-
The Journal of Physiology Sep 19741. Experiments were carried out in unanaesthetized cats to find out if a prostaglandin is the mediator (a) for the long lasting fever which often follows injections of...
1. Experiments were carried out in unanaesthetized cats to find out if a prostaglandin is the mediator (a) for the long lasting fever which often follows injections of phsyiological salt solutions into the cerebral ventricles or into the cisterna magna, as well as their perfusions through the cerebral ventricles, and (b) for the sodium fever which occurs during a perfusion of the cerebral ventricles with calcium-free artificial c.s.f. A fever mediated by prostaglandin should be accompanied by an increase of prostaglandin activity in cisternal c.s.f., and be abolished or prevented by antipyretics like paracetamol or indomethacin which inhibit prostaglandin synthesis. Both criteria were applied.2. The fever which follows injections or perfusions of physiological salt solutions appears to be mediated by a prostaglandin of the E series, probably E(2) (PGE(2)) because it was accompanied by increased prostaglandin E-like activity in the c.s.f. and abolished by paracetamol and indomethacin. During the first few days after pre-treatment of the cats with intramuscular chloramphenicol the injections were rarely followed by fever.3. The fever which occurs during a perfusion with calcium-free artificial c.s.f. appears not to be mediated by prostaglandin, because it was not associated with increased prostaglandin activity in the cisternal effluent, and not prevented by paracetamol or indomethacin, although these antipyretics usually attenuated the fever.4. A perfusion of the cerebral ventricles with artificial c.s.f. containing calcium in an abnormally high concentration (6.25 mM) brought down fever produced by PGE(1), or PGE(2), or bacterial pyrogen.
Topics: Acetaminophen; Animals; Body Temperature; Calcium; Cats; Cerebral Ventricles; Cerebrospinal Fluid; Chloramphenicol; Cisterna Magna; Fever; Indomethacin; Injections; Perfusion; Prostaglandin Antagonists; Prostaglandins; Pyrogens; Shigella dysenteriae; Sodium Chloride
PubMed: 4215879
DOI: 10.1113/jphysiol.1974.sp010675 -
Investigative Ophthalmology & Visual... Jul 2020Cyclic adenosine monophosphate (cAMP) and peroxisome proliferator-activated receptor alpha (PPARα) levels mediate extracellular matrix (ECM) changes by altering the...
PURPOSE
Cyclic adenosine monophosphate (cAMP) and peroxisome proliferator-activated receptor alpha (PPARα) levels mediate extracellular matrix (ECM) changes by altering the levels of hypoxia-inducible factor 1-alpha (HIF-1α) in various tissues. We aimed to determine, in the sclera of guinea pigs, whether a prostanoid receptor (EP2)-linked cAMP modulation affects PPARα and HIF-1α signaling during myopia.
METHODS
Three-week-old guinea pigs (n = 20 in each group), were monocularly injected with either an EP2 agonist (butaprost 1 µmol/L/10 µmol/L), an antagonist (AH6809 10 µmol/L/30 µmol/L) or a vehicle solution for two weeks during normal ocular growth. Separate sets of animals received these injections and underwent form deprivation (FD) simultaneously. Refraction and axial length (AL) were measured at two weeks, followed by scleral tissue isolation for quantitative PCR (qPCR) analysis (n = 10) and cAMP detection (n = 10) using a radioimmunoassay.
RESULTS
Butaprost induced myopia development during normal ocular growth, with proportional increases in AL and cAMP levels. FD did not augment the magnitude of myopia or cAMP elevations in these agonist-injected eyes. AH6809 suppressed cAMP increases and myopia progression during FD, but had no effect in a normal visual environment. Of the diverse set of 27 genes related to cAMP, PPARα and HIF-1α signaling and ECM remodeling, butaprost differentially regulated 15 of them during myopia development. AH6809 injections during FD negated such differential gene expressions.
CONCLUSION
EP2 agonism increased cAMP and HIF-1α signaling subsequent to declines in PPARα and RXR mRNA levels, which in turn decreased scleral fibrosis and promoted myopia. EP2 antagonism instead inhibited each of these responses. Our data suggest that EP2 suppression may sustain scleral ECM structure and inhibit myopia development.
Topics: Alprostadil; Animals; Cyclic AMP; Extracellular Matrix; Guinea Pigs; Hypoxia-Inducible Factor 1, alpha Subunit; Myopia, Degenerative; PPAR alpha; Prostaglandin Antagonists; Prostaglandins E, Synthetic; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction; Xanthones
PubMed: 32725213
DOI: 10.1167/iovs.61.8.44 -
Medical Hypotheses Oct 2020A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The...
A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-α; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D (PGD) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD in the airways, which inhibits the host dendritic cell response via the DP receptor signaling. Second, PGD is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD/DP signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.
Topics: Adult; Betacoronavirus; COVID-19; Carbazoles; Child; Coronavirus Infections; Dendritic Cells; Humans; Lymphopenia; Models, Immunological; Molecular Targeted Therapy; Myeloid Cells; Pandemics; Pneumonia, Viral; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Respiratory System; SARS-CoV-2; Sulfonamides; T-Lymphocytes; Thromboxane A2
PubMed: 32759007
DOI: 10.1016/j.mehy.2020.110122 -
Journal of the American Society of... Nov 2012Urinary excretion of lipocalin-type PGD(2) synthase (L-PGDS), which converts PG H(2) to PGD(2), increases in early diabetic nephropathy. In addition, L-PGDS expression...
Urinary excretion of lipocalin-type PGD(2) synthase (L-PGDS), which converts PG H(2) to PGD(2), increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD(2) contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD(2) might be a strategy to slow the progression of renal fibrosis in CKD.
Topics: Animals; Carbazoles; Disease Models, Animal; Fibrosis; Humans; Interleukin-13; Interleukin-4; Intramolecular Oxidoreductases; Kidney Diseases; Lipocalins; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin D2; RNA, Messenger; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Sulfonamides; Th2 Cells; Ureteral Obstruction
PubMed: 22997255
DOI: 10.1681/ASN.2012020126 -
Kidney International Nov 1980
Review
Topics: Animals; Anti-Inflammatory Agents; Bartter Syndrome; Glomerular Filtration Rate; Humans; Indomethacin; Kidney; Prostaglandin Antagonists; Prostaglandins; Regional Blood Flow; Renin; Thromboxanes; Water-Electrolyte Balance
PubMed: 7007713
DOI: 10.1038/ki.1980.179 -
Cells Jun 2021Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles...
Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ's effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ and MAGL inhibitor KML29, or PGJ + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ alone. KML29's failure to suppress PGE ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ has been shown to be neuroprotective, treatments combining PGJ with these PG synthesis inhibitors do not enhance PGJ's neuroprotection.
Topics: Animals; Benzodioxoles; Disease Models, Animal; Male; Meloxicam; Neuroprotective Agents; Optic Neuropathy, Ischemic; Piperidines; Prostaglandin Antagonists; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells
PubMed: 34207618
DOI: 10.3390/cells10061440 -
Proceedings of the National Academy of... Nov 1985Current dogma holds that nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibition of the synthesis and release of prostaglandins. However, NSAIDs also inhibit the...
Current dogma holds that nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibition of the synthesis and release of prostaglandins. However, NSAIDs also inhibit the activation of neutrophils, which provoke inflammation by releasing products other than prostaglandins. We now report that NSAIDs (e.g., indomethacin, piroxicam) inhibit activation of neutrophils by inflammatory stimuli, such as C5-derived peptides and leukotriene B4, even when cyclooxygenase products generated in suspensions of stimulated neutrophils (prostaglandin E and thromboxanes) are present. Sodium salicylate (3 mM) greatly inhibited aggregation of neutrophils but had no effect on aggregation of platelets or production of thromboxane induced by arachidonate. Sodium salicylate and other NSAIDs also inhibit calcium movements (45Ca uptake, changes in fluorescence of chlortetracycline and quin-2). Aspirin, sodium salicylate, indomethacin, and piroxicam also enhanced the poststimulation increase in intracellular cyclic AMP. NSAIDs therefore inhibit early steps in neutrophil activation as reflected by their capacity to inhibit movements of Ca and to enhance intracellular levels of cyclic AMP.
Topics: Anti-Inflammatory Agents; Aspirin; Blood Platelets; Calcium; Cell Aggregation; Complement C5; Cyclic AMP; Cyclooxygenase Inhibitors; Indomethacin; Leukotriene B4; Lymphocyte Activation; Neutrophils; Piroxicam; Prostaglandin Antagonists; Salicylates; Superoxides; Thiazines; Thromboxane A2
PubMed: 2997778
DOI: 10.1073/pnas.82.21.7227 -
Respiratory Research Feb 2007Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous...
BACKGROUND
Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.
METHODS
Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model.
RESULTS
TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia.
CONCLUSION
This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.
Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carbazoles; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Immunization; In Vitro Techniques; Inflammation; Mice; Mice, Inbred BALB C; Prostaglandin Antagonists; Pulmonary Eosinophilia; Radioligand Assay; Receptors, Immunologic; Receptors, Prostaglandin; Sensitivity and Specificity; Sulfonamides
PubMed: 17328802
DOI: 10.1186/1465-9921-8-16 -
The Journal of Clinical Investigation Jul 2001
Review
Topics: Animals; Aspirin; Biological Transport; Bone Resorption; Cell Nucleus; Colonic Neoplasms; Cyclooxygenase Inhibitors; Drug Design; Female; Fever; GTP-Binding Proteins; Humans; Hypersensitivity; Inflammation; Ischemia; Mice; Mice, Knockout; Neovascularization, Pathologic; Pain; Placenta; Pregnancy; Prostaglandin Antagonists; Prostaglandins; Protein Structure, Tertiary; Receptors, Prostaglandin; Receptors, Thromboxane; Signal Transduction; Thromboxanes; Vasodilation
PubMed: 11435452
DOI: 10.1172/JCI13455 -
Molecular and Cellular Endocrinology Jul 2015Endometriosis is an inflammatory gynecological disease of reproductive-age women. The prevalence of endometriosis is 5-10% in reproductive-age women. Modern medical...
Endometriosis is an inflammatory gynecological disease of reproductive-age women. The prevalence of endometriosis is 5-10% in reproductive-age women. Modern medical treatments are directed to inhibit the action of estrogen in endometriotic cells. However, hormonal therapies targeting estrogen can be prescribed only for a short time because of their undesirable side effects. Recent studies from our laboratory, using human endometriotic epithelial cell line 12Z and stromal cell line 22B derived from red lesion, discovered that selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits adhesion, invasion, growth, and survival of 12Z and 22B cells by modulating integrins, MMPs and TIMPs, cell cycle, survival, and intrinsic apoptotic pathways, suggesting multiple epigenetic mechanisms. The novel findings of the present study indicate that selective pharmacological inhibition of EP2 and EP4: (i) decreases expression of DNMT3a, DNMT3b, H3K9me3, H3K27me3, SUV39H1, HP1a, H3K27, EZH2, JMJD2a, HDAC1, HDAC3, MeCP2, CoREST and Sin3A; (ii) increases expression of H3K4me3, H3H9ac, H3K27ac; and (iii) does not modulate the expression of DNMT1, hSET1, LSD1, MBD1, p300, HDAC2, and JMJD3 epigenetic machinery proteins in an epithelial and stromal cell specific manner. In this study, we report for the first time that inhibition of PGE2-EP2/EP4 signaling modulates DNA methylation, H3 histone methylation and acetylation, and epigenetic memory machinery proteins in human endometriotic epithelial cells and stromal cells. Thus, targeting EP2 and EP4 receptors may emerge as long-term nonsteroidal therapy for treatment of active endometriotic lesions in women.
Topics: Acetylation; Biphenyl Compounds; Cell Line; DNA Methylation; Endometriosis; Epigenesis, Genetic; Female; Gene Expression Regulation; Histones; Humans; Prostaglandin Antagonists; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Xanthones
PubMed: 25843056
DOI: 10.1016/j.mce.2015.03.023