Concentrations of Lipopolysaccharide-Binding Protein, Bactericidal/Permeability-Increasing Protein, Soluble Cd14 and Plasma Lipids in Relation to Endotoxaemia in Patients With Alcoholic Liver Disease

Abstract

There is increasing evidence that gut leakage in persons with chronic alcohol misuse leads to endotoxaemia, which might contribute to the development of alcoholic hepatitis or cirrhosis. In addition, it was recently shown that the endotoxin-binding capacity of whole blood is reduced in these patients. To analyse this phenomenon, we measured the concentration of functionally important endotoxin-binding plasma components which modify the action of endotoxin. In patients with minimal (n = 10), intermediate (n = 9), and cirrhotic alcoholic liver disease (n = 11), and healthy controls (n = 11), plasma endotoxin was determined in a limulus assay. The concentration of lipoproteins was assessed by measuring apolipoproteins, the other factors were directly measured in immunoassays. In the entire group of alcoholics, endotoxin and the concentration of binding factors that are involved in the action of endotoxin on its target cells (LPS-binding protein and sCD14) were increased. Endotoxin antagonists, such as bactericidal/permeability-increasing protein and high-density lipoprotein, were increased in the pre-cirrhotic stages, whereas a significant reduction of the latter was observed in cirrhosis. Low-density lipoprotein remained unchanged. The elevation of binding factors in the pre-cirrhotic stages of alcoholic liver disease might attenuate the effects of endotoxaemia, whereas in cirrhosis the reduction of high density lipoprotein, to which large quantities of endotoxin bind, may contribute to its pro-inflammatory effects.

Lack of sexual dimorphism in alcohol-induced liver damage (ALD) in rats treated chronically with ethanol-containing low carbohydrate diets: The role of ethanol metabolism and endotoxin

“…First, in rat ALD models in which sex differences have been observed, ethanol treatment resulted in elevated plasma endotoxin concentrations of 40-100 pg/ml (Ikegima et al, 1998;Nanji et al, 2002) and the molecular mechanism proposed for the sexual dimorphism involves increased Kupffer cell sensitivity to endotoxin through estrogen-mediated expression of the endotoxin receptor CD14 (Ikegima et al, 1998). In the models used in the current study, endotoxin concentrations only ranged from 3-14 pg/ml and are similar to the average endotoxin levels of 8-10 pg/ml observed in human alcoholics (Bode et al, 1987;Fukui et al, 1991;Urbaschek et al, 2000;Schafer et al, 2002). Bode et al (1987) and Fukui et al (1991) observed elevated endotoxin to comparable levels reported by the Thurman group in rats infused ethanol IG (>20 pg/ml) in only 34% of alcoholic cirrhotics with no correlation to levels of serum enzymes such as ALT.…”

Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis

“…Consistent with the abnormal gut permeability in alcoholic cirrhosis [4], chronic exposure of liver macrophages to portal blood endotoxemia [8] is associated to elevated LBP and CD14 serum concentrations. In our patients, we cannot conclude on the absence of participation of these two cytokines in the pathogenesis of AH, as their concentrations have not been assessed in liver and kupffer cells.…”

“…The action of endotoxin on target cells is mediated by two glycoproteins, lipopolysaccharide binding protein (LBP) and CD14. Lipopolysaccharide binding protein, the synthesis of which is increased in the presence of endotoxemia [8,9], acts as a carrier for endotoxin molecules, and has been proposed as a good marker of long-term exposure to endotoxin [10]. The endotoxin-LBP complex then binds to CD14, a membrane-bound receptor on Kupffer cells, to activate the cellular production of inflammatory mediators [11].…”

“…In CD14-deficient mice [12], alcoholic liver injury is reduced. In patients with alcoholic liver disease, circulating concentrations of the lipoproteins LBP and CD14 are elevated [8,11], with LBP correlating to serum CD14 in patients with cirrhosis [10].…”

Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis?

“…These polypeptides are upregulated during acute and chronic pancreatitis (21,28,30,47) and, specifically, by LPS, which appears to be increased in some alcoholics (56). We examined the effect of alcohol on PAP-1 and PSP/reg expression and the response to an LPS challenge using acute secretory stress proteins as a surrogate marker of the inflammatory response in the pancreas and as potential protective mechanisms that might be altered by chronic alcohol ingestion.…”