Prostaglandin E2 and phagocytosis of inhaled particulate matter by airway macrophages in cystic fibrosis

BackgroundExposure to particulate matter (PM) air pollution is associated with adverse health outcomes in children with cystic fibrosis (CF). Airway macrophages (AM) phagocytose and retain inhaled PM in vivo, and the area of carbon in AM reflects both inhaled PM dose and phagocytic function. Since airway prostaglandin-E₂ (PGE₂) is increased in CF, and PGE₂ suppresses AM phagocytosis, we sought evidence for PGE₂-mediated suppression of AM phagocytosis of inhaled carbonaceous PM in CF.MethodsAfter informed consent, urine was obtained from 20 controls and 24 CF children. In the subgroup of older children, at least one induced sputum was done in 20 controls and 19 CF children. Urinary tetranor PGEM, the major metabolite of PGE₂, and sputum PGE₂ were measured by mass spectrometry. The area of carbon in AM was determined by image analysis. Exposure to PM was assessed by modelling and personal monitoring. The effect of either PGE₂ or CF sputum supernatant on phagocytosis of diesel exhaust particle (DEP) by AM was assessed in vitro. Data were analysed by t-test.ResultsBoth urinary tetranor PGEM (P<0.05), and sputum PGE₂ (P<0.05) were increased in CF . Despite no difference in PM exposure between groups, the area of phagocytosed carbon by AM was decreased in children with CF (P<0.01). PGE₂ suppressed phagocytosis of DEP by AM from both controls and CF (P<0.0001). CF sputum supernatant suppressed phagocytosis of DEP by AM (P<0.0001) in a PGE₂-dependent manner.ConclusionIncreased PGE₂ in the CF airway suppresses phagocytosis of inhaled PM by AM.     

Prostaglandin E2 in pyloric stenosis

Prostaglandins are presumed to have many cytoprotective properties that play a role in the pathogenesis of duodenal ulcer and its complications where decreased levels of prostaglandin E2 (PGE2) impair gastric motility, oppose ionic membrane influx, and enhance obstructive changes. These are just some of the mechanisms that may cause pyloric obstruction and may result from decreased PGE2 levels. To evaluate this hypothesis, 17 patients with duodenal ulcer complicated by pyloric stenosis were examined. Biopsy specimens were obtained from the duodenal bulb, ulcer margins, gastric antrum, fundus, and gastric secretions. Prostaglandin E2 levels were measured and compared with those taken from the same areas during a second endoscopy in a later quiescent or exacerbated phase. During the active phase of pyloric stenosis, decreased levels of PGE2 were found in the gastroduodenal tissues and secretions were compared with levels found during convalescence. These level differences were statistically significant. A correlation between the severity of the clinical and endoscopic findings and the PGE2 levels was found. A further decrease in PGE2 levels in the second endoscopy were indicative of the presence of scar tissue, representing an irreversible obstructive peptic disease.     

Prostaglandin E2 in renal transplant recipients

The concentrations of prostaglandin E₂ (PGE₂), sodium, potassium and creatinine were determined in the blood and urine of 50 renal transplant recipients treated with cyclosporine A or azathioprine, as immunosuppressive agents, for at least one year post transplantation. Fourteen healthy subjects served as control group. The urinary PGE₂ excretion was significantly decreased in all treated renal transplant recipients and this reduction was associated with significant decrease in urinary excretion of sodium and potassium. On the other hand, a high elevation in blood PGE₂ concentration was observed while no significant changes were seen in sodium and potassium levels in the blood of these renal transplant recipients. The observations suggest an association between urinary PGE₂ reduction and immunosuppressive treatments in renal transplant recipients; also, PGE₂ may regulate intra-renal haemodynamics and influence the renal tubular electrolyte excretion. Moreover, urinary PGE₂ can be used as an indicator of successful renal transplantation.     

Prostaglandin E2 production during hepatic regeneration downregulates Kupffer cell IL-6 production.

The liver possesses the remarkable ability to regenerate to its original size after a 70% partial hepatectomy. There has been little effort to characterize the Kupffer cells' role in this unique mammalian reparative physiologic phenomenon. The capacity of rat Kupffer cells (KC) isolated at specific intervals after partial hepatectomy to produce interleukin-6 (IL-6) and prostaglandin E2 (PGE2) in response to endotoxin was evaluated in standard RPMI-1640 (1200 microM L-arginine) and arginine-depleted RPMI-1640 (10 microM L-arginine) media. Regenerating liver KC 48 to 120 hours after partial hepatectomy responded to endotoxin stimulation with a significantly greater (p less than 0.05) production of IL-6 in standard RPMI-1640. Because Kupffer cells function in an environment where high arginase activity results in negligible L-arginine levels, the 10 microM L-arginine RPMI-1640 was used to simulate the true hepatic microenvironment. Production of IL-6 by regenerating liver KC was further increased (p less than 0.05) by placing these same KC in 10 microM L-arginine RPMI-1640 tissue culture media. During the same period, regenerating liver KC produced significantly (p less than 0.01) more PGE2 than sham-operated KC in both standard and low-arginine media. When the cyclo-oxygenase inhibitor indomethacin (1 x 10(-5) M) was added to cultures, the PGE2 production was inhibited, and IL-6 production was upregulated (p less than 0.05) in arginine-depleted cultures. The authors conclude that during hepatic regeneration KC IL-6 production is elevated but controlled in an autoregulatory fashion by KC PGE2 production.     

Prostaglandin E2 is raised in kwashiorkor.

OBJECTIVE: Infection is a common occurrence in children with kwashiorkor. It has been suggested that infection in kwashiorkor results from immune depression, and that the immune depression of kwashiorkor is caused by a diet-associated elevation of prostaglandin E2 (PGE2). The purpose of this study was to determine whether levels of PGE2 are abnormal in children with kwashiorkor. SETTING AND SUBJECTS: Plasma PGE2 and plasma proteins were measured in children admitted with oedematous kwashiorkor, and compared with PGE2 in children with cerebral palsy. RESULTS: Plasma PGE2 was higher in children with kwashiorkor than in control children (7.25 +/- 3.5 v. 3.51 +/- 1.59, P < 0.01). Within the kwashiorkor study group there was a significant negative correlation between log-transformed serum PGE2 and total plasma protein (r = -0.59, P < 0.001), plasma albumin (r = -0.63, P < 0.001), weight-for-age (r = -0.37, P < 0.05), and height-for-age (r = -0.37, P < 0.05). The difference in mean values of PGE2 in children with kwashiorkor who recovered from the illness and those who died was not significant (7.1 +/- 2.6 v. 9.1 +/- 4.8, P = 0.36). CONCLUSION: Significantly higher PGE2 levels in children with kwashiorkor provide adequate reason for the depression of immune function known to occur in these children. Elevated PGE2 levels may also be implicated in other components of the illness.     

Prostaglandin E2 promotes hypotension on low-sodium hemodialysis

The influence of low-sodium dialysate (126 mmol/l) on plasma levels of prostaglandin E2 (PGE2) and PGF2 alpha, plasma renin activity (PRA) and arterial blood pressure was investigated in 16 patients on maintenance hemodialysis. PGE2 rose more than tenfold and there was a significant increase in PGF2 alpha and PRA. Mean arterial pressure dropped by 30 mm Hg causing discomfort in several patients. By contrast, conventional hemodialysis against 140 mmol/l of sodium was followed by less pronounced changes in plasma prostaglandins, and reduction of blood pressure was moderate (13 mm Hg). It is suggested that vasodilating prostaglandins may contribute to dialysis hypotension. Their origin may not be confined to the kidneys but rather extend to the lungs and circulating blood cells. The in vitro generation of prostaglandins was demonstrated when donor blood was circulated in an extracorporeal dialysis system.     

Prostaglandin E2 in prostatitis and prostatic adenoma

The measurement of prostaglandin E2 (PGE2) concentrations in the serum and prostatic fluid of healthy men, patients with prostatic hyperplasia and of patients with prostatitis was attempted and correlated to the state of disease, respectively. PGE2-concentrations with prostatic fluid of healthy men were found to be significantly lower than in patients with prostatitis. Corresponding to the course of treatment concentrations normalized, being favorably influenced by sitosterin as an adjuvant medication. Compared to healthy men, PGF2 concentrations in the prostatic fluid of patients with hyperplasia of the prostate incline to lower levels.     

Prostaglandin E2 in duodenal ulcer complications.

Prostaglandins are presumed to have cytoprotective properties and may play a role in the pathogenesis of duodenal ulcer and its complications. To evaluate this hypothesis, 35 patients with either duodenal ulcer bleeding (18 patients) or gastric outlet obstruction (17 patients) were investigated. Biopsies were taken from gastroduodenal tissues and secretions for prostaglandin E2 (PGE2) levels. These levels were compared to those taken from the same areas during a later endoscopy. A correlation was found between the severity of the clinical endoscopic findings and PGE2 levels. Increased levels of PGE2 were found in the quiescent phase and decreased levels found during the deteriorated phase. These differences of PGE2 levels were found to be of significant value (P less than 0.002). Furthermore, the patients in which the PGE2 levels were decreased at second endoscopy needed surgery. PGE2 may, thus, be a factor in duodenal ulcer pathogenesis and its complications, and be used as a prognostic marker and guide.     

Prostaglandin E2 metabolite levels during diabetic ketoacidosis

Insulin therapy was withdrawn from 15 well-controlled type I diabetic subjects for no longer than 18 h to examine the sequence with which 13,14-dihydro-15-keto-PGE2 (PGE-m), glucagon, norepinephrine, and epinephrine increased in circulating blood in diabetic subjects becoming ketoacidotic. Fourteen of 15 patients had increments in PGE-m; 12/12, 12/15, and 13/15 had increments in glucagon, norepinephrine, and epinephrine, respectively. Six of the 15 patients developed mild diabetic ketoacidosis (DKA) by 12-18 h; all had nonmeasurable C-peptide levels. This DKA group had significantly greater increments of PGE-m (835 +/- 130 versus 276 +/- 111 pg/ml, mean +/- SEM, P less than 0.01) but not glucagon, norepinephrine, or epinephrine compared with the 9 non-DKA patients. In the DKA group, there were significant PGE-m and glucagon increments in the circulation by 3 h, significant norepinephrine increments by 9 h, and epinephrine increments in 5/6 patients by 12 h (not statistically significant) of insulin withdrawal. These studies document that (1) PGE-m accumulates in the circulation during DKA, (2) PGE-m and glucagon increase before catecholamines, and (3) PGE-m, glucagon, and catecholamine levels promptly return to normal levels when insulin therapy is reinstituted. It is suggested that elevated PGE-m levels early in the onset of DKA may represent a host-defense mechanism.     

Prostaglandin E2 activity in the synovial-like membrane

The events leading to aseptic loosening of total hip prostheses occur within the synovial-like membrane that forms around the prosthetic components. Prostaglandin E₂ (PGE₂) activity in this membrane is believed to be one of the factors that cause aseptic loosening. In this study, the authors investigated the correlation between grades of loosening and levels of PGE₂-like activity in the membranes surrounding the implants in 14 patients in which total hip arthroplasty revisions were performed. The membranes of patients with high degrees of loosening demonstrated high levels of PGE₂-like activity (P < .01). Among the many factors contributing to loosening of total hip arthroplasties, PGE₂ appears to have an important role with its bone-resorbing properties.     

Prostaglandin E2 prevents disuse-induced cortical bone loss.

The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloaded)-induced cortical bone loss as well as add extra bone to underloaded bones. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to simultaneous right hindlimb immobilization by bandaging and daily subcutaneous doses of 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). Disuse-induced cortical bone loss occurred by enlarging the marrow cavity and increasing intracortical porosity. PGE2 treatment of disuse shafts further increased intracortical porosity above that in disuse alone controls. This bone loss was counteracted by enhancement of periosteal and corticoendosteal bone formation. Stimulation of periosteal and corticoendosteal bone formation slightly enlarged the total tissue (cross-sectional) area and inhibited marrow cavity enlargement. These PGE2-induced activities netted the same percentage of cortical bone with a different distribution than the beginning and age-related controls. These findings indicate the PGE2-induced increase in bone formation compensated for the disuse and PGE2-induced bone loss, and thus prevented immobilization-induced bone loss.     

Abrogation of epidermal antigen-presenting cell function by ultraviolet radiation administered in vivo

The exposure of animals to ultraviolet radiation (UVR) can result in dramatic alterations to their immunologic potential. Loss of ability to be contact-sensitized to skin-reactive chemicals applied to UVR-exposed surfaces, and an enhanced susceptibility to tumors induced by UVR represent two well-documented effects of such exposure. The skin Langerhans' cell (LC) is a cell type, having antigen presentation capabilities, which is functionally inactivated by UVR. The localized loss in the ability to induce a contact hypersensitivity (CS) response and the early events associated with the acquisition of a tumor-susceptible state have been hypothesized to involve LC inactivation by UVR. In this report we have investigated the relationship between the UVR-mediated loss of CS responsiveness and antigen-presenting cell (APC) function by LC following in vivo exposure of animals to UVR. The UVR-mediated loss of CS responsiveness was found to be both time-dependent and dosage-dependent, but the loss of epidermal APC function following the UVR exposure of dissociated epidermal cells or skin was immediate and dosage-dependent. The lack of time dependency associated with the loss of epidermal APC function may be due to the nature of the assay system being employed. Add-back experiments, using the proliferation of purified antigen-primed T-cells as a read-out system to evaluate APC function, require that the accessory cell be totally functional. Initiation of CS responses may still be possible, however, with LC that are partially UVR-inactivated. Lymph-node-associated and circulating accessory cells could be integrated into the response, providing any necessary components that the UV-inactivated LC lacks. We tested this possibility and conclude from these studies that this is indeed a viable possibility. Our results, therefore, provide a possible explanation for apparent differences in LC UVR susceptibility observed when in vitro and in vivo assays are employed.     

Impairment of antigen-presenting cell function by ultraviolet radiation. II. Effect of in vitro ultraviolet irradiation on antigen-presenting cells

The s.c. injection of 10 mM 2,4,6-trinitrobenzene sulfonic acid (TNBS) derivatized splenic adherent cells (SACs) into syngeneic mice primes for contact sensitivity or delayed-type hypersensitivity (DTH) when these animals are challenged with picryl chloride on the ear or trinitrophenol (TNP)-coupled cells in the footpad, respectively. If recipient mice are exposed to ultraviolet light (UV) irradiation and are immunized with normal TNP-treated SACs, they develop marked DTH reaction upon challenge but develop limited DTH reactions if immunized with hapten-derivatized SACs that had been obtained from UV-treated recipients. Moreover, if the SACs are obtained from normal mice but are treated in vitro with UV light (1.2 to 1.4 mJ/cm2/sec over the wavelength range 280 to 340 nm at a tube to target distance of 20 cm) these cells can neither prime nor elicit hapten-specific T cell immunity in UV-treated recipients. If UV-treated TNP SACs are used to prime UV-irradiated recipients, TNP-specific suppressor T cells are generated rather than T effector cells.     

Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturation

While cyclooxygenases are important in endochondral bone formation during fracture healing, mechanisms involved in prostaglandin E2 (PGE2) regulation of chondrocyte maturation are incompletely understood. The present study was undertaken to determine if PGE2 effects on chondrocyte differentiation are related to modulation of the bone morphogenetic protein (BMP) signaling pathway. In primary murine sternal chondrocytes, PGE2 differentially regulated genes involved in differentiation. PGE2 induced type II collagen and MMP-13, had minimal effects on alkaline phosphatase, and inhibited the expression of the maturational marker, type X collagen. In BMP-2–treated cultures, PGE2 blocked the induction of type X collagen. All four EP receptors were expressed in chondrocytes and tended to be inhibited by BMP-2 treatment. RCJ3.1C5.18 chondrocytes transfected with the protein kinase A (PKA) responsive reporter, CRE-luciferase, showed luciferase induction following exposure to PGE2, consistent with activation of PKA signaling and the presence of the EP2 and EP4 receptors. Both PGE2 and the PKA agonist, dibutyryl cAMP, blocked the induction of the BMP-responsive reporter, 12XSBE, by BMP-2 in RCJ3.1C5.18 chondrocytes. In contrast, PGE2 increased the ability of TGF-β to activate the TGF-β-responsive reporter, 4XSBE. Finally, PGE2 down-regulated BMP-mediated phosphorylation of Smads 1, 5, and 8 in RCJ3.1C5.18 cells and in primary murine sternal chondrocytes. Altogether, the findings show that PGE2 regulates chondrocyte maturation in part by targeting BMP/Smad signaling and suggest an important role for PGE2 in endochondral bone formation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 785–792, 2009     

Differential Expression of Prostaglandin E2 Receptors in Porcine Kidney Transplants

BackgroundAcute rejection of a kidney allograft results from adaptive immune responses and marked inflammation. The eicosanoid prostaglandin E2 (PGE2) modulates the inflammatory response, is generated by cyclooxygenase 2 (COX-2), and binds to 1 of the 4 G protein-coupled E prostanoid cell surface receptors (EP1-4). Receptor activation results in in proinflammatory (EP1 and EP3) or anti-inflammatory (EP2 and EP4) responses. We theorized that expression of the components of the COX-PGE2-EP signaling pathway correlates with acute rejection in a porcine model of allogeneic renal transplantation.MethodCOX-2 enzyme and EP receptor protein expression were quantitated with western blotting and immunohistochemistry from allotransplants (n = 18) and autotransplants (n = 5). Linear regression analysis was used to correlate EP receptor expression with the Banff category of rejection.ResultsPigs with advanced rejection demonstrated significant increases in serum PGE2 metabolites, while pigs with less rejection demonstrated higher tissue concentrations of PGE2 metabolites. A significant negative correlation between COX-2 expression and Banff category of rejection (R = ?0.877) was shown. Rejection decreased expression of EP2 and EP4. For both receptors, there was a significant negative correlation with the extent of rejection (R = ?0.760 and R = ?0.891 for EP2 and EP4, respectively). Rejection had no effect on the proinflammatory receptors EP1 and EP3.ConclusionDownregulation of COX-2 and the anti-inflammatory EP2 and EP4 receptors is associated with acute rejection in unmatched pig kidney transplants, suggesting that the COX-2-PGE2-EP pathway may modulate inflammation in this model. Enhancing EP2 and/or EP4 activity may offer novel therapeutic approaches to controlling the inflammation of acute allograft rejection.     

Effect of Local Prostaglandin E2 on Fracture Callus in Rabbits

We investigated the effect of local infusion with prostaglandin E₂ (PGE₂) in doses of 0.0003 to 4.0 mg/hour per kg body weight for 6 weeks on a plated unilateral osteotomy in rabbits. PGE₂ caused a dose-dependent stimulation of callus formation. Total bone mineral content increased, although the mineral content per volume of the callus was reduced. In another experiment, PGE₂ was infused either in the first half or in the second half of the healing period. No effect of PGE₂ infusion could be observed in the first half of the 6-week healing period, whereas PGE₂ infusion during the second half caused callus stimulation.     

Laparoscopic insufflation of the abdomen depresses cardiopulmonary function

Summary Recently we have used the laparoscope to remove the gallbladder in critically ill patients in order to spare them the operative trauma of laparotomy. However, increased intraperitoneal pressure may have deleterious cardiopulmonary effects. This was investigated in a dog model. Insufflation of the abdomen with carbon dioxide decreased the mean cardiac output to less than 80% of baseline (P<0.004). This was aggravated by the reverse Trendelenburg position and partially alleviated by the Trendelenburg position. Mean arterialPCO₂ and mean peak airway pressure significantly rose. These effects are of doubtful clinical significance in the majority of patients. However, to extend the benefits of laparoscopy to patients with decreased cardiopulmonary reserve, hemodynamic and carbon dioxide monitoring should be used because measures to improve venous return, augment cardiac output, and counteract the increase inPCO₂ and peak airway pressure may be required.Presented at the Society of American Gastrointestinal Endoscopic Surgeons, April 11, 1992, Washington DC