Stilbazulenyl nitrone decreases oxidative stress and reduces lung injury after hemorrhagic shock/resuscitation and LPS.

Multiorgan failure is a major cause of late morbidity and mortality after trauma. Reactive oxygen species generated during shock/resuscitation contribute to tissue injury by priming the immune system for an exaggerated response to subsequent inflammatory stimuli such as LPS. Stilbazulenyl nitrone (STAZN) is a novel second-generation azulenyl nitrone that has been shown to have potent antioxidant properties in a rat model of brain ischemia. We hypothesized that STAZN may confer protection against lung injury after shock/resuscitation and LPS by reducing oxidative stress and lowering the production of NF-kappaB-dependent pro-inflammatory cytokines. Sprague-Dawley rats were submitted to a two-hit model of lung injury involving hemorrhagic shock/resuscitation and subsequent intratracheal LPS injection, with and without intraperitoneal injections of STAZN. STAZN reduced overall lung injury in response to LPS alone and also after shock/resuscitation plus LPS. STAZN also reduced plasma levels of 8-isoprostane, a proxy measure of oxidative stress, indicating its antioxidant activity in vivo. The effect of STAZN was, at least in part, related to its effect on nuclear translocation of NF-kappaB and generation of the pro-inflammatory cytokine TNF-alpha. Azulenyl nitrones such as STAZN represent a promising novel class of antioxidants for treating organ injury.

Death of rat sympathetic ganglion cells in vitro caused by neurite transection: effect of extracellular calcium.

Calcium entry into neurons secondary to excitotoxic insults is believed to cause neuronal death after trauma and ischemia, but the role of calcium influx in neuronal death after neurite transection independent of excitotoxicity has not been clearly defined. This study assesses the effect of variations in extracellular calcium concentration ([Ca2+]e) from 50 nM to 5 mM on cell death, in 14-day-old cultures of dissociated sympathetic neurons from the superior cervical ganglia of newborn rats. The neurites were transected with a custom-made injury device, and cell death was assessed with propidium iodide and fluorescence microscopy. We found that neurite transection caused a significant increase (p < 0.05) in cell death at all [Ca2+]e studies, but there was no significant difference in mortality at the various [Ca2+]e. Cell death significantly increased between 2 and 24 h postinjury at all three [Ca2+]e. Cell death increased with decreasing distance between the cell body and the transection site, and there was a significant decrease in mortality at distances greater than 0.66 mm, irrespective of the [Ca2+]e. These results suggest that influx of extracellular calcium is not responsible for posttransection cell death, suggesting that calcium release from internal stores or calcium-independent cell death mechanisms are triggered by neurite transection.