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-stim ulating factor (G-CSF) would overactivate the nonspecific immune syste m by recruiting and priming leukocytes with consequent aggravation of inflammatory tissue lesions, recombinant (r) G-CSF pretreatment was pr otective in various experimental non-neutropenic models of inflammatio n, The mechanisms of protection, however, are not fully understood, Us ing intravital fluorescence microscopy, we show that rG-CSF enhances l eukocyte endothelial cell interaction within the microvasculature of n ormal rat livers, whereas rG-CSF pretreatment of animals exposed to li popolysaccharide (LPS) attenuates the LPS-induced leukocytic response, including stasis in sinusoids as well as rolling and adherence in pos tsinusoidal 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-arter ially administered latex particles associated with attenuation of proi nflammatory cytokine release (tumor necrosis factor alpha and interleu kin-6). Finally, rG-CSF reduced LPS-induced nutritive perfusion failur e and hepatocellular excretory dysfunction. This study provides eviden ce for a distinct, possibly tumor necrosis factor alpha-dependent modu lation of LPS-induced cellular response within the liver by rG-CSF, th ereby achieving protection against microcirculatory perfusion failure and hepatic dysfunction.