Phenyl-N-tert-butylnitrone demonstrates broad-spectrum inhibition of apoptosis-associated gene expression in endotoxin-treated rats.
Systemic exposure to gram-negative bacterial substances such as lipopolysaccharide (LPS, or endotoxin) induces an uncontrolled, massive inflammatory reaction which culminates in multiple system organ failure and death. Septic shock often does not respond to corticosteroids; however, certain low-molecular-weight antioxidant compounds have been discovered to possess potent anti-inflammatory action, and some of these novel compounds can rescue animals from experimentally induced septic shock. Phenyl-N-tert-butylnitrone (PBN) is the archetype of the nitrone class of antioxidants which we have previously shown to suppress LPS-induced cytokine biosynthesis in vivo. Using a multiprobe ribonuclease protection assay, we now demonstrate the ability of PBN to suppress proapoptotic gene expression in the LPS-induced model of endotoxic shock. The broad-spectrum gene-suppressive affects of PBN are discussed in the context of inflammatory signal transduction and models are proposed to explain why certain antioxidants may also possess anti-inflammatory and antiapoptotic properties.
Stewart
C A
CA
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, Oklahoma 73104, USA.
Hyam
K
K
Wallis
G
G
Sang
H
H
Robinson
K A
KA
Floyd
R A
RA
Kotake
Y
Y
Hensley
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003497:Cyclic N-Oxides; D015870:Gene Expression / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009589:Nitrogen Oxides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D003497:Cyclic N-Oxides; D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D012333:RNA, Messenger; C029217:phenyl-N-tert-butylnitrone