IngentaConnect Biological and Clinical Significance of Endotoxemia in the Course...

Authors: Caradonna, L.; Mastronardi, M.L.; Magrone, T.; Cozzolongo, R.; Cuppone, R.; Manghisi, O.G.; Caccavo, D.; Pellegrino, N.M.; Amoroso, A.; Jirillo, E.; Amati, L.

Source: Current Pharmaceutical Design, Volume 8, Number 11, 1 May 2002 , pp. 995-1005(11)

Publisher: Bentham Science Publishers

Abstract:

Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes / macrophages. In turn, LPS-activated monocytes / macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)- agr

, interleukin (IL)-1 bgr

, IL-6, IL-8 and IL-12 are the major mediators.

Before therapy (To) and at the end of 6-month interferon (IFN)- agr

/ Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients.

At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg / ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg / ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg / ml).

In terms of serum cytokine concentration, at T6 IFN- ggr

levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values.

The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity . In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration.

Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed.

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