herbimycin and Hemorrhage

Although it has been suggested that some biological activities of platelet-activating factor (PAF) are mediated by, at least in part, reactive oxygen intermediates (ROI), the precise mechanisms underlying the interaction between the two remains to be elucidated. Antioxidants, such as alpha-tocopherol acid succinate, N-acetyl-L-Cysteine, pyrrolidinedithiocarbamate failed to inhibit PAF-induced immediate systemic reactions such as lethality, symptoms of disseminated intravascular coagulation, and histological changes such as pulmonary edema and hemorrhage in renal medullae 10 min following PAF injection. In contrast. antioxidants significantly inhibited both the in vivo and in vitro PAF-induced NF-kappaB activation and NF-kappaB-dependent TNF-alpha expression. The effects of the antioxidants were due to their inhibition of PAF-induced degradation of IkappaBalpha, a protein responsible for keeping NF-kappaB in an inactive form. A protein tyrosine kinase and N-tosyl-L-phenylalanine chloromethyl ketone sensitive serine protease were involved in both PAF- and H2O2-induced NF-kappaB activation. Collectively, these data indicate that the PAF-induced NF-kappaB activation is selectively mediated through the generation of ROI.

Topics: Acetylcysteine; Animals; Antioxidants; Azepines; Benzoquinones; Disseminated Intravascular Coagulation; DNA-Binding Proteins; Female; Gene Expression Regulation; Genistein; Hemorrhage; Hydrogen Peroxide; I-kappa B Proteins; Isoflavones; Kidney Medulla; Lactams, Macrocyclic; Lethal Dose 50; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Platelet Activating Factor; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Pulmonary Edema; Pyrrolidines; Quinones; Reactive Oxygen Species; Rifabutin; Serine Proteinase Inhibitors; Signal Transduction; Specific Pathogen-Free Organisms; Succinic Acid; Thiocarbamates; Tosylphenylalanyl Chloromethyl Ketone; Triazoles; Tumor Necrosis Factor-alpha; Vitamin E