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 lipopolysac charide (LPS, or endotoxin) induces an uncontrolled, massive inflammatory r eaction which culminates in multiple system organ failure and death. Septic shock often does not respond to corticosteroids; however, certain low-mole cular-weight antioxidant compounds have been discovered to possess potent a nti-inflammatory action, and some of these novel compounds can rescue anima ls from experimentally induced septic shock. Phenyl-N-tert-butylnitrone (PB N) is the archetype of the nitrone class of antioxidants which we have prev iously shown to suppress LPS-induced cytokine biosynthesis in vivo. Using a multiprobe ribonuclease protection assay, we now demonstrate the ability o f PEN to suppress proapoptotic gene expression in the LPS-induced model of endotoxic shock. The broad-spectrum gene-suppressive affects of PEN are dis cussed in the context of inflammatory signal transduction and models are pr oposed to explain why certain antioxidants may also possess anti-inflammato ry and anti-apoptotic properties. (C) 1999 Academic Press.