The intraperitoneal administration of lipopolysaccharide from SalmoneUa typhimurium (1 mg/kg) caused a fall in the rat colonic temperature of about 2TC at an ambient temperature of 22 ± 3TC. The hypothermia induced by the lipopolysaccharide was abated in a dose-dependent manner by the administration of indomethacin. Other inhibitors of prostaglandin synthetase such as aspirin, flufenamic acid, and phenylbutazone had effects similar to those of indomethacin. When various prostaglandins were injected intracerebroventricularly, only prostaglandin D2 caused a dose-dependent fall in the colonic temperature at doses between 1.2 and 6 nmol/kg. Microinjection of prostaglandin D2 into the preoptic area caused hypothermia of about 1°C. However, injection ofprostaglandin D2 into the posterior hypothalamus had little effect on the colonic temperature. The hypothermia caused by prostaglandin D2 was not abated by the administration of indomethacin. The amount of prostaglandin D2 increased significantly in the preoptic/hypothalamic region of rat brain 1 hr after the intraperitoneal administration of the lipopolysaccharide, whereas such increase was not observed in rats pretreatedwith indomethacin. The in vitro incubation ofthe preoptic/ hypothalamic slices with the lipopolysaccharide also increased the amount of prostaglandin D2. These results suggest that the intraperitoneal administration of the lipopolysaccharide induces the release of prostaglandin D2 in the preoptic/hypothalamic area of rat brain and that the latter compound is involved in the hypothermic response of rats to the lipopolysaccharide.Since Milton and Wendlandt found that prostaglandin (PG) E1 is a potent pyrogenic agent in cats in 1970 (1) and Vane's discovery that antiinflammatory and antipyretic drugs inhibit PG synthesis (2), the rise in body temperature caused by pyrogens has been considered to be mediated by the formation of PG(s) in the brain (3-8). The E series PGs have been identified in the brain as well as in the cerebrospinal fluid and suggested as a mediator of hyperthermia by Milton and co-workers (5-8), although Cranston et al. reported results contradicting this hypothesis (9-11). Bacterial endotoxin [lipopolysaccharide (LPS)] is a pyrogen that causes fever in a variety ofmammals. However, in rodents, such as rats, guinea pigs, and mice, it causes hypothermia instead of hyperthermia (12)(13)(14)(15)(16)(17). Recently the PG profile in the brain ofthese animals was clarified and PGD2 was found to be the major PG (18)(19)(20). The synthesis and degradation of PGD2 in the brain have been studied extensively in our laboratory (20,21). In this communication, we demonstrate that indomethacin and other inhibitors of PG synthesis abate the hypothermia of rats induced by the intraperitoneal administration of LPS from Salmonella typhimurium and that PGD2 in the brain is at least in part responsible for the hypothermia.MATERIALS AND METHODS Intraventricular Injection of PGs. Male Wistar rats weighing 380-420 g were anesthetized with intraperiton...

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Changes in arachidonate metabolism were examined in mouse peritoneal macrophages incubated with tarious types of lipoproteins. Oxidized low density lipoprotein (LDL) was incorporated by macrophages and stimulated macrophage prostaglandin E2 (PGE2) and leukotriene C4 syntheses, respectively, 10.8-and 10.7-fold higher than by the control. Production of 6-keto-PGFI,, a stable metabolite of prostacyclin, was also stimulated. No stimulation was found with native LDI, which was minimally incorporated by the cells. Acetylated LDL and beta-migrating very low density lipoprotein (Ol-VLDL), though incorporated more efficiently than oxidized LDL, also had no stimulatory effect. When oxidized LDL was separated into the lipoprotein-lipid peroxide complex and free lipid peroxides, most of the stimulatory activity was found in the former fraction, indicating that stimulation of arachidonate metabolism in the cell is associated with uptake of the lipoprotein-lipid peroxide complex. These results suggest that peroxidative modification of LDL could contribute to the progression of atheroma by stimulating arachidonate metabolism during incorporation into macrophages.

The presence of prostaglandins D2, E2, and F2 alpha was demonstrated and their contents measured in various regions of postmortem human brain, pineal body, and pituitary by using specific radioimmunoassays and gas chromatography-mass spectrometry. The three prostaglandins were widely distributed in similar concentrations ranging from several hundred pg/g wet weight to about 40 ng/g wet weight. Prostaglandins D2 and E2 showed consistent and similar regional distributions in all six brains tested; amounts were high in pineal body, pituitary, olfactory bulb, and hypothalamus. On the other hand, prostaglandin F2 alpha was distributed more evenly. Prostaglandin D synthetase and prostaglandin E synthetase activities were found in cerebrum homogenate from a single subject and were recovered from the 100,000 X g supernatant. The presence of 1 mM glutathione, reduced form, markedly stimulated the activity of prostaglandin E synthetase, but did not affect prostaglandin D synthetase activity. Activity of 15-hydroxyprostaglandin dehydrogenase was found in the cerebrum homogenate and was partially purified. This enzyme required NADP as a cofactor and copurified with prostaglandin E 9-ketoreductase.

SummarySubnormal platelet responses to thromboxane A2 (TXA2) were found in a patient with polycythemia vera, and the mechanism of this dysfunction was analyzed. The patient’s platelets showed defective aggregation and release reaction to arachidonic acid, enzymatically generated TXA2 and synthetic TXA2 mimetics (STA2, U-46619). In contrast, they showed normal responses to thrombin. When the platelet TXA2 receptor was examined with both a 125I-labelled derivative of a TXA2 receptor antagonist ([125I]-PTA-OH) and a 3H-labelled TXA2 agonist ([3H]U-46619), the equilibrium dissociation rate constants (Kd) and the maximal concentrations of binding sites (Bmax) of the patient’s platelets to both ligands were within normal ranges, suggesting that the binding capacity of their TXA2 receptor was normal. STA2 failed to induce normal elevation in the. cytoplasmic free calcium ion concentration, phosphatidic acid formation and 40 kD protein phosphorylation in the patient’s platelets, whereas these responses to thrombin were within normal ranges. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) also evoked normal response in the 40 kD protein phosphorylation in the patient’s platelets. These results suggested that the patient’s platelets had TXA2 receptor abnormalities which were characterized by defective transduction of the binding signal to postreceptor reactions after normal TXA2 binding.