SYNTHESIS OF PROSTAGLANDIN-H SYNTHASE-2 BY HUMAN ALVEOLAR MACROPHAGESIN RESPONSE TO LIPOPOLYSACCHARIDE IS INHIBITED BY DECREASED CELL OXIDANT TONE

We previously demonstrated that lipopolysaccharide (LPS) increases exp ression of the prostaglandin H synthase-2 (PGHS-2) gene (Hempel, S. L, , Monick, M. M., and Hunninghake, G. W. (1994) J. Clin. Invest. 93, 39 1-396). In this study, the expression of the PGHS-2 gene in response t o changes in cell oxidant tone was studied. During LPS exposure, inhib ition of synthesis of the free radical, NO, resulted in a small decrea se in prostaglandin E(2) synthesis that did not reach statistical sign ificance. There was no effect on enzyme mass or mRNA. In contrast, inc ubation of alveolar macrophages in the presence of LPS plus the antiox idant pyrrolidine dithiocarbamate, the spin trap 5,5-dimethyl-1-pyrrol ine-N-oxide, or hypoxia, resulted in near complete inhibition of prost aglandin E(2) synthesis, PGHS-2 enzyme synthesis, and gene transcripti on of PGHS-2 mRNA. There was no evidence of cytotoxicity. These result s demonstrate that synthesis of PGHS-2 in response to LPS is inhibited by agents that decrease cell oxidant tone.