Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular dysfunction in mice.
Kupffer cells (KCs) have been implicated in the leukocyte recruitment and microvascular dysfunction associated with liver inflammation. The overall objective of this study was to assess the role of KCs in the leukocyte adhesion and oxidative stress elicited in the liver by gut ischemia/reperfusion (I/R). The accumulation of rhodamine-6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) were monitored (by intravital microscopy) in mouse liver for 1 hour after a 15-minute period of normothermic intestinal ischemia. Autofluorescence of pyridine nucleotide [NAD(P)H] was measured as an index of mitochondrial O2 consumption and redox status. Leukostasis, as well as increases in NPS and NAD(P)H autofluorescence (indicating hypoxia), were observed in the liver at 60 minutes after gut I/R. Pretreatment with gadolinium chloride (GdCl3), which reduces KC function, attenuated the liver leukostasis and NPS elicited by gut I/R. The platelet activating factor (PAF) antagonist, WEB2086, and a tumor necrosis factor (TNF)-alpha-specific antibody were also effective in attenuating the gut I/R-induced leukostasis and NAD(P)H autofluorescence. The findings of this study suggest that KCs play an important role in mediating the leukocyte recruitment, impaired sinusoidal perfusion, and tissue hypoxia elicited in the liver after gut I/R. These KC-mediated responses appear to involve the participation of both PAF and TNF-alpha.
Horie
Y
Y
Department of Physiology, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Wolf
R
R
Russell
J
J
Shanley
T P
TP
Granger
D N
DN
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply*; D007728:Kupffer Cells / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology*; D008102:Liver Circulation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D019007:P-Selectin / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015427:Reperfusion Injury / Q000503:physiopathology*; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D001381:Azepines; D005343:Fibrinolytic Agents; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C052518:WEB 2086; D009249:NADP; D005682:Gadolinium; D000410:Alanine Transaminase; C038958:gadolinium chloride