrosis factor alpha (TNF-alpha) and IL-6 significantly increased in LPS-treated animals. Plasma nitrite/nitrate levels increased significantly in LPS groups compared with non-LPS controls; however, frontal cortex nitrotyrosine levels only increased in the BDL + LPS rats (P < 0.005 versus BDL controls).


CONCLUSIONS
Injection of LPS into cirrhotic rats induces pre-coma and exacerbates cytotoxic edema because of the synergistic effect of hyperammonemia and the induced inflammatory response. Although the exact mechanism of how hyperammonemia and LPS facilitate cytotoxic edema and pre-coma in cirrhosis is not clear, our data support an important role for the nitrosation of brain proteins.
Wright
Gavin
G
Liver Failure Group, Institute of Hepatology, Division of Medicine, University College London, 69-75 Chenies Mews, London, UK.
Davies
Nathan A
NA
Shawcross
Debbie L
DL
Hodges
Stephen J
SJ
Zwingmann
Claudia
C
Brooks
Heather F
HF
Mani
Ali R
AR
Harry
David
D
Stadlbauer
Vanessa
V
Zou
Zhengsheng
Z
Zou
Zheng
Z
Williams
Roger
R
Davies
Ceri
C
Moore
Kevin P
KP
Jalan
Rajiv
R
D000641:Ammonia / Q000097:blood; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology* / Q000473:pathology; D002196:Capillaries / Q000473:pathology / Q000648:ultrastructure; D001651:Cholestasis, Extrahepatic / Q000150:complications* / Q000473:pathology; D003128:Coma / Q000209:etiology* / Q000473:pathology; D003243:Consciousness; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications*; D022124:Hyperammonemia / Q000150:complications; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D046529:Microscopy, Electron, Transmission; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; C002744:3-nitrotyrosine; D014443:Tyrosine; D000641:Ammonia