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.
Tawadros
P S
PS
Department of Surgery, University of Toronto, and St. Michael's Hospital, Keenan Research Centre, Toronto, Ontario, Canada.
Powers
K A
KA
Yang
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I
Becker
D A
DA
Ginsberg
M D
MD
Szaszi
K
K
Kapus
A
A
Rotstein
O D
OD
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects*; D008171:Lung Diseases / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
D000975:Antioxidants; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C459743:stilbazulenyl nitrone; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost