Differential effects of GdCl3- or MDP treatment on rat liver microcirculation and gene expression in the hepatic non-parenchymal cell fraction in LPS shock.
BACKGROUND
Dichloromethylenebisphosphonate (MDP) and gadolinium chloride (GdCl(3)) are substances frequently used for experimental depletion of Kupffer Cells (KC) in models of endotoxin shock. The aim was to determine whether depletion of KC through pretreatment with GdCl(3) or MDP alters the hepatic microcirculation during lipopolysaccharide (LPS)-induced shock in rats and to test if there are substance-specific differences.


METHODS
Rats received either MDP or GdCl(3) or saline prior to induction of LPS shock. Hepatic microcirculation was evaluated by intravital microscopy (sinusoidal diameter, sinusoidal bloodflow, leukocyte adhesion), and the gene expression in the hepatic non-parenchymal cell fraction was determined by RT-PCR.


RESULTS
GdCl(3) pretreatment prevented sinusoidal narrowing but did not restore sinusoidal blood flow and did not normalize leukocyte-endothelial interaction time after LPS. In contrast, MDP pretreatment improved hepatic microcirculation consistently for all parameters measured compared to GdCl(3) pretreated animals. In the non-parenchymal cell fraction, eNOS gene expression was preserved and gene expression of TNF-alpha was blocked after MDP but not after GdCl(3) application prior to LPS shock.


CONCLUSIONS
The results show that GdCl(3) and MDP cannot be used equivalently for experimental KC depletion in the condition of LPS-induced shock. These findings should be taken into consideration in studies that evaluate the role of Kupffer cells in models of endotoxin-induced shock.
Department of Trauma, Hand and Reconstructive Surgery, J.W. Goethe University, Frankfurt/Main, Germany. d.henrich@trauma.uni-frankfurt.de
Dirk
D
Henrich
Mark
M
Lehnert
Carsten
C
Herzog
Stephan
S
Niederlaender
Borna
B
Relja
Lars
L
Conzelmann
Ingo
I
Marzi
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D004002:Clodronic Acid / Q000494:pharmacology*; D004195:Disease Models, Animal; D005682:Gadolinium / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000098:blood supply*; D008297:Male; D008833:Microcirculation / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D050071:Bone Density Conservation Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D005682:Gadolinium; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C038958:gadolinium chloride