Prostaglandins and opioids.

In guinea-pig small intestine, rat brain in vitro and neuroblastomaXglioma hybrid cells, opioids specifically inhibit the action of E prostaglandins. In the whole rat, E prostaglandins, administered centrally, antagonize the antinociceptive action of morphine. E prostaglandins also antangonize the induction of opioid tolerant/dependence. In turn, tolerance/dependent preparations respond with added intensity to E prostaglandins. The antagonism between opioids and E prostaglandins does not occur at the opioid receptor; but, certainly in some preparations and probably in others, this antagonism occurs at the coupling or catalytic unit of a neuronal adenylate cyclase that opioids inhibit and E prostaglandins stimulate. The proposition that antagonism of E prostaglandin at appropriate neurons in the brain is part of the natural mechanism of opioid analgesia remains possible, but unproven, and is worth continued investigation.     

Prostaglandins mediate the fetal pulmonary response to intrauterine inflammation

Intra-amniotic (IA) lipopolysaccharide (LPS) induces intrauterine and fetal lung inflammation and increases lung surfactant and compliance in preterm sheep; however, the mechanisms are unknown. Prostaglandins (PGs) are inflammatory mediators, and PGE(2) has established roles in fetal lung surfactant production. The aim of our first study was to determine PGE(2) concentrations in response to IA LPS and pulmonary gene expression for PG synthetic [prostaglandin H synthase-2 (PGHS-2) and PGE synthase (PGES)] and PG-metabolizing [prostaglandin dehydrogenase (PGDH)] enzymes and PGE(2) receptors. Our second study aimed to block LPS-induced increases in PGE(2) with a PGHS-2 inhibitor (nimesulide) and determine lung inflammation and surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid PGE(2) concentrations increased (P < 0.05) 12 h and 3-6 days after LPS. Fetal lung PGHS-2 mRNA and PGES mRNA increased 2 (P = 0.0084) and 7 (P = 0.014) days after LPS, respectively. In study 2, maternal intravenous nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later. Nimesulide inhibited LPS-induced increases in PGE(2) and decreased fetal lung IL-1β and IL-8 mRNA (P ≤ 0.002) without altering lung inflammatory cell infiltration. Nimesulide decreased surfactant protein (SP)-A (P = 0.05), -B (P = 0.05), and -D (P = 0.0015) but increased SP-C mRNA (P = 0.023). Thus PGHS-2 mediates, at least in part, fetal pulmonary responses to inflammation.     

Prostaglandins in human seminal plasma. Prostaglandins and related factors 46

This study on human seminal plasma sought after the compounds which either possess the dienone chromophore or can be converted into it by treatment with sodium hydroxide. In addition, this investigation led to the isolation of 8 more (PGs) prostaglandins which were present in higher concentrations than the previously recognized PGs. Samples of human seminal plasma were subjected to silicic acid chromatography, reversed phase partition chromatography, thin layer chromatography, and gas liquid chromatography which isolated those 8 PGs not previously recognized. 4 of these compounds, PGE1-217, PGE2-217, PGE1-278, and PGE2-278 were known from earlier studies but had not been isolated from natural sources. The other 4 were 19 hydroxy derivatives of the 4 abovementioned compounds. The concentrations of the previously recognized PGs were recently determined and it was found that the 19 hydroxy derivatives were present in concentrations 4 times higher than the PGE compounds.     

Prostaglandins and premenstrual syndrome.

We examined plasma PGF2 alpha, PGE, PGE2, TXB2 and 6-keto-PGF1 alpha at intervals throughout 3 menstrual cycles in 20 patients with PMS. Similar measurements throughout 1 menstrual cycle were made in 12 age-matched control women. The plasma concentration of PGF2 alpha in the late luteal phase was significantly lower in patients with PMS compared with that in the control subjects. The plasma concentrations of PGE in the middle follicular phase and middle luteal phase, PGE2 alpha in the middle follicular phase and TXB2 in the middle and late luteal phase were significantly higher in 20 patients compared with the values in the controls. A disturbance of PG metabolism may contribute to the etiology of PMS.     

Prostaglandins and cardiac anaphylaxis.

Manifestations of cardiac anaphylaxis include sinus tachycardia and arrhythmias, both of which result from histamine release. The marked decrease in coronary flow, which also occurs during cardiac anaphylaxis, cannot be attributed solely to histamine release.To indirectly assess the possible role of prostaglandins in cardiac anaphylaxis, hearts from sensitized guinea pigs were challenged $\text{in}$$\text{vitro}$ in the presence of indomethacin. This resulted in a marked increase in histamine release, which caused a greater tachycardia and an increase in the incidence of arrhythmias. Moreover, for the same degree of histamine release sinus rate increments were larger in the presence of indomethacin. However, despite the enhanced cardiac dysfunction, coronary flow rate did not decrease.The results suggest that, during cardiac anaphylaxis, prostaglandins modulate histamine release and the effects of released histamine. Furthermore, since we have found that PGF_2α is released from the anaphylactic heart, we tentatively ascribe the anaphylactic reduction in coronary flow to the elaboration of PGF_2α.     

Tryptophan and the immune response

The immune system continuously modulates the balance between responsiveness to pathogens and tolerance to non-harmful antigens. The mechanisms that mediate tolerance are not well understood, but recent findings have implicated tryptophan catabolism through the kynurenine metabolic pathway as one of many mechanisms involved. The enzymes that break down tryptophan through this pathway are found in numerous cell types, including cells of the immune system. Some of these enzymes are induced by immune activation, including the rate limiting enzyme present in macrophages and dendritic cells, indoleamine 2,3-dioxygenase (IDO). It has recently been found that inhibition of IDO can result in the rejection of allogenic fetuses, suggesting that tryptophan breakdown is necessary for maintaining aspects of immune tolerance. Two theories have been proposed to explain how tryptophan catabolism facilitates tolerance. One theory posits that tryptophan breakdown suppresses T cell proliferation by dramatically reducing the supply of this critical amino acid. The other theory postulates that the downstream metabolites of tryptophan catabolism act to suppress certain immune cells, probably by pro-apoptotic mechanisms. Reconciling these disparate views is crucial to understanding immune-related tryptophan catabolism and the roles it plays in immune tolerance. In this review we examine the issue in detail, and offer additional insight provided by studies with antibodies to quinolinate, a tryptophan catabolite which is also necessary for nicotinamide adenine dinucleotide (NAD +) production. In addition to the immunomodulatory actions of tryptophan catabolites, we discuss the possible involvement of quinolinate as a means of replenishing NAD + in leucocytes, which is depleted by oxidative stress during an immune response.     

Pentastomids and the immune response

Pentastomids are a class of crustacean endoparosites that, as adults, parasitize the respiratory tract of vertebrates. They have evolved some unique strategies for long-term survival in vertebrate lungs which appear to be equally useful in thwarting inflammatory responses in the tissues of intermediate hosts. In this article, John Riley outlines the possible biological roles and immunological relevance of pentastomid excretory/secretory (E/S) products that may be important to parasite survival.