Effects of exogenous ubiquitin in lethal endotoxemia

Recent data indicated a potential role for extracellular ubiquitin in hematopoiesis and inflammation. The biological significance and therapeutic potential of these findings in vivo are unknown. Based on its in vitro abilities to inhibit endotoxin-stimulated tumor necrosis factor alpha (TNFα) production, we hypothesized that exogenous ubiquitin has salutary effects on sequelae caused by endotoxin in vivo. Anesthetized and mechanically ventilated swine were infused with endotoxin for 3 hours. Ubiquitin was administered intravenously either 15 minutes before or 45 minutes after the endotoxin infusion was started. Albumin was administered to a control group. An additional control group received only ubiquitin. Ex vivo endotoxin evoked TNFα production was measured using a whole blood assay. Ubiquitin and TNFα concentrations were determined by enzyme-linked immunosorbent assay. Ubiquitin reduced mortality ( P < .05), prevented development of pulmonary failure ( P < .05), reduced fluid requirements ( P < .05), and diminished erythema and edema formation. Ubiquitin pretreatment was more effective than treatment 45 minutes after an endotoxin infusion was started. In vivo ubiquitin administration alone inhibited ex vivo endotoxin-evoked TNFα secretion, but had no effect on TNFα serum levels after endotoxin infusion. In vivo ubiquitin administration has salutary actions during lethal endotoxemia and inhibits ex vivo whole blood TNFα production upon endotoxin stimulation. The clinical appearance after ubiquitin treatment in endotoxemia indicates the endothelium as another potential target cell population for interactions with ubiquitin. A novel therapeutic approach to a broad variety of diseases, in which endotoxin triggers immune activation, is suggested.