The phagocytic activity of the reticuloendothelial system (RES) in the liver is important in host resistance to shock. Fibronectin is a large molecular weight glycoprotein which influences particulate uptake by phagocytic cells. This study addressed the effect of repeated low-dose endotoxin challenge on immunoreactive fibronectin and reticuloendothelial phagocytic function in rats. Intravenous Escherichia coli endotoxin increased circulating immunoreactive fibronectin by 100% within 24 hr; normalization was within 96 hr. Elevated fibronectin levels at 48 hr were associated with increased plasma opsonic activity as tested by liver slice phagocytic assay and RES stimulation, and in uitro uptake of gelatinized target particles by Kupffer cells in liver slices from endotoxin treated rats was signif%cantly inckeased. Endotoxin tolerance was produced by repeated low dose challenge with endotoxin for 7 days and was associated with RES stimulation, even though the circulating fibronectin concentrations had returned to normal. By immunofluorescence, insoluble fibronectin was widely distributed in the liver in a pattern analogous to the sinusoidal vascular network. We suggest that increased RES phagocytic activity after low dose endotoxin challenge is due to early elevation of plasma fibronectin and cellular stimulation of phagocytic function followed by a sustained stimulation of Kupffer cells in the presence of normal fibronectin levels. Both cellular and humoral factors may contribute to increased Kupffer cell phagocytic activity during endotoxin tolerance.
Endotoxin, the lipopolysaccharide component of' Gram-negative bacterial cell walls, has been implicated in the circulatory sequelae of' traumatic injury (1) and sepsis (2). High doses of endotoxin may act directly through injury to vascular endothelial cells (3, 4) or indirectly by activation of the alternate complement pathway (5) and initiation of intravascular coagulation (6). Both processes lead to sequestration of activated neutrophils in the lung and other organs which may be a factor in organ dysfunction and altered vascular permeability. Reticuloendothelial system (RES) activity appears to influence the outcome of various forms of circulatory shock, including endotoxemia (7-9). Tolerance to endotoxin, which is achieved with repetitive low-dose endotoxin challenge, is associated with enhanced phagocytosis by Kupffer cells ( 1 0 , l l ) and cross-tolerance