Higher Prostaglandin E2 Research Articles

Prostaglandin E2 and BDNF levels in rat hippocampus are negatively correlated with status epilepticus severity: No impact on survival of seizure-generated neurons

Partial and generalized status epilepticus (pSE and gSE) trigger the same level of progenitor cell proliferation in adult dentate gyrus, but survival of new neurons is poor after gSE. Here, we show markedly elevated levels of prostaglandin E2 (PGE2) and brain-derived neurotrophic factor (BDNF) in rat hippocampal formation at 7 days following pSE but not gSE. Administration of the cyclooxygenase (COX) inhibitor flurbiprofen for 1 week, starting at day 8 post-SE, abated PGE2 and decreased BDNF levels, but did not affect survival of new neurons 4 weeks later. Thus, high PGE2 and BDNF levels induced by pSE are probably not of major importance for survival of new neurons during the first days after formation. We propose that they modulate other aspects of synaptic and cellular plasticity, and thereby may influence epileptogenesis.

The shunt from the cyclooxygenase to lipoxygenase pathway in human osteoarthritic subchondral osteoblasts is linked with a variable expression of the 5-lipoxygenase-activating protein

Osteoarthritis (OA) is characterized by articular cartilage degradation and hypertrophic bone changes with osteophyte formation and abnormal bone remodeling. Two groups of OA patients were identified via the production of variable and opposite levels of prostaglandin E2 (PGE2) or leukotriene B4 (LTB4) by subchondral osteoblasts, PGE2 levels discriminating between low and high subgroups. We studied whether the expression of 5-lipoxygenase (5-LO) or 5-LO-activating protein (FLAP) is responsible for the shunt from prostaglandins to leukotrienes. FLAP mRNA levels varied in low and high OA groups compared with normal, whereas mRNA levels of 5-LO were similar in all osteoblasts. Selective inhibition of cyclooxygenase-2 (COX-2) with NS-398-stimulated FLAP expression in the high OA osteoblasts subgroup, whereas it was without effect in the low OA osteoblasts subgroup. The addition of PGE2 to the low OA osteoblasts subgroup decreased FLAP expression but failed to affect it in the high OA osteoblasts subgroup. LTB4 levels in OA osteoblasts were stimulated about twofold by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plus transforming growth factor-β (TGF-β), a situation corresponding to their effect on FLAP mRNA levels. Treatments with 1,25(OH)2D3 and TGF-β also modulated PGE2 production. TGF-β stimulated PGE2 production in both OA osteoblast groups, whereas 1,25(OH)2D3 alone had a limited effect but decreased the effect of TGF-β in the low OA osteoblasts subgroup. This modulation of PGE2 production was mirrored by the synthesis of COX-2. IL-18 levels were only slightly increased in a subgroup of OA osteoblasts compared with normal; however, no relationship was observed overall between IL-18 and PGE2 levels in normal and OA osteoblasts. These results suggest that the shunt from the production of PGE2 to LTB4 is through regulation of the expression of FLAP, not 5-LO, in OA osteoblasts. The expression of FLAP in OA osteoblasts is also modulated differently by 1,25(OH)2D3 and TGF-β depending on their endogenous low and high PGE2 levels.

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

The mammary gland, like most tissues, produces measurable amounts of prostaglandin E2 (PGE2), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E2 synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E2 synthase (cPGES). High PGE2 levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE2 metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE2 biosynthesis are poorly understood. We demonstrate that expression of COX-1, generally considered constitutive, increases dramatically with lactogenic differentiation of the murine mammary gland. Concordantly, total PGE2 levels increase throughout mammary development, with highest levels measured in lactating tissue and breast milk. In contrast, COX-2 expression is extremely low, with only a modest increase detected during mammary involution. Expression of the G(s)-coupled PGE2 receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE2 production is dependent on COX-1, as PGE2 levels are nearly undetectable in COX-1-deficient mammary glands. Interestingly, PGE2 levels are similarly reduced in lactating glands of mPGES1-deficient mice, indicating that PGE2 biosynthesis results from the coordinated activity of COX-1 and mPGES1. We thus provide evidence for the first time of functional coupling between COX-1 and mPGES1 in the murine mammary gland in vivo.

Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80–77 kDa) in autoimmune human and NOD monocytes and activator STAT5A (96–94 kDa) and B (94–92 kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.

Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients

Objective To determine the capacity of human subchondral osteoarthritic osteoblasts (Ob) to produce interleukin (IL)-1β, IL-6, transforming growth factor-β (TGF-β) and prostaglandin E2 (PGE2), and determine if a relationship exists between IL-1β, TGF-β, PGE2 and IL-6 production.Methods We measured the abundance of IL-1β, IL-6, TGF-β and PGE2 using very sensitive ELISA in conditioned-media of human primary subchondral Ob from normal individuals and osteoarthritic patients. Selective inhibition of IL-6 or IL-6 receptor signaling was performed to determine its effect on PGE2 production whereas the inhibiton of PGE2 production was performed to determine its effect on IL-6 production. The expression of bone cell markers and urokinase plasminogen activator (uPA) activity was also determined.Results Osteoarthritic Ob produced all these factors with greater variability than normal cells. Interestingly, the production of IL-6 and PGE2 by osteoarthritic Ob separated patients into two subgroups, those whose Ob produced levels comparable to normal (low producers) and those whose Ob produced higher levels (high producers). In those cells classified as high osteoarthritic Ob, PGE2 and IL-6 levels were increased two- to three-fold and five- to six-fold, respectively, compared with normal. In contrast, while using their IL-6 and PGE2 production to separate osteoarthritic Ob into low and high producers, we found that IL-1β levels were similar in normal and all osteoarthritic Ob. Using the same criteria, TGF-β levels were increased in all osteoarthritic Ob compared with normal. Reducing PGE2 synthesis by Indomethacin [a cyclo-oxygenase (COX) -1 and -2 inhibitor] reduced IL-6 levels in all osteoarthritic Ob, whereas Naproxen (a more selective COX-2 inhbitor) reduced PGE2 and IL-6 levels only in the high osteoarthritic group. Conversely, PGE2 addition to osteoarthritic Ob enhanced IL-6 production in both groups. Moreover, the addition of parathyroid hormone also stimulated IL-6 production to similar normal levels in both osteoarthritic groups. In contrast, using an antibody against IL-6 or IL-6 receptors did not reduce PGE2 levels in either group. The evaluation of alkaline phosphatase activity, osteocalcin release, collagen type I and uPA activity in osteoarthritic Ob failed to show any differences between these cells regardless to which subgroup they were assigned.Conclusions These results indicate that IL-6 and PGE2 production by subchondral Ob can discriminate two subgroups of osteoarthritic patients that cannot otherwise be separated by their expression of cell markers, and that endogenous PGE2 levels influence IL-6 synthesis in osteoarthritic Ob. Copyright 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.

Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation.

The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized. Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1-EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE2 during an inflammatory process can modulate ensuing platelet responses.

The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines.

Cyclooxygenase (COX) is rate-limiting for arachidonic acid metabolism to the prostanoid family of eicosanoids. Some human breast cancers, notably those which are estrogen receptor (ER)-negative with high metastatic potential, produce high levels of prostaglandin E2 (PGE2). In some cell types, expression of the inducible COX-2 isoform occurred in association with a ras gene mutation. We determined COX-1 and COX-2 expression, and the corresponding PGE2 secretions, in 4 ER-negative human breast cancer cell lines, the MCF10A breast epithelial cell line, and the same non-cancerous line transfected with a mutated ras gene. The highly invasive MDA-MB-231 and Hs578T cancer cell lines, which possess a mutated Ki-ras and H-ras, respectively, expressed constitutive and inducible COX-2, and produced high PGE2 levels; the less invasive MDA-MB-435 and SK-BR-3 lines, without a mutated ras, possessed only low levels of COX-2, and secreted correspondingly low PGE2 levels. Similarly, the ras transfectant, but not parental MCF10A cells, expressed inducible COX-2. Chemosuppression with a selective COX-2 inhibitor may be effective only in that minority of breast cancers which have a mutated ras gene.

Muscarinic inhibition of substance P induced ion secretion in piglet jejunum

We examined the effects of the muscarinic agonist carbachol on ion secretion induced by substance P (SP) in piglet jejunal tissues mounted in Ussing chambers. Tetrodotoxin was present in all solutions to inhibit neural activity. Carbachol added 10 min prior to 0.75 microM SP dose dependently inhibited subsequent SP responses, with 90% inhibition at 10 microM carbachol. Addition of an equipotent dose of SP (7.5 microM) had no effect on subsequent carbachol-induced secretion. Carbachol's inhibition of SP-induced secretion was evident for at least 45 min and was abolished by prior addition of the M3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), but remained intact in the presence of the M2 antagonist gallamine or the nicotinic antagonist mecamylamine. Atropine added 10 min after carbachol restored subsequent SP responses toward control levels. Carbachol also reduced secretory responses to histamine and, to a lesser extent, prostaglandin E2 (PGE2). SP-induced secretion was not affected by prior addition of histamine and was reduced by PGE2 only at the highest PGE2 concentration. The results suggest that activation of the epithelial M3 receptor by carbachol inhibits subsequent secretory responses to the calcium-mediated agonists SP and histamine in piglet jejunum. This may reflect muscarinic activation of a negative messenger in epithelial cells that limits Cl- secretion.

Fetal sheep endocrine responses to sustained hypoxemic stress after chronic fetal placental embolization.

The purpose of this study was to determine the endocrine and circulatory responses of the ovine fetus, near term, to sustained hypoxemic stress superimposed on chronic hypoxemia. Fetal sheep were chronically embolized (n = 7) for 10 days between 0.84 and 0.91 of gestation via the descending aorta until arterial oxygen content was decreased by approximately 30%. Control animals (n = 8) received saline only. On experimental day 10, both groups were embolized over a 6-h period until fetal arterial pH decreased to approximately 7.00. Regional distribution of lower body blood flows was measured on day 10, before and at the end of acute embolization. On day 10, the chronically embolized group had lower arterial oxygen content (P < 0.05), Po2 (P < 0.01), and placental blood flow (P < 0.05) than controls and higher prostaglandin E2 (PGE2) and norepinephrine plasma concentrations (both P < 0.05). In response to a superimposed sustained hypoxemic stress, there was a twofold greater increase in PGE2 in the chronically embolized group than in the control group (P < 0.05). However, the increase in fetal plasma cortisol in response to superimposed hypoxemic stress was similar in both groups, despite significantly lower adrenocorticotropic hormone and adrenal cortex blood flow responses in the chronically hypoxemic group (both P < 0.05). We conclude that PGE2 response to a sustained superimposed reduction in placental blood flow, leading to metabolic acidosis, is enhanced under conditions of chronic hypoxemia and may play an important role for the maintenance of the fetal cortisol response to an episode of superimposed acute stress.

Synergism between prostaglandin E2 and isoproterenol in stimulating glucose oxidation in the heart.

The increase in cardiac contractile function following adrenergic stimulation is accompanied by increased glucose metabolism. Since prostaglandin E2 (PGE2) can internalize beta-receptors, we determined what effects PGE2 and isoproterenol have on glycolysis and glucose oxidation in the isolated working rat heart. All hearts were perfused with Krebs-Henseleit buffer containing 11 mM [5-3H, 14C(U)]glucose, 100 microU/mL insulin, and 3% albumin. In the presence of 0.4 mM palmitate and 1.25 mM free Ca2+, isoproterenol (3 x 10(-8) M) increased the heart rate x peak systolic pressure product from 27 +/- 1 to 43 +/- 1 mmHg.beats.min-1.10(3) (1 mmHg = 133.3 Pa). This was accompanied by an increase in glycolytic rates from 3564 +/- 231 to 7775 +/- 475 nmol.g-1 dry weight min-1 and an increase in glucose oxidation from 930 +/- 72 to 2591 +/- 239 nmol.g-1 dry weight.min-1. Addition of PGE2 (10(-9) M) did not affect the isoproterenol stimulation of glycolysis, but caused a further increase in glucose oxidation (to 3863 +/- 495 nmol.g-1 dry weight.min-1). In the absence of isoproterenol, 10(-9) M PGE2 had no effect on either glycolysis or glucose oxidation. When perfusate [Ca2+] was raised to 2.5 mM, a significant increase in glycolysis was seen in control hearts (from 3564 +/- 231 to 5679 +/- 374 nmol.g-1 dry weight.min-1). The effects of isoproterenol and PGE2 on glucose metabolism remained, although the synergistic effects of PGE2 on glucose oxidation were less dramatic. When 1.2 mM palmitate was present in hearts perfused with 2.5 mM Ca2+, a decrease was seen in both glycolysis (from 5679 +/- 374 to 3027 +/- 346 nmol.g-1 dry weight.min-1) and glucose oxidation (from 1056 +/- 170 to 221 +/- 29 nmol.g-1 dry weight.min-1). Even at this high concentration of fatty acid, isoproterenol stimulated glucose oxidation (from 221 +/- 29 to 859 +/- 69 nmol.g-1 dry weight min-1), and addition of PGE2 resulted in a significant further increase (1021 +/- 139 nmol.g-1 dry weight.min-1). These data demonstrate that concentrations of PGE2 that bind to the high affinity cardiac PGE2 receptor have no effect on glucose metabolism in the absence of beta-agonists. In the presence of isoproterenol, which dramatically stimulates both glycolysis and glucose oxidation, PGE2 has a synergistic effect on glucose oxidation at lower fatty acid concentrations. These findings suggest that PGE2 receptors in the heart function to potentiate rather than decrease beta-adrenergic stimulation of glucose metabolism.

Increased Thromboxane B&lt;sub&gt;2&lt;/sub&gt; and Prostaglandin E&lt;sub&gt;2&lt;/sub&gt; Levels Precede Clinical Acute Respiratory Distress Syndrome after Esophageal Resection

The acute respiratory distress syndrome (ARDS) is a frequent, nonsurgical complication after esophageal resection, and requires immediate counter measures. We recently described the time course of ARDS after esophageal resection as being clinically very consistent, with a peak of pulmonary edema on postoperative day 5. In the present study, we investigated the time course of ARDS mediators such as thromboxane B2 (TxB2), prostaglandin E2 (PGE2) and endotoxin in the central venous and arterial blood of patients who had undergone esophagectomy and subsequently developed ARDS. Serum PGE2 levels in control patients were 3.2 ± 5.9 ng/ml, and 10.5 ± 6.3 ng/ml in patients who developed ARDS, with a trend towards higher PGE2 levels in ARDS patients early postoperatively. TxB2 levels ranged between 0.9 and 1.4 ng/ml in ARDS as well as control patients during the intraoperative course and the first 2 postoperative days, with a trend towards higher peripheral TxB2 levels in ARDS patients. This study provides evidence that PGE2 and TxB2 start to increase in parallel with the rise in pulmonary effusions seen on the chest X rays of patients who develop the clinical picture of ARDS.

The effect of morphine on formalin-evoked behaviour and spinal release of excitatory amino acids and prostaglandin E2 using microdialysis in conscious rats.

1. In the present study, the object was to examine the effects of morphine on spinal release in vivo of excitatory amino acids (EAA), prostaglandin E2 (PGE2), and a marker for nitric oxide (NO) synthesis, citrulline (Cit), evoked by a protracted noxious stimulus produced by the injection of formalin into the paw. Spinal release was monitored in conscious rats using a microdialysis probe implanted into the subarachnoid space with the active site placed at the level of the lumbar enlargement. In split dialysate samples. EAAs were measured by high performance liquid chromatography (h.p.l.c.) and PGE2 was determined by radioimmunoassay. 2. Resting concentrations in nmol ml-1 for the amino acids (mean +/- s.e.mean, n = 21) were: 4.8 +/- 0.4 for glutamate (Glu), 0.8 +/- 0.1 for aspartate (Asp), 8.8 +/- 0.8 for taurine (Tau), 24 +/- 3 for glycine (Gly), 19 +/- 3 for serine (Ser), 5.2 +/- 0.8 for asparagine (Asn), 64 +/- 4 for glutamine (Gln) and 5.2 +/- 0.4 for Cit. Mean basal release for PGE2 was 12 +/- 1 pmol ml-1. 3. Subcutaneous (s.c.) injection of 5% formalin evoked a biphasic flinching behaviour (phase 1: 0-9 min and phase 2: 10-60 min) of the injected paw. Corresponding to phase 1 behaviour, there was a significant increase (50-100%) in spinal levels of Glu, Asp, Tau, Gly, Cit and PGE2, but not Ser, Asn and Gln. A significant (P < 0.01) second phase increase in release was observed only for Cit and PGE2. However, Glu and Asp levels were increased by approximately 45%. 4. Injection of morphine sulphate (3 mg kg-1, s.c.) had no effect on resting release, but produced a significant suppression of the formalin-evoked behaviour and release of Glu, Asp, Tau, Gly, Cit and PGE2. The effect of morphine was reversed by pretreatment with 1 mg kg-1 naloxone. Naloxone by itself did not change the release or behaviour of the formalin test.5. This study demonstrates that both spinal EAA and PGE2 release patterns correlate with behavioural nociceptive responses in the formalin test and that morphine suppresses the formalin-evoked behaviours and spinal release. The reversal by naloxone of the morphine effect indicates mediation via an opioid receptor.

Anti-inflammatory activity of the leukotriene B4 receptor antagonist, SC-41930, in colitic cotton-top tamarins

Cotton-top tamarins (CTTs) with histologically confirmed persistent and active colitis were given the leukotriene B4 (LTB4) receptor antagonist, SC-41930, (10 mg/kg BW, by gavage b.i.d.) for eight weeks. Anti-inflammatory activity was evaluated by colonic biopsy, stool consistency and the level of the lipid mediators LTB4 and prostaglandin E2 (PGE2) in rectal dialysates. Stool consistency did not improve with treatment but did not worsen. Blood chemistry (ALT, AST, LDH) and hematological parameters neither showed any untoward effects of SC-41930 treatment nor was there any effect on body weight. In rectal dialysate LTB4 levels were significantly reduced from pretreatment level of 4.87±1.46 ng/ml to 1.07±0.67 and 2.45±0.13 ng/ml at 4 and 8 weeks, respectively, and higher prostaglandin E2 (PGE2) over time. Histologically, 5/7 improved, 1/7 remained the same and 1/7 worsened. Oral SC-41930 treatment was safe and associated with an anti-colitic effect. The reduced LTB4 levels (affecting granulocyte degranulation and recruitment into tissues) and increased PGE2 (perhaps exerting a mucosal protective effect) may, in part explain the observed efficacy of this compound in active tamarin colitis. Use of the CTT model could provide insight into the inflammatory mediator contribution to idiopathic colitis and serve as a useful bridge between preclinical pharmacology and the assessment of these compounds in the medical management of human inflammatory bowel disease.

Cerebrospinal Fluid lnterleukin-6, Prostaglandin E2 and Autoantibodies in Patients with Neuropsychiatric Systemic Lupus Erythematosus and Central Nervous System Infections

Cerebrospinal fluid (CSF) from patients with a variety of central nervous system (CNS) disorders was assayed for cytokines, prostaglandins, and autoantibodies. CSF interleukin-6 (IL-6) in patients with CNS infection (374.24 +/- 92.61 pg/mL) and neuropsychiatric systemic lupus erythematosus (NP-SLE) (71.40 +/- 5.89 pg/mL) were significantly higher than in patients with CNS inflammation (33.92 +/- 29.36 pg/mL) or controls (non-inflammatory CNS diseases) (4.35 +/- 3.00 pg/mL). Interleukin-1 beta, interferon alpha, and tumor necrosis factor alpha were undetectable in these samples: CSF prostaglandin E2 (PGE2) also exhibited similar patterns as IL-6. CSF immunoglobulin G (IgG) in patients with NP-SLE (8.84 +/- 1.80 mg/dL) was much higher than in patients with CNS infection (4.65 +/- 3.09 mg/dL), CNS inflammation (2.54 +/- 1.24 mg/dL), or controls (2.11 +/- 1.03 mg/dL). CSF autoantibodies against calf thymus antigens were present in patients with NP-SLE but not in patients with CNS infection as demonstrated by immunoblot. These results suggest that high IL-6 and PGE2 in CSF favors the diagnosis of CNS infection, while modestly elevated IL-6, high IgG, and autoantibodies against calf thymus antigens in CSF are the features of NP-SLE.

Isolated pulmonary infection acts as a source of systemic tumor necrosis factor

To investigate the local secretion of tumor necrosis factor (TNF) in the lung as a source for systemic TNF. Prospective, randomized experimental trials. Laboratory. Hartley guinea pigs. Female guinea pigs were challenged intratracheally with 10(3) to 10(9) Escherichia coli. Two and eight hrs after the bacterial challenge, colony-forming units of bacteria in the lung and blood, TNF and prostaglandin E2 (PGE2) in the bronchoalveolar lavage fluid, and serum TNF concentrations were determined. At the same time, alveolar macrophages were harvested and cultured in vitro, and TNF and PGE2 secretions were measured. TNF and PGE2 concentrations were either not detected in bronchoalveolar lavage fluid or were found in very low levels in control animals. High concentrations of TNF and PGE2, however, were found in bacteria-challenged animals. Two hours after inoculation of bacteria, TNF in the bronchoalveolar lavage fluid had a significant correlation with TNF values in the serum. The TNF concentration in aortic blood was significantly higher than TNF concentration in right atrial blood. For comparable inocula, TNF in the bronchoalveolar lavage fluid after 8 hrs was significantly lower than at 2 hrs, but PGE2 levels remained high. Lipopolysaccharide-stimulated alveolar macrophage secretion of TNF in vitro was depressed in animals with high PGE2 levels in bronchoalveolar lavage fluid and high numbers of viable bacteria in the lungs. During pulmonary Gram-negative infection, the lungs may be a major source of TNF in the blood. The magnitude of TNF secretion by the lungs is highly dependent on the intensity of infection during its early stages. By 8 hrs after onset of infection, TNF secretion appears to downregulate, possibly by endogenous PGE2.

Macrophage function in response to PGE2, L-arginine deprivation, and activation by colony-stimulating factors is dependent on hematopoietic stimulus.

Different macrophage preparations were compared for functional capacity in conditions of high prostaglandin E2 (PGE2) or low L-arginine concentrations. Macrophages derived in vitro from bone marrow progenitor cells (bone marrow-derived macrophages, BMDMs) using colony-stimulating factor 1 (CSF-1) as the myelopoietic stimulus displayed a greater sensitivity to PGE2-induced suppression of tumor necrosis factor alpha (TNF-alpha) secretion than did macrophages derived using granulocyte-macrophage colony-stimulating factor (GM-CSF). Neither BMDM population was inhibited by PGE2 for the direct cytolysis of L929 cells (TNF-alpha sensitive), and only GM-CSF-derived macrophages showed decreased killing of TNF-alpha-resistant K562 targets. Exogenous cAMP inhibited TNF-alpha secretion, but not nitrite secretion, by both BMDM populations. GM-CSF-derived macrophages accumulated less cAMP following PGE2 treatment than did CSF-1-derived macrophages. Removing L-arginine from the medium did not inhibit cytotoxicity or PGE2 secretion, but the listeriacidal activity specific to interferon-gamma plus lipopolysaccharide (LPS)-activated GM-CSF-derived macrophages was blocked by removal of L-arginine. Treatment with CSF-1 or GM-CSF alone did not activate the macrophages, but GM-CSF efficiently primed both BMDM populations for augmented TNF-alpha secretion in response to secondary stimulation using LPS. However, GM-CSF augmented the LPS-induced production of nitrite and PGE2 by CSF-1-derived macrophages only. These results demonstrate the potential for differential macrophage function within inflammatory sites based on the hematopoietic stimulus under which the macrophage is derived and the specific conditions present in the lesion.

Elevated plasma prostaglandin E2 levels in schizophrenia.

Plasma levels of prostaglandin E2 (PGE2) were determined with radioimmunoassay in 40 DSM-III schizophrenics, 15 patients with other mental disorders, and 23 normal controls. The mean value of plasma immunoreactivity of PGE2 was significantly higher in the schizophrenic patients than in the normal controls. Schizophrenic patients with high plasma PGE2 levels had more guilt feelings and hallucinatory behavior on BPRS, relatively successful heterosexual relations, and a higher incidence of birth complications.

Longterm olsalazine treatment: pharmacokinetics, tolerance and effects on local eicosanoid formation in ulcerative colitis and Crohn's colitis.

To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.

Formation of a synovial-like membrane at the bone-cement interface. Its role in bone resorption and implant loosening after total hip replacement.

Histologic evaluation of tissue surrounding the loosened components after joint replacement reveals the presence of a synovial-like lining adjacent to the polymethyl methacrylate cement. The tissue is heavily infiltrated with particulate cement as well as polyethylene associated with a foreign body-type giant cell reaction. That this tissue response may be responsible for the bone lysis associated with loosening is suggested by the demonstration of high prostaglandin E2 levels and enhanced bone resorbing activity in the tissue culture medium of fragments from this membrane.

Plastic filing from dialysis tubing induces prostanoid release from macrophages

Multiorgan, abnormalities in dialysis patients (for example, hepatosplenomegaly, granulomatous hepatitis, cytopenia from hypersplenism) have recently been ascribed to the loading of macrophages (MO) with silicone particles released from the pump segment of dialysis tubing. In the present study, the effect of chronic intravenous or intraperitoneal loading of rats with silicone, polyvinylchloride (PVC) and polyurethane (PU) particles on arachidonic acid metabolism of peritoneal MO and splenic cells was examined in vitro. Intravenous injections of silicone, PVC, or PU particles caused accumulation of the material within the lysosomes of MO of spleen, liver, and lung. Spontaneous release of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was significantly increased in peritoneal MO of rats injected with silicone, PVC, or PU (Control: 4.27 +/- 0.85 ng PGE2/ml/24 hr; silicone 51.9 +/- 13.2; PVC 57.5 +/- 10.6; PU 28.8 +/- 2.3). Zymosan or LPS stimulated PGE2 release from control MO, but caused no consistent further elevation of high basal PGE2 release from MO after particle loading. Furthermore, increased spontaneous and stimulated TXB2 release was also observed in spleen cells of rats given intravenous injection of silicone particles. It is concluded that storage of plastic particles (silicone, PVC, and PU) by macrophages stimulates arachidonic acid metabolism.