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

ABSTRACT

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.