The primary function of thromboxane A2 (TXA2) in the lung is thought to be the regulation of vascular tone and platelet reactivity. However, the possibility that this major secretory product of the alveolar macrophage (AM) may participate in the regulation of cytokine release, as do eicosanoids such as prostaglandin E2 (PGE2), has not been explored. Therefore, we studied the effect of the specific TXA2 synthesis inhibitor UK 38,485 (Dazmegrel) on the production of eicosanoids and cytokines by normal human AM activated with lipopolysaccharide (LPS) and by AM from coal miners. LPS significantly increased the production of PGE2 and TXA2 by AM but had no effect on leukotriene B4 (LTB4) production. LPS also increased the release of tumor necrosis factor (TNF) and interleukin-1 (IL-1) by AM. UK 38,485 (35 nM - 3.5 microM) inhibited both basal and LPS-stimulated TXA2 production as well as TNF release in a dose-dependent manner. PGE2 production was increased by UK 38,485 but the increase was not dose-dependent. UK 38,485 had no effect on either LTB4 production or LPS stimulated IL-1 release. UK 38,485 also inhibited basal TXA2 and TNF production by AM from coal miners. TNF release was also inhibited by suprofen, in association with the inhibition of both PGE2 and TXA2 production, suggesting that TXA2-associated release of TNF is not linked to an elevation of PGE2 production. These findings suggest a previously undescribed role for TXA2 in lung injury which involves the specific linkage between the production of TXA2 and the release of TNF by the activated AM.