Structure-function correlation of tight junctional impairment after intrahepatic and extrahepatic cholestasis in rat liver

Background & Aims: Tight junctions, the only barrier between blood and bile, are crucial in bile formation. The aim of this study was to correlate changes in morphology and permeability by comparing structural parameters with marker secretion into normal and cholestatic rat bile. Methods: Cholestasis was induced by bile duct ligation or 5 and 21 days of ethinylestradiol administration. Quantitated structural parameters included junctional length, strand number, junctional depth, and spacing of junctional particles. Junctional permeability was probed with horseradish peroxidase and dextrans of increasing sizes. Results: Junctional length was decreased slightly by ethinylestradiol (-16% after 21 days) but increased by ligation (77%). Mean strand number decreased from 4.6 to 3.7 after 21 days of ethinylestradiol and 3.4 after ligation associated with increased junctional depth. The proportions of morphologically horseradish peroxidase-positive junctions increased from 4% to 15% after 21 days of ethinylestradiol and to 56% after ligation. Horseradish peroxidase secretion was increased twofold by ethinylestradiol and 6.5-fold by ligation, paralleled by an increase of dextran size selectivity from 70,000 to 79,000 daltons after ethinylestradiol and to 266,000 daltons after ligation. Conclusions: Impairment of junctional integrity is paralleled with the degree of cholestasis, whereas correlation of morphological and physiological alterations shows a close structure-function relationship.