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Immunology May 2014Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully...
Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2 / Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness.
Topics: Animals; Anti-Inflammatory Agents; Aspergillus fumigatus; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; Eosinophils; Lung; Male; Ovalbumin; Prostaglandin D2; Pulmonary Aspergillosis; Pulmonary Eosinophilia; Rats; Rats, Wistar; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction
PubMed: 24329550
DOI: 10.1111/imm.12234 -
Journal of Immunology (Baltimore, Md. :... Jul 2014Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor...
Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3(+) T cells but not in monocytes and CD3(+)/CD4(+) T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.
Topics: Adolescent; Adult; Animals; Blotting, Western; CD3 Complex; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Female; Flow Cytometry; Humans; Immunohistochemistry; Indoles; Killer Cells, Natural; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; T-Lymphocytes; Th2 Cells; Young Adult
PubMed: 24929001
DOI: 10.4049/jimmunol.1303484 -
British Journal of Pharmacology May 2016Prostanoids derived from COX-2 and EP receptors are involved in vascular remodelling in different cardiovascular pathologies. This study evaluates the contribution of...
BACKGROUND AND PURPOSE
Prostanoids derived from COX-2 and EP receptors are involved in vascular remodelling in different cardiovascular pathologies. This study evaluates the contribution of COX-2 and EP1 receptors to vascular remodelling and function in hypertension.
EXPERIMENTAL APPROACH
Spontaneously hypertensive rats (SHR) and angiotensin II (AngII)-infused (1.44 mg · kg(-1) · day(-1), 2 weeks) mice were treated with the COX-2 inhibitor celecoxib (25 mg · kg(-1) · day(-1) i.p) or with the EP1 receptor antagonist SC19220 (10 mg · kg(-1) · day(-1) i.p.). COX-2(-/-) mice with or without AngII infusion were also used.
KEY RESULTS
Celecoxib and SC19220 treatment did not modify the altered lumen diameter and wall : lumen ratio in mesenteric resistance arteries from SHR-infused and/or AngII-infused animals. However, both treatments and COX-2 deficiency decreased the augmented vascular stiffness in vessels from hypertensive animals. This was accompanied by diminished vascular collagen deposition, normalization of altered elastin structure and decreased connective tissue growth factor and plasminogen activator inhibitor-1 gene expression. COX-2 deficiency and SC19220 treatment diminished the increased vasoconstrictor responses and endothelial dysfunction induced by AngII infusion. Hypertensive animals showed increased mPGES-1 expression and PGE2 production in vascular tissue, normalized by celecoxib. Celecoxib treatment also decreased AngII-induced macrophage infiltration and TNF-α expression. Macrophage conditioned media (MCM) increased COX-2 and collagen type I expression in vascular smooth muscle cells; the latter was reduced by celecoxib treatment.
CONCLUSIONS AND IMPLICATIONS
COX-2 and EP1 receptors participate in the increased extracellular matrix deposition and vascular stiffness, the impaired vascular function and inflammation in hypertension. Targeting PGE2 receptors might have benefits in hypertension-associated vascular damage.
Topics: Animals; Celecoxib; Cells, Cultured; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; Dinoprostone; Dose-Response Relationship, Drug; Humans; Hypertension; Male; Mice; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Prostaglandin E, EP1 Subtype; Structure-Activity Relationship; Vascular Stiffness
PubMed: 26856544
DOI: 10.1111/bph.13457 -
British Journal of Pharmacology Dec 1986TRK-100, a stable analogue of prostaglandin I2 (PGI2), relaxed isolated arteries of the dog precontracted with PGF2 alpha or K+; the relaxation was in the order of...
TRK-100, a stable analogue of prostaglandin I2 (PGI2), relaxed isolated arteries of the dog precontracted with PGF2 alpha or K+; the relaxation was in the order of mesenteric and renal greater than coronary and femoral greater than basilar and middle cerebral arteries. The relaxation by TRK-100 was not affected by treatment with atropine, propranolol, cimetidine, aminophylline, and indomethacin, but was suppressed by diphloretin phosphate, a prostaglandin antagonist. Treatment with TRK-100 attenuated the contraction induced by PGF2 alpha and Ca2+ in mesenteric and basilar arteries previously exposed to Ca2+-free medium, but did not significantly alter the contractile response to Ca2+ in the arteries exposed to Ca2+-free medium and depolarized by excess K+. TRK-100 and nitroglycerin relaxed isolated mesenteric arteries to a similar extent; however, when continuously infused into mesenteric arteries in anaesthetized dogs, TRK-100 produced greater vasodilatation than nitroglycerin. It is concluded that TRK-100 relaxes dog mesenteric and renal arteries more than cerebral arteries; the relaxation appears to derive from interference with the release of Ca2+ from intracellular stores and with the transmembrane Ca2+ influx through a receptor-operated channel. TRK-100 may vasodilate large and small mesenteric arteries and resistance vessels to a similar extent, whereas nitroglycerin preferentially dilates the large artery.
Topics: Animals; Basilar Artery; Calcium; Dinoprost; Dogs; Epoprostenol; Female; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitroglycerin; Polyphloretin Phosphate; Prostaglandins F; Splanchnic Circulation; Vasodilator Agents
PubMed: 3101928
DOI: 10.1111/j.1476-5381.1986.tb11174.x -
British Journal of Pharmacology Feb 2007The prostamides (prostaglandin-ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX-2 from the respective endocannabinoids anandamide and...
BACKGROUND AND PURPOSE
The prostamides (prostaglandin-ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX-2 from the respective endocannabinoids anandamide and 2-arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists.
EXPERIMENTAL APPROACH
The isolated feline iris was used as a key preparation, where prostanoid FP receptors and prostamide activity co-exist. Activity at human recombinant FP and other prostanoid receptors was determined using stable transfectants.
KEY RESULTS
In the feline iris, AGN 204396 produced a rightward shift of the dose-response curves for prostamide F2alpha and the prostamide F2alpha analog bimatoprost but did not block the effects of PGF2alpha and synthetic FP receptor agonists. Studies on human recombinant prostanoid receptors confirmed that AGN 204396 did not behave as a prostanoid FP receptor antagonist. AGN 204396 exhibited no antagonism at DP and EP1-4, but was a highly effective TP receptor antagonist. Contrary to expectation, the FP receptor antagonist AL-8810 efficaciously contracted the cat iris. AGN 204396 did not affect AL-8810 induced contractions, demonstrating that AL-8810 and AGN 204396 are pharmacologically distinct. Unlike AL-8810, the ethylamide derivate of AL-8810 was not an agonist. Al-8810 did not block prostamide F2alpha activity. Finally, AGN 204396 did not block PGE2-glyceryl ester activity.
CONCLUSIONS AND IMPLICATIONS
The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2alpha and PGE2-glyceryl ester.
Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cats; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; In Vitro Techniques; Iris; Oxazoles; Receptors, Prostaglandin; Recombinant Proteins
PubMed: 17179945
DOI: 10.1038/sj.bjp.0706989 -
Neurobiology of Disease Oct 2012Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles...
Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF(2α) and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP(-/-)) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7±6.3% less neurologic dysfunction and 36.4±6.0% smaller infarct volumes than did vehicle-treated mice after 48h of permanent middle cerebral artery occlusion (pMCAO); FP(-/-) mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca(2+) levels in cultured neurons and established that FP-related Ca(2+) signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.
Topics: Animals; Brain; Brain Ischemia; Calcium; Cell Death; Cells, Cultured; Dinoprost; Dose-Response Relationship, Drug; Male; Mice; Mice, Knockout; Neurons; Neuroprotective Agents; Reactive Oxygen Species; Receptors, Prostaglandin
PubMed: 22709986
DOI: 10.1016/j.nbd.2012.06.003 -
American Journal of Physiology.... Nov 2009Progesterone (P4) inhibits the gastrointestinal muscle contraction by downregulating Galpha(q/11) proteins that mediate contraction, by upregulating Galpha(s) proteins...
Progesterone (P4) inhibits the gastrointestinal muscle contraction by downregulating Galpha(q/11) proteins that mediate contraction, by upregulating Galpha(s) proteins that mediate relaxation, and by altering the pattern of cyclooxygenase (COX) enzymes and prostaglandins. We aimed to examine whether P4 treatment of guinea pigs in vivo affects basal colon motility [basal motility index (MI)] by altering the levels and actions of PGF(2alpha) and PGE(2). Guinea pigs were treated with intramuscular (IM) P4 for 4 days. The BASAL MI, the PGF(2alpha)-induced contraction, and PGE(2)-induced inhibition of contraction were examined in muscle strips and cells. The levels of PGF(2alpha) and PGE(2) were measured by radioimmunoassay. Treatment with P4 reduced the basal MI, the levels of PGF(2alpha), and PGF(2alpha)-induced contraction. P4 increased PGE(2) levels, and PGE(2) induced relaxation. Pretreatment with IM RU-486 (10 mg/kg per day), a P4 receptor antagonist, 1 h before P4 blocked the actions of P4. The PGF(2alpha) antagonist Al-1180 abolished basal MI and PGF(2alpha)-induced contraction. N-ethylmaleimide, which blocks unoccupied membrane receptors, blocked Ach and VIP actions but had no effect on PGF(2alpha) and PGE(2) effects. A COX-1 inhibitor decreased and a COX-2 inhibitor increased PGF(2alpha) levels; GTPgammaS increased and GDPbetaS decreased the levels of PGF(2alpha). Galpha(q/11) protein antibodies (Abs) reduced PGF(2alpha) levels, and Galpha(i3) Abs blocked its motor actions. Galphas Abs increased PGF(2alpha) but decreased PGE(2) levels. We concluded that P4 decreases basal MI by reducing PGF(2alpha) levels caused by downregulation of Galpha(q/11) and that PGF(2alpha)-induced contraction was blocked by downregulating Galpha(i3). P4 also decreased the basal MI by increasing PGE(2) levels, and PGE(2) induced relaxation by upregulating Galpha(s) proteins.
Topics: Acetylcholine; Animals; Antibodies; Colon; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Ethylmaleimide; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gq-G11; GTP-Binding Proteins; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Male; Mifepristone; Muscle Contraction; Muscle, Smooth; Myocytes, Smooth Muscle; Pertussis Toxin; Progesterone; Prostaglandins; Receptors, Prostaglandin; Vasoactive Intestinal Peptide
PubMed: 20501437
DOI: 10.1152/ajpgi.00184.2009 -
British Journal of Pharmacology Jan 19961. In isolated ring preparations of the rabbit saphenous vein, prostaglandin E2 (PGE2) caused well-defined, stable and concentration-dependent relaxations of KCl... (Comparative Study)
Comparative Study
1. In isolated ring preparations of the rabbit saphenous vein, prostaglandin E2 (PGE2) caused well-defined, stable and concentration-dependent relaxations of KCl contracted tissues with a mean potency (p[A50]) of 9.39. 2. The prostanoid EP-receptor agonists, PGE1, 11-deoxy PGE1, 16,16-dimethyl PGE2 and misoprostol were all full agonists in this preparation. The EP2-receptor selective agonists, butaprost and AH13205, and the EP1/EP3-receptor selective agonist, sulprostone, also relaxed this tissue but were at least 300 times less potent than PGE2. 3. Prostaglandin D2 (PGD2), the DP-receptor agonist, BW245C, and the IP-receptor agonist, cicaprost, caused concentration-dependent relaxations of the rabbit saphenous vein but were at least 60 times less potent than PGE2. 4. The selective EP4-receptor antagonist, AH23848B (30 microM), antagonized the PGE2 concentration-effect (E/[A]) curves yielding a pA2 estimate of 4.96. The EP1/DP-receptor antagonist, AH6809 (10 microM), had no effect on the location of PGE2 E/[A] curves. 5. The stable thromboxane A2-mimetic, U46619, elicited concentration-dependent contractions of the rabbit saphenous vein (p[A50] = 8.01) however, PGE2 and prostaglandin F2 alpha (PGF2 alpha) were unable to produce a contractile response. The response to U46619 was competitively antagonized by the TP-receptor antagonist, GR32191B, yielding a pKB estimate of 7.08. 6. In the rabbit isolated ear artery, PGE2, misoprostol and AH13205 relaxed tissues pre-contracted with phenylephrine. PGE2 (p[A50] = 7.04) and misoprostol were equipotent, whereas AH13205 was some 40 fold less potent. AH23848B (30 microM) and AH6809 (1 and 10 microM) caused no significant shift in the location of PGE2 E/[A] curves. 7. These data suggest that the rabbit isolated saphenous vein contains prostanoid, EP-, DP-, IP- and TP-receptors. Based on antagonist affinity information and agonist potency orders, the rabbit saphenous vein contains an inhibitory prostanoid EP-receptor different from that in the rabbit ear artery, but comparable to the recently described EP4-receptor.
Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arteries; Biphenyl Compounds; Dinoprostone; Dose-Response Relationship, Drug; Ear; Heptanoic Acids; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Phenylephrine; Prostaglandin Endoperoxides, Synthetic; Prostaglandins E; Rabbits; Receptors, Prostaglandin E; Saphenous Vein; Thromboxane A2; Vasoconstrictor Agents
PubMed: 8825337
DOI: 10.1111/j.1476-5381.1996.tb15148.x -
Journal of Applied Physiology... Jun 1999Aging is associated with a number of physiological changes that may cause the kidney to rely to a greater extent on vasodilatory PGs for normal functioning. Acute... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Aging is associated with a number of physiological changes that may cause the kidney to rely to a greater extent on vasodilatory PGs for normal functioning. Acute exercise has been shown to cause renal vasoconstriction that may be partially buffered by vasodilatory PGs. To determine the relative importance of renal PGs during exercise in older adults, we compared the renal effects of the PG inhibitor ibuprofen (1.2 g/day for 3 days) vs. a placebo control in a cohort of eight younger (24 +/- 2 yr) and eight older (64 +/- 2 yr) women during treadmill exercise ( approximately 57% maximal oxygen consumption) in the heat (36 degrees C). This over-the-counter dose of ibuprofen reduced renal PG (i.e., PGE2) excretion by 47% (P < 0. 05). Acute exercise in the heat caused dramatic decreases in glomerular filtration rate, renal blood flow, and sodium excretion in both age groups. PG inhibition was associated with greater decreases in urine production and free water clearance (P < 0.05). There were no drug-related declines in glomerular filtration rate or renal blood flow. We conclude that PG inhibition has only modest effects on renal function during exercise. Also, the lack of hemodynamic changes with PG inhibition indicates that healthy well-hydrated older women are not in a renal PG-dependent state.
Topics: Adult; Aged; Aging; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Double-Blind Method; Exercise; Female; Glomerular Filtration Rate; Heat Stress Disorders; Humans; Ibuprofen; Kidney; Middle Aged; Prostaglandin Antagonists; Renal Circulation; Sodium
PubMed: 10368359
DOI: 10.1152/jappl.1999.86.6.1936 -
FASEB Journal : Official Publication of... May 2019Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases...
Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX-activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to , produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on-target actions, we found that: ) COX or 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, ) FLAP and 5-LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, ) zileuton blocks resolution-initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and ) that the 15-LOX-1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.-Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Cyclooxygenase Inhibitors; Humans; Leukotriene Antagonists; Leukotrienes; Lipoxygenase; Lipoxygenase Inhibitors; Macrophages; Metabolome; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 30735438
DOI: 10.1096/fj.201802509R