Platelet-activating factor induces nitric oxide synthesis in Trypanosoma cruzi-infected macrophages and mediates resistance to parasite infection in mice

Trypanosoma cruzi replicates in nucleated cells and is susceptible to being killed by gamma interferon-activated macrophages through a mechanism depen dent upon NO biosynthesis, In the present study, the role of platelet-activ ating factor (PAF) in the induction of NO synthesis and in the activation o f the trypanocidal activity of macrophages was investigated. In vitro, PAF induced NO secretion by T. cruzi-infected macrophages and the secreted NO i nhibited intracellular parasite growth. The addition of a PAF antagonist, W EB 2170, inhibited both NO biosynthesis and trypanocidal activity. The indu cible NO synthase/L-arginine pathway mediated trypanocidal activity, since it was inhibited by treatment with L-N-monomethyl arginine (L-NMMA), an L-a rginine analog. PAF-mediated NO production in infected macrophages appears to be dependent on tumor necrosis alpha (TNF-alpha) production, since the a ddition of a neutralizing anti-TNP alpha monoclonal antibody mAb inhibited NO synthesis, To test the role of PAF in mediating resistance or susceptibi lity to T. cruzi infection, infected mice were treated with WEB 2170, a PAF antagonist, These animals had higher parasitemia and earlier mortality tha n did vehicle-treated mice, Taken together, our results suggest that PAF be longs to a group of mediators that coordinate the mechanisms of resistance to infections with intracellular parasites.