DOSE-RELATED PATTERN OF SINUSOIDAL LEUKOCYTE ADHESION IN SUBLOBULAR REGIONS OF THE LIVER AFTER SYSTEMIC ENDOTOXIN CHALLENGE IN THE RAT

The unique arrangement of large numbers of fixed tissue macrophages, e ndothelial, and parenchymal cells along hepatic sinusoids as well as t heir key role in the acute phase response makes the liver a primary ta rget organ in endotoxemia. Pathogenesis of hepatic failure in endotoxe mia is incompletely understood, but microcirculatory failure as well a s leukocyte-endothelial interaction in response to inflammatory mediat ors may relate to it. Using intravital fluorescence microscopy, sinuso idal widths, leukocyte flow velocity, and sublobular leukocyte (white blood cell (WBC)) adhesion characteristics 1 h after randomized intrav enous application of 0, 0.1, 1, or 5 mg/kg b.w. Escherichia coli endot oxin O 111 B4 (ETX) were evaluated in female Sprague-Dawley rats (n = 6-8/group). Whereas the bolus injection of ETX caused only minor concu rrent macrohemodynamic effects, a significant increase of permanent WB C adhesion especially in periportal areas (0 mg, 2.1 +/- 0.7%; 0.1 mg, 16.2 +/- 3.6%*; 1 mg, 15.5 +/- 1.0%**; 5 mg, 13.2 +/- 2.3%* (**p < . 01, p < .05, compared to vehicle)) was found in all groups 60 min aft er ETX challenge. In contrast, an increase of WBC margination in midzo nal and pericentral regions was only seen with the higher doses of 1 o r 5 mg/kg ETX, respectively. The sublobular pattern of WBC margination is consistent with the concept of regulation of WBC adhesion by infla mmatory mediators released by lipopolysaccharide-stimulated Kupffer ce lls in vivo. We propose that overwhelming the detoxifying capacity of predominantly periportally located Kupffer cells with large amounts of ETX may lead to activation of pericentral-located resting macrophages paralleled by a rise of adhering leukocytes.