Immunomodulatory action of G-CSF in a rat model of endotoxin-induced liver injury: an intravital microscopic analysis of Kupffer cell and leukocyte response.
In contrast to the anticipation that in sepsis granulocyte colony-stimulating factor (G-CSF) would overactivate the nonspecific immune system by recruiting and priming leukocytes with consequent aggravation of inflammatory tissue lesions, recombinant (r) G-CSF pretreatment was protective in various experimental non-neutropenic models of inflammation. The mechanisms of protection, however, are not fully understood. Using intravital fluorescence microscopy, we show that rG-CSF enhances leukocyte endothelial cell interaction within the microvasculature of normal rat livers, whereas rG-CSF pretreatment of animals exposed to lipopolysaccharide (LPS) attenuates the LPS-induced leukocytic response, including stasis in sinusoids as well as rolling and adherence in postsinusoidal venules with subsequent tissue infiltration. Moreover, rG-CSF, which did not affect Kupffer cell activity in normal rat livers, reduced the immediate activation of Kupffer cells on LPS exposure, as indicated in vivo by the delayed adherence/phagocytosis of intra-arterially administered latex particles associated with attenuation of proinflammatory cytokine release (tumor necrosis factor alpha and interleukin-6). Finally, rG-CSF reduced LPS-induced nutritive perfusion failure and hepatocellular excretory dysfunction. This study provides evidence for a distinct, possibly tumor necrosis factor alpha-dependent modulation of LPS-induced cellular response within the liver by rG-CSF, thereby achieving protection against microcirculatory perfusion failure and hepatic dysfunction.
Vollmar
B
B
Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Messner
S
S
Wanner
G A
GA
Hartung
T
T
Menger
M D
MD
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008099:Liver / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor