Synthesis of prostaglandin H synthase-2 by human alveolar macrophages in response to lipopolysaccharide is inhibited by decreased cell oxidant tone.

We previously demonstrated that lipopolysaccharide (LPS) increases expression of the prostaglandin H synthase-2 (PGHS-2) gene (Hempel, S.L., Monick, M.M., and Hunninghake, G.W. (1994) J. Clin. Invest. 93, 391-396). In this study, the expression of the PGHS-2 gene in response to changes in cell oxidant tone was studied. During LPS exposure, inhibition of synthesis of the free radical, NO., resulted in a small decrease in prostaglandin E2 synthesis that did not reach statistical significance. There was no effect on enzyme mass or mRNA. In contrast, incubation of alveolar macrophages in the presence of LPS plus the antioxidant pyrrolidine dithiocarbamate, the spin trap 5,5-dimethyl-1-pyrroline-N-oxide, or hypoxia, resulted in near complete inhibition of prostaglandin E2 synthesis, PGHS-2 enzyme synthesis, and gene transcription of PGHS-2 mRNA. There was no evidence of cytotoxicity. These results demonstrate that synthesis of PGHS-2 in response to LPS is inhibited by agents that decrease cell oxidant tone.