prostaglandin-d2 and Hypoxia

Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, whereas the second was placebo aspirin swallowed with a pill. Both placebos were given after a conditioning procedure, whereby either real oxygen or real aspirin was administered for three consecutive sessions to reduce headache pain. We found that after real oxygen conditioning, placebo oxygen induced pain relief along with a reduction in ventilation, blood alkalosis and salivary prostaglandin (PG)E2, yet without any increase in blood oxygen saturation (SO2). By contrast, after real aspirin conditioning, placebo aspirin induced pain relief through the inhibition of all the products of cyclooxygenase, that is, PGD2, PGE2, PGF2, PGI2, thromboxane (TX)A2, without affecting ventilation and blood alkalosis. Therefore, two different placebos, associated to two different therapeutic rituals, used two different pathways to reduce headache pain. The analgesic effect following placebo oxygen was superior to placebo aspirin. These findings show that different placebos may use different mechanisms to reduce high altitude headache, depending on the therapeutic ritual and the route of administration. In clinical trials, placebos and outcome measures should be selected very carefully in order not to incur in wrong interpretations.

Topics: Adult; Dinoprost; Dinoprostone; Epoprostenol; Female; Headache; Humans; Hypoxia; Male; Oxygen; Prostaglandin D2; Thromboxane A2

Endothelin-1 (ET-1) is a potent stimulus for the secretion of atrial natriuretic peptide (ANP) and hypoxia stimulates the release of ET-1, which is involved in the regulation of atrial ANP secretion. However, the precise mechanism of endogenous ET-1 in the regulation of hypoxia-induced ANP secretion is unclear. Therefore, this study aimed to investigate the mechanism of hypoxia-induced endogenous ET-1 regulation of ANP secretion in isolated perfused hypoxic beating rat atria. The results of this study showed that acute hypoxia significantly stimulated ET-1 release and upregulated the expression of its type A as well as type B receptors (ETA and ETB receptors). Endogenous ET-1 induced by hypoxia markedly upregulated the expression of cyclooxygenase 2 (COX2) through activation of its two receptors, leading to an increase in lipocalin-type prostaglandin D synthase (L-PGDS) expression and prostaglandin D2 (PGD2) production. L-PGDS-derived PGD2 activated peroxisome proliferator-activated receptor γ (PPARγ), ultimately promoting hypoxia-induced ANP secretion. Conversely, L-PGDS-derived PGD2 may in turn regulate L-PGDS expression by a nuclear factor erythroid-2-related factor 2 (NRF2)-mediated feedback mechanism. These results indicate that endogenous ET-1 induced by hypoxia promotes hypoxia-induced ANP secretion by activation of COX2-L-PGDS-PPARγ signaling in beating rat atria. In addition, the positive feedback loop between L-PGDS-derived PGD2 and L-PGDS expression induced by hypoxia is part of the mechanism of hypoxia-induced ANP secretion by endogenous ET-1.

Topics: Animals; Atrial Natriuretic Factor; Cyclooxygenase 2; Endothelin-1; Gene Expression Regulation; Heart Atria; Hypoxia; Intramolecular Oxidoreductases; Isolated Heart Preparation; Lipocalins; NF-E2-Related Factor 2; PPAR gamma; Prostaglandin D2; Rats; Signal Transduction

We have previously shown that PPAR-γ agonist 15d-PGJ2 inhibited neuronal autophagy after cerebral ischemia/reperfusion injury. However, the underlying mechanism of its regulatory role in neuronal autophagy remains unclear. This study was designed to test the hypothesis that 15d-PGJ2 upregulated Bcl-2 which binds to Beclin 1, and thereby inhibits autophagy. We performed cell viability assay, cytotoxicity assay, western blot, and co-immunoprecipitation to analyze autophagy activities in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced autophagy in cultured cortical neurons. 15d-PGJ2 treatment significantly decreased LC3-II/LC3-I ratio and Beclin 1 expression, but increased p62 expression. Autophagic inhibitor 3-methyladenine decreased LC3-II levels, increased neuronal cell viability, and mimicked some protective effect of 15d-PGJ2 against OGD/R injury. OGD/R-induced autophagy coincided with decreases in Bcl-2 expression and increases in Beclin 1 expression. 15d-PGJ2 treatment upregulated Bcl-2 expression and decreased Beclin 1 expression, and inhibit the dissociation of Beclin1 from Bcl-2 significantly. Bcl-2 siRNA abrogated the effect of 15d-PGJ2 on Beclin 1, LC3-II and p62, and influence cell viability and LDH level, while scRNA did not. PPAR-γ agonist 15d-PGJ2 exerts neuroprotection partially via inhibiting neuronal autophagy after OGD/R injury. The inhibition of autophagy by 15d-PGJ2 is mediated through upregulation of Bcl-2.

Topics: Animals; Autophagy; Cell Survival; Cells, Cultured; Female; Glucose; Hypoxia; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Pregnancy; Prostaglandin D2; Proto-Oncogene Proteins c-bcl-2; Up-Regulation

15-Deoxy-∆(12,14)-PGJ(2) (15d-PGJ(2)) and thiazolidinedione attenuate reactive oxygen species (ROS) production via a peroxisome proliferator-activated receptor-gamma (PPAR-γ)-dependent pathway. Nonetheless, how PPAR-γ mediates ROS production to ameliorate ischemic brain injury is not clear. Recent studies indicated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in the vascular system. In the present study, we used an in vitro oxygen-glucose deprivation and reoxygenation (hypoxia reoxygenation [HR]) paradigm to study whether PPAR-γ interacts with NADPH oxidase, thereby regulating ROS formation in cerebral endothelial cells (CECs). With pharmacological (PPAR-γ antagonist GW9662), loss-of-function (PPAR-γ siRNA), and gain-of-function (Ad-PPAR-γ) approaches, we first demonstrated that 15d-PGJ(2) protected HR-treated CECs against ROS-induced apoptosis in a PPAR-γ-dependent manner. Results of promoter and subcellular localization analyses further revealed that 15d-PGJ(2), by activating PPAR-γ, blocked HR-induced NF-κB nuclear translocation, which led to inhibited transcription of the NADPH oxidase subunit p22phox. In summary, we report a novel transrepression mechanism whereby PPAR-γ downregulates hypoxia-activated p22phox transcription and the subsequent NADPH oxidase activation, ROS formation, and CEC apoptosis.

Topics: Animals; Apoptosis; Brain; Cells, Cultured; Endothelial Cells; Hypoxia; Mice; NADPH Oxidases; PPAR gamma; Prostaglandin D2; Reactive Oxygen Species; Transcription, Genetic

Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ(12)-PGJ2 and 15-deoxy-Δ(12,14)-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥10μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture.

Topics: Animals; Apoptosis; Carbazoles; Cells, Cultured; Cerebral Cortex; Cyclopentanes; Dose-Response Relationship, Drug; Embryo, Mammalian; Hypoxia; Intramolecular Oxidoreductases; Lipocalins; Mice; Mice, Knockout; Neurons; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Sulfonamides

15-Deoxy-Δ-prostaglandin (15d-PG)J(2) is an electrophilic oxidant that dilates the coronary vasculature. This lipid can adduct to redox active protein thiols to induce oxidative posttranslational modifications that modulate protein and tissue function.. To investigate the role of oxidative protein modifications in 15d-PGJ(2)-mediated coronary vasodilation and define the distal signaling pathways leading to enhanced perfusion.. Proteomic screening with biotinylated 15d-PGJ(2) identified novel vascular targets to which it adducts, most notably soluble epoxide hydrolase (sEH). 15d-PGJ(2) inhibited sEH by specifically adducting to a highly conserved thiol (Cys521) adjacent to the catalytic center of the hydrolase. Indeed a Cys521Ser sEH "redox-dead" mutant was resistant to 15d-PGJ(2)-induced hydrolase inhibition. 15d-PGJ(2) dilated coronary vessels and a role for hydrolase inhibition was supported by 2 structurally different sEH antagonists each independently inducing vasorelaxation. Furthermore, 15d-PGJ(2) and sEH antagonists also increased coronary effluent epoxyeicosatrienoic acids consistent with their vasodilatory actions. Indeed 14,15-EET alone induced relaxation and 15d-PGJ(2)-mediated vasodilation was blocked by the EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE). Additionally, the coronary vasculature of sEH-null mice was basally dilated compared to wild-type controls and failed to vasodilate in response to 15d-PGJ(2). Coronary vasodilation to hypoxia in wild-types was accompanied by 15d-PGJ(2) adduction to and inhibition of sEH. Consistent with the importance of hydrolase inhibition, sEH-null mice failed to vasodilate during hypoxia.. This represents a new paradigm for the regulation of sEH by an endogenous lipid, which is integral to the fundamental physiological response of coronary hypoxic vasodilation.

Topics: Amino Acid Sequence; Animals; Epoxide Hydrolases; Hypoxia; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Molecular Sequence Data; Myocardium; Oxidation-Reduction; Prostaglandin D2; Rats; Rats, Wistar; Signal Transduction; Vasodilation

Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS-deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade.

Topics: Animals; Cells, Cultured; Cyclooxygenase 2; Enzyme Activation; Glucocorticoids; Heart; Hypoxia; Intramolecular Oxidoreductases; Lipocalins; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Oxygen; Prostaglandin D2; Rats; Signal Transduction

Peroxisome proliferator-activated receptor (PPAR)-gamma may counteract tissue fibrosis via its anti-inflammatory actions, while hypoxia, a new pro-fibrotic factor, reportedly modifies PPAR-gamma expression. However, the effects of hypoxia on the expression and anti-inflammatory actions of PPAR-gamma have yet remained to be clarified in renal tubular cells.. Confluent human proximal renal tubular epithelial cells (HPTECs) were exposed to hypoxia (1% O2) and/or TNF-alpha at 10 ng/ml for up to 48 h. The cells were incubated with PPAR-gamma agonists, 15d-PGJ2 or pioglitazone, for 30 min before stimulation. Precise amounts of PPAR-gamma and MCP-1 mRNA and protein were measured by TaqMan quantitative PCR and immunoblot or ELISA, respectively.. A cDNA array analysis identified PPAR-gamma as one of the hypoxia-affected genes in HPTECs. Hypoxia reduced mRNA levels of PPAR-gamma at 24 and 48 h and protein levels at 6 and 48 h. Knockout of hypoxia-inducible factor-1alpha (HIF-1alpha) with its dominant negative form did not block the hypoxia-induced reduction in PPAR-gamma expression. PPAR-gamma's activation with 15d-PGJ2 or pioglitazone reduced basal and TNF-alpha-stimulated MCP-1 expression at mRNA and protein levels at 24 h under normoxia. MCP-1 reduction rates at basal mRNA and protein levels were slightly but significantly lower during hypoxia than normoxia (9 vs 69% and 36 vs 42%, respectively, for 15d-PGJ2, and 0 vs 34% and 12 vs 21%, respectively, for pioglitazone). Finally, a specific inhibitor for PPAR-gamma, GW9662, weakened the MCP-1-decreasing effect of 15d-PGJ2 by about 30%, under basal conditions, while it abolished the effect of pioglitazone almost completely.. Hypoxia-induced loss of function of PPAR-gamma reduces anti-inflammatory effects of PPAR-gamma activation, possibly modulating inflammatory responses in the diseased kidney.

Topics: Antioxidants; Cells, Cultured; Chemokine CCL2; Cyclic N-Oxides; Gene Expression Regulation; Humans; Hypoglycemic Agents; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Diseases; Kidney Tubules, Proximal; Oligonucleotide Array Sequence Analysis; Pioglitazone; PPAR gamma; Prostaglandin D2; RNA, Messenger; Spin Labels; Thiazolidinediones; Tumor Necrosis Factor-alpha

Chronic hypoxia-induced pulmonary hypertension results partly from proliferation of smooth muscle cells in small peripheral pulmonary arteries. Therefore, we examined the effect of hypoxia on growth of pulmonary artery smooth muscle cells (PASMCs) from human distal pulmonary arteries. Initial studies identified that serum-induced proliferation of explant-derived PASMCs was inhibited under hypoxic conditions (3-4 kPa in medium). However, selection of hypoxia-stimulated cells was achieved by culturing cells at low density under conditions of prolonged hypoxia (1-2 wk). In hypoxia-inhibited and -stimulated cells, Western blotting revealed hypoxic induction of cyclooxygenase (COX)-2, which was dependent on the activation of p38(MAPK), but not COX-1, inducible nitric oxide synthase (iNOS), or hemoxygenase-1 (HO-1). Hypoxic induction of COX-2 was also observed in the media of pulmonary arteries in lung organ culture. Hypoxia induced a 4- to 5-fold increase (P < 0.001) in prostaglandin (PG)E(2), PGD(2), PGF(2alpha), and 6-keto-PGF(1alpha) release from PASMCs. Hypoxic inhibition of proliferation was attenuated by incubation with indomethacin (10 micro M), or the COX-2 antagonist, NS398 (10 micro M), but not by the COX-1 antagonist, valeryl salicylate (0.5 mM). In conclusion, we have isolated cells from human peripheral pulmonary arteries that are either inhibited or stimulated by culture under hypoxic conditions. In both cell types hypoxia modulates cell proliferation by induction of COX-2 and production of antiproliferative prostaglandins. Induction of COX-2 may contribute to the inhibition of hypoxia-induced pulmonary vascular remodeling.

Topics: 6-Ketoprostaglandin F1 alpha; Cell Division; Cells, Cultured; Cyclooxygenase 2; Dinoprost; Dinoprostone; Humans; Hypoxia; Isoenzymes; Membrane Proteins; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; p38 Mitogen-Activated Protein Kinases; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery

In this study, the capacity of hepatocytes to degrade prostaglandins diminished if the partial oxygen pressure dropped below 5%. This decrease was accompanied by an increased lactate/pyruvate ratio, a decrease in fatty acid oxidation and a drop in the ATP level. The degradation of exogenous adenosine increased with decreasing oxygen tension. At a partial oxygen pressure below 10%, the conversion of uric acid to allantoin, the final catabolite of adenosine in the rat, was strongly inhibited, resulting in the accumulation of uric acid in the medium. A good correlation was observed between the partial oxygen pressure, the oxidation of uric acid to allantoin and the degradation of prostaglandins D2 and E2, suggesting a peroxisomal pathway of hepatic prostaglandin oxidation. Subcellular fractionation of liver homogenates revealed peroxisomes as the site of degradation of prostaglandins D2 and E2 augmented by cytosolic components. The similarity of the degradation products found in the cell-free system, in hepatocytes and in the perfused liver further supports a peroxisomal degradation of prostaglandins in vivo. Stimulated liver macrophages (Kupffer cells) produced the same amount and pattern of eicosanoids at 1% and 21% O2. Even the formation of superoxide remained unaffected down to a partial pressure of 1%. At partial O2 pressures below 1%, the production of prostaglandins and superoxide became strongly inhibited. These results indicate that essential oxygenation reactions in activated Kupffer cells, including prostaglandin synthesis, possess high affinities to oxygen, while the peroxisomal pathway of prostaglandin oxidation in hepatocytes is sensitive to an O2 tension as low as 5%.

Topics: Adenosine; Animals; Energy Metabolism; Hypoxia; Kupffer Cells; Liver; Oxidation-Reduction; Oxygen; Partial Pressure; Prostaglandin D2; Prostaglandins; Rats; Rats, Wistar; Superoxides

Primary cultures of rat Kupffer cells liberated significant amounts of prostaglandin (PG) D2, PGE2, and thromboxane (measured as thromboxane B2) when exposed to reoxygenation after 4 h of hypoxia. After a delayed onset, prostanoids were released at high rates for at least 8 h and after that time 700 pmol PGD2, 280 pmol PGE2, and 200 pmol thromboxane per 10(6) cells had been liberated. Unlike prostanoid release, leukotriene B4 production in reoxygenated cell cultures was only twice as much as in aerobic controls. Superoxide dismutase and catalase had no effect on PGD2, PGE2, and thromboxane production, indicating that prostanoid formation was independent of reactive oxygen species generated extracellularly and of cell injury. On the other hand, diphenyliodonium, as well as amiloride, blocked hypoxia-reoxygenation-induced PGD2, PGE2, and thromboxane release. The elevated prostanoid synthesis was preceded by increases in intracellular pH (from 7.23 to 7.38) and in intracellular Ca2+ (from 55 nM to a maximum level of 807 nM). These observations suggest a participation of NADPH oxidase and a related Na(+)-H+ exchange in the enhanced prostanoid synthesis, probably through the induction of an increased intracellular Ca2+ concentration.

Topics: Amiloride; Animals; Anti-Infective Agents; Biphenyl Compounds; Calcimycin; Calcium; Carrier Proteins; Cell Survival; Cells, Cultured; Dinoprostone; Hydrogen-Ion Concentration; Hypoxia; Kupffer Cells; Leukotriene B4; Male; NADH, NADPH Oxidoreductases; NADPH Oxidases; Onium Compounds; Oxidation-Reduction; Oxygen; Prostaglandin D2; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers; Tetradecanoylphorbol Acetate; Thromboxane B2

Pulmonary and systemic vascular and cardiac effects of intravenous prostaglandin D2 (PGD2), given at 0.1, 1.0, and 10 micrograms/kg, were measured in chronically instrumented lambs during normoxia and hypoxia at ages 2-3, 9-14, and greater than or equal to 21 days. During normoxia, PGD2 was not a pulmonary vasodilator at low dose and caused mild pulmonary vasoconstrictor changes at 10 micrograms/kg in young lambs; normoxic older lambs had pulmonary vasoconstriction at both 1 microgram/kg and 10 micrograms/kg doses. With hypoxemia, PGD2 caused mild pulmonary vasodilation at all doses in the youngest lambs, converted the normoxic 9-14-day-old lambs' pressor response to a nonresponse, and attenuated the high-dose pulmonary vasoconstriction in the greater than or equal to 21 day lambs. PGD2 was a directly dose-related systemic pressor (+5-20 mmHg) at all ages during both normoxia and hypoxia. Heart rate and cardiac output decreased in a dose-dependent fashion during both normoxia and hypoxia. The PGD2-induced cardiac depression was unaltered by age or ventilatory hypoxemia. PGD2 response of the lamb pulmonary circulation changes from marginal dilation to constriction during the late postnatal development. During the same period, PGD2 dose-related systemic pressor and cardiac depressant effects remain stable. Thus, the circulatory effects of PGD2 are complexly interrelated with age, dose, and presence of hypoxemia.

Topics: Animals; Animals, Newborn; Cardiovascular System; Coronary Circulation; Female; Heart; Hypoxia; Male; Prostaglandin D2; Prostaglandins D; Sheep

We have observed that the contents of prostaglandin (PG) D2 and 6-keto-PGF1 alpha were five times higher than those of PGE2 and PGF2 alpha in rat gastric mucosa. In order to elucidate the role of PGs in the function of gastric mucosa, we studied the effect of hypoxia on the levels of PGs in relation to the degree of gastric mucosal lesions. 6-Keto-PGF1 alpha levels were significantly decreased only by severe and long-term hypoxia (10% O2, 18 hours) when severe ulcerative lesions were observed. PGE2 levels were significantly decreased even by mild and short-term hypoxia (13% O2, 4 hours) when slight ulcerative lesions were observed. PGF2 alpha and PGD2 levels were significantly decreased by mild and short-term hypoxia; however, there was no significant difference from the control group under severe and long-term hypoxia. These results suggest that each of the PGs plays a different role in the pathogenesis of acute gastric mucosal lesions induced by hypoxia.

Topics: Animals; Dinoprost; Dinoprostone; Epoprostenol; Gastric Mucosa; Hypoxia; Male; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Stomach Ulcer

Although the mechanism underlying hypoxic pulmonary vasoconstriction remains undefined, various reports have suggested that mast cells and cell-derived mediators may be important in the production of this phenomenon. We investigated the effect of reducing oxygen tension on the release from human lung fragments of the mast cell-derived mediators histamine, prostaglandin (PG) D2 and peptide leukotrienes, as well as the release of the largely non-mast cell-derived mediators PGE2, PGF2 alpha, prostacyclin metabolite (6-keto-PGF1 alpha) and the thromboxane A2 metabolite (thromboxane B2). The effect of reducing oxygen tension on both basal mediator release and release triggered by goat antihuman immunoglobulin E was studied. Reducing pO2 of buffer in which lung fragments were placed from 161 to 54 mm Hg resulted in no spontaneous release of histamine, PGD2 or peptide leukotrienes. However, hypoxia had a marked effect on mediator release triggered by goat antihuman immunoglobulin E. Although net histamine release was relatively unaffected (control 13.9 +/- 2.7%, hypoxic 12.7 +/- 2.1%), hypoxic treatment resulted in an 89% inhibition of PGD2 release (control 47.7 +/- 17.4 ng/g of lung, hypoxic 5.26 +/- 1.91 ng/g of lung) and an 81% inhibition of peptide leukotriene release (control 22.5 +/- 7.6 ng/g of lung, hypoxic 4.37 +/- 2.4 ng/g of lung). Similar inhibition was seen for non-mast cell-derived mediators, including PGF2 alpha, prostacyclin metabolite and thromboxane B2, and probably for PGE2. We conclude that hypoxic treatment of human lung fragments in vitro results in no spontaneous release of preformed or newly formed mediators but that it markedly alters mediator release after goat antihuman immunoglobulin E triggering.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Histamine Release; Humans; Hypoxia; Immunoglobulin E; Leukotriene E4; Lung; Mast Cells; Oxygen; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; SRS-A; Thromboxane A2; Thromboxane B2

We investigated the effects of prostaglandins (PG) E1, I2 and D2 on the pulmonary vascular bed of newborn rats subjected to chronic hypoxia. Forty seven newborn rats were exposed to chronic hypoxia (10% oxygen) for 23 days and divided into five groups which received PGE1 (N = 10), PGI2 (N = 9), PGD2 (N = 11), placebo (N = 9) or served as controls (N = 8). The PG's were administered by implanting slow release subcutaneous pellets delivering an average daily dose of 1 microgram. Thirteen newborn rats in room air received either placebo or served as controls. All rats were killed after 23 days and heart-lung preparations were perfusion fixed with glutaraldehyde. Appropriate blocks were processed for quantitative morphometry of the pulmonary parenchyma, arteries and arterioles. For analysis the pulmonary vessels were grouped by external diameter, i.e. 30-50 mu and 50-100 mu. External diameter/lumen diameter, an index of medial smooth muscle mass, was 1.39 +/- 0.02 in room air controls, this index of medial muscle mass was significantly increased (p less than 0.01) to 1.53 +/- 0.03 in hypoxic controls and the PGD2 and PGI2 groups. However, the PGE1 group did not have medial hypertrophy evidenced by a medial muscle mass index of 1.34 +/- 0.04, similar to room air controls. These findings suggest that PGE1 may prevent the development of medial hypertrophy that occurs in chronic hypoxia.

Topics: Alprostadil; Animals; Animals, Newborn; Arterioles; Body Weight; Chronic Disease; Epoprostenol; Female; Hematocrit; Hypoxia; Lung; Prostaglandin D2; Prostaglandins D; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Inbred Strains; Vasodilator Agents