These studies have direct clinical relevance to the multisystem deficits seen in mechanical biliary obstruction (Fig. 3). Defects in two crucial elements of effective phagocytosis (chemotaxis and intracellular killing) have been demonstrated in obstructive jaundice. At the same time, complete diversion of bile (containing bile salts and s-IgA) from the gut lumen causes changes in the endogenous bacterial flora, loss of mucosal integrity, and decreased endotoxin inactivation, resulting in portal bacteremia, endotoxemia, and increased translocation to mesenteric lymph nodes. This increased load comes at a time when the liver is metabolically impaired and RES function is abnormal. Decreased hepatic clearance of intrabiliary bacteria may contribute to the development of cholangitis (by both ascending and hematogenous routes). Inadequate RES control of portal bacteremia results in "spillover" with subsequent systemic bacteremia and localization of organisms in the lungs where they may contribute to pulmonary dysfunction or pneumonia. Although reversal of jaundice is readily accomplished by either external or internal biliary drainage, chronic biliary obstruction results in functional alterations in the liver which are reversed, generally incompletely, only after weeks or months of decompression. External biliary decompression fails to restore the enterohepatic circulation, preventing bile salts, s-IgA, and other substances from entering the lumen of the gut. It is not as effective as internal biliary drainage in reversing RES dysfunction or restoring immune parameters. Even with internal drainage, restoration of normal function in these systems takes weeks or months. Muramyl dipeptide analogues show some promise. A possible unifying mechanism may provide the clues to further experiments which will suggest better ways of reducing the morbidity and mortality in these patients. All macrophages share common functions which include not only phagocytosis but also antigen processing and the production of cytokines. The immune dysfunction noted in obstructive jaundice may be due to inadequate or inappropriate antigen processing or cytokine production by macrophages or to abnormal hepatocyte-Kupffer cell interactions. Kupffer cells are the largest pool of macrophages. Most numerous in periportal areas, Kupffer cells process significant quantities of enteric-derived antigens and Kupffer cell blockade results in an exaggerated response to these antigens. Kupffer cells also act as important scavengers of endotoxin, which stimulates the release of TNF and IL-6.(ABSTRACT TRUNCATED AT 400 WORDS)