Hemophagocytic syndrome (HPS) is a fatal complication of severe viral infections such as Epstein-Barr virus (EBV) and recently, SARS CoV and H5N1 influenza. The pathogenesis of HPS is presumed to result from an enhanced Th1 cytokine secretion and systemic macrophage activation. Since peroxisome proliferators activated receptor (PPAR) agonists, regulators of cholesterol metabolism, have been shown to exhibit profound effects on the inhibition of proinflammatory cytokines and macrophage activation, rosiglitazone, a PPAR-gamma agonist, was adopted for the potential control of HPS using a rabbit model of Herpesvirus papio (HVP, an EBV homologue)-associated HPS. In vitro, rosiglitazone was shown to inhibit macrophage activation and secretion of tumor necrosis factor-alpha through inhibition of NFkB signaling in U937 cell line. Different doses of rosiglitazone were fed to rabbits after intravenous injection of 5 × 107 copies of HVP virus at different time courses (7 days and 20 days, respectively) of infection. As compared to the control group which succumbed consistently at around one month, the 4 mg rosiglitazone-treated group showed significant improvement of survival when fed at early stage (7 days) of infection (p < 0.01), while a higher dosage (8 mg) is needed to achieve therapeutic effect at advanced stage (20 days) of infection (p < 0.05). The viral load, TNF-alpha cytokine levels, and laboratory parameters also showed significant improvement in the rosiglitazone-treated group. Therefore, rosiglitazone, in addition to its therapeutic effect for metabolic syndrome, appears to represent a potential regimen for the control of HPS associated with virus infections.
Date:
2008-12
Relation:
International Journal of Infectious Diseases. 2008 Dec;12:E168-E169.
