Oxpentifylline in endotoxaemia.

Oxpentifylline (pentoxifylline), which is known to have pharmacological effects in animal models of respiratory distress syndrome, multiorgan failure, and shock, was tested in human beings after injection of endotoxin. Of ten healthy volunteers, nine met the inclusion criterion of a rise in body temperature of at least 1.0 degrees C after 100 ng endotoxin (Salmonella abortus equi) as a bolus injection. Serum levels of tumour necrosis factor alpha (TNF) and interleukin-6 (IL-6) were both significantly higher than baseline levels 2 h and 3 h after endotoxin injection. 3 weeks later the nine volunteers were again injected with 100 ng endotoxin and oxpentifylline (500 mg over 4 h) was also infused. There was no rise in TNF levels, though IL-6 levels rose in parallel with body temperature. These data suggest that oxpentifylline blocks the endotoxin-induced synthesis of TNF in man and, therefore, could possibly have beneficial effects in clinical endotoxaemia.

Mononuclear phagocytes and eicosanoids: aspects of their synthesis and biological activities.

Mononuclear phagocytes convert arachidonic acid and other unsaturated fatty acids from intracellular sources to a variety of oxygenated metabolites such as prostaglandins and leukotrienes which are secreted into the surrounding medium. Other oxidative products such as hydroxylinoleic acids are reacylated into cellular constituents. The underlying metabolic pathways are activated by numerous stimuli of exogenous or endogenous origin. Depending on the state of activation and cell differentiation, the organ of origin and the nature of the stimulus used, macrophages elaborate a distinct spectrum of oxidative arachidonic acid metabolites. The contribution of these metabolites to the proinflammatory properties of macrophages is twofold: As autocrine signals they modulate the synthesis of diverse macrophage products and they influence cellular functions of other cells such as T-lymphocytes.

Lipoxygenase inhibitors suppress formation of tumor necrosis factor in vitro and in vivo.

Injection of endotoxin in D-galactosamine sensitized mice resulted in increased serum levels of tumor necrosis factor as determined in a fibroblast cytolysis assay. Concomitant injection of different lipoxygenase inhibitors decreased the titer of TNF. When the lipoxygenase inhibitors were tested in macrophage cultures stimulated with LPS, they prevented the production of TNF. Indomethacin, a blocker of cyclooxygenase was neither in vivo nor in vitro effective in the prevention of the endotoxin-induced synthesis of TNF. The involvement of superoxide anion in this effect was excluded by use of superoxide dismutase which did not influence the formation of TNF in macrophages.

Lipoxygenase inhibitors suppress formation of tumor necrosis factor in vitro and in vivo.

The LPS induced synthesis of tumor necrosis factor in macrophage cultures, as determined in a fibroblast cytolysis assay was found to be effectively blocked by inhibitors of lipoxygenases. Likewise, the presence of tumor necrosis factor in serum of D-galactosamine sensitized mice after challenge with endotoxin was suppressed by the lipoxygenase inhibitors. Indomethacin, a blocker of cycclooxygenase was neither in vivo nor in vitro effective in the prevention of the endotoxin-induced synthesis of TNF. From LPS-treated macrophages we were able to isolate 13-hydroxylinoleic acid, a lipoxygenase product, which is significantly increased after LPS treatment of the cells, covalently bound to cellular constituents and may, therefore, be possibly involved in the formation of TNF.