Role of endotoxin in the hepatic microvascular inflammatory response to ethanol.
Kupffer cells (KC) and gut-derived bacterial endotoxin have been implicated in the aetiology of alcoholic liver disease. Using in vivo microscopic methods, we have shown that ethanol ingestion in mice causes a dose dependent increase in leucocyte adhesion and endothelial cell swelling in hepatic sinusoids. Activation of KC is elicited at low doses while depression occurs at high doses and with chronic exposure. The responses are exacerbated in the presence of endotoxaemia or sepsis and are not seen in endotoxin-resistant animals, implicating a role for endotoxin in the ethanol-induced inflammatory response. In addition, the responses are abolished with anti-TNF alpha suggesting that TNF alpha is a primary mediator of these events. Nitric oxide (NO) initially appears to play an important role in these events by stabilizing the TNF alpha-mediated hepatic microvascular inflammatory response to acute ethanol ingestion, thereby helping to protect the liver from ischaemia and leucocyte induced oxidative injury. Finally, an ongoing clinical study has confirmed a mild systemic endotoxaemia in patients hospitalized for alcoholic liver disease. All of these results support important roles for endotoxin, cytokines, nitric oxide and sinusoidal lining cells in the pathophysiology of liver injury resulting from ethanol alone or in combination with infection.
McCuskey
R S
RS
Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson 85724, USA.
Nishida
J
J
Eguchi
H
H
McDonnell
D
D
Baker
G L
GL
Ekataksin
W
W
Krasovich
M A
MA
Rudi
V
V
Seitz
H K
HK
Urbaschek
B
B
D000818:Animals; D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D007249:Inflammation; D007728:Kupffer Cells / Q000378:metabolism / Q000502:physiology; D007962:Leukocytes / Q000473:pathology; D008099:Liver / Q000098:blood supply*; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016207:Cytokines; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide