An Inhibitor of Thromboxane Production Attenuates Tumor Necrosis Factor Release by Activated Human Alveolar Macrophages

"Tumor necrosis factor alpha (TNFa) and thromboxane A2 (TXA2) are major products of the activated alveolar macrophage and serve as key mediators of lung injury. In order to determine if the synthesis ofTXA2 and the release ofTNFa are associated, the production of these inflammatory agents by the human alveolar macrophage (AM), as a result of activation by lipopolysaccharide (LPS), was assessed in the absence and presence of the thromboxane synthase inhibitors UK 38,485 (Dazmegrel) and OKY 046. UK 38,485 and OKY 046 inhibited both LPS-stimulated TXA2 production and TNFa release in a dose-dependent manner. Prostaglandin E2 (PGE2) production was not increased by UK 38,485 or OKY 046. Neither LPS nor UK 38,485 had any effect on LT84 production by AM. Neither UK 38,485 or OKY 046 had any effect on LPS-stimulated interleukin-I beta release. However, the TXA2 mimetic, U46619, did not stimulate TNFa release by AM either in the absence or presence of UK 38,485. These findings suggest that 1) UK 38,485 and OKY 046 are inhibitors of both TXA2 production and TNFa release by activated human AM, 2) UK 38,485 probably does not exert its inhibitory action on TNFa release through effects on eicosanoid production and 3) the possibility that TNFa- and TXA2-induced lung injury may be subject to amelioration by imidazole-based compounds should be further evaluated.IntroductionTumor necrosis factor alpha (TNFa), produced by monocytes and macrophages, is a potent peptide mediator of lung injury (1,2). The exaggerated release of TNFa has been implicated in the etiology of acute lung reactions such as septic shock of bacterial or viral origin (3,4). The role of TNFa is expressed primarily through its ability to activate a variety of cell types within the lung environment including polymorphonuclear leukocytes (PMNs, ref. 5), type II epithelial cells (6) and fibroblasts (7). The role of lipid mediators in lung disease has also been extensively characterized (1). In particular, the relationship between pulmonary inflammation and fibrosis and the production of oxygenated derivatives of arachidonic acid (here termed ""eicosanoids"") appears to be a key factor in a variety of disease processes in the lung (8). The alveolar macrophage (AM) synthesizes primarily prostaglandin E2 (PGE2). thromboxane A2 (TXA2) and leukotriene 84 (LT84, ref. 9). These eicosanoids have been shown to produce a variety of effects in the lung including bronchial smooth muscle dilatation (PGE2, ref. 10), vascular smooth muscle contraction and platelet aggregation (TXA2, ref. 11) and oedema and immune cell extravasation (LT84, ref. 12)."