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British Journal of Cancer Dec 1982Lung primary carcinomas and normal tissue from 136 patients have been extracted for prostaglandins, and the findings examined in relation to histology. In most cases,...
Lung primary carcinomas and normal tissue from 136 patients have been extracted for prostaglandins, and the findings examined in relation to histology. In most cases, tumours yielded more prostaglandin-like material (PG-lm), as judged by bioassay, than did normal tissue from the same lungs. Amounts varied with tumour types, in the following ascending order: small-cell carcinomas, large-cell undifferentiated carcinomas, well-differentiated squamous carcinomas, poorly-differentiated adenocarcinomas, poorly differentiated squamous carcinomas, and well-differentiated adenocarcinomas. Tumour PG-lm was highest when necrosis or the neutrophil content of the tumours were moderate, whereas PG-lm from normal lung tissue correlated with the number of macrophages. Chromatography indicated the presence of various prostaglandins, in agreement with our recent findings using gas chromatography--mass spectrometry.
Topics: Adenocarcinoma; Biological Assay; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Dinoprostone; Humans; Lung; Lung Neoplasms; Mitosis; Prostaglandins; Prostaglandins E
PubMed: 6295425
DOI: 10.1038/bjc.1982.298 -
Kidney International Feb 1982The relationship of renal prostaglandins to antidiuretic hormone action and water diuresis was examined in 13 normal subjects and 2 subjects with diabetes insipidus....
The relationship of renal prostaglandins to antidiuretic hormone action and water diuresis was examined in 13 normal subjects and 2 subjects with diabetes insipidus. Following overnight water deprivation, a oral water load caused a prompt and sustained rise in the rate of urinary PGE2 excretion from 7.7 +/- 1.2 to 81.6 +/- 26.4 ng/hr (P less than 0.0001) in 7 normal subjects. Because the simultaneous increase in urinary excretion of urea was only 17% of the rise in urinary PGE2, passive wash-out of renal PGE2 probably accounts for only a small fraction of the increment in PGE2 excretion. Administration of the antidiuretic hormone analogue DDAVP to 6 normal subjects during sustained water diuresis resulted in a decrease in PGE2 excretion and urine flow rate comparable to that of dehydrated subjects. Thus, PGE2 excretion varied directly with urine flow rate over a wide range of states of hydration in all 13 normal subjects. One patient with central diabetes insipidus and one with nephrogenic diabetes insipidus demonstrated a similar positive correlation of PGE2 excretion rate and urinary flow rate in states of hydration, dehydration, and after administration of DDAVP. In the patient with nephrogenic diabetes insipidus, this relationship of PGE2 excretion rate to urine flow rate was unaffedted by DDAVP over a broad range of urine flow rates. Inhibition of prostaglandin synthesis with indomethacin in 6 normal subjects resulted in a significant decline in free water clearance (7.7 +/- 1.0 to 4.7 +/- 0.9 ml/min. P less than 0.001) and an increase in the minimal UOsm (61 +/- 4 to 93 +/- 19 mOsm/kg. P less than 0.01) achieved during water diuresis without a change in creatinine or osmolar clearances. Furthermore, the tightly linked relationship of PGE2 excretion rate to urine flow rate was reduced in 5 of 6 subjects during indomethacin treatment. We conclude that urinary PGE2 excretion varies directly with urine flow rate and is not directly dependent on ADH activity or state of hydration in man. The rise in PGE2 excretion during water diuresis may enhance the excretion of free water since indomethacin treatment blunted free water clearance while suppressing the rise in PGE2 excretion.
Topics: Adult; Arginine Vasopressin; Deamino Arginine Vasopressin; Dehydration; Diabetes Insipidus; Dinoprostone; Diuresis; Female; Humans; Indomethacin; Kidney; Male; Middle Aged; Prostaglandins E; Urination
PubMed: 6951096
DOI: 10.1038/ki.1982.31 -
Kidney International Jul 1984Unilateral ureteral obstruction in rabbits leads to an influx of macrophages into the kidney, a proliferation of interstitial cells, and an increase in arachidonic acid... (Comparative Study)
Comparative Study
Unilateral ureteral obstruction in rabbits leads to an influx of macrophages into the kidney, a proliferation of interstitial cells, and an increase in arachidonic acid metabolism. The role of the macrophage in the metabolic changes of hydronephrosis was investigated by using endotoxin and nitrogen mustard. The in vivo administration of endotoxin, a macrophage agonist, 1 hour before perfusion of the hydronephrotic kidney markedly enhanced (fourfold to tenfold) the peptide-stimulated arachidonic acid metabolism of the perfused kidney. Nitrogen mustard made animals leukopenic and prevented the influx of macrophages into the hydronephrotic kidney. The peptide-stimulated arachidonic acid metabolism of these kidneys was suppressed, and no enhancement was seen with in vivo endotoxin administration. The macrophage thus appears to be an essential determinant of the enhanced arachidonic acid metabolism seen in experimental hydronephrosis. An inhibitory effect of prostaglandin E2 on macrophage function in this model of renal inflammation was also demonstrated. Hydronephrotic animals were given aspirin during the period of unilateral ureteral obstruction to prevent in vivo prostaglandin E2 production. In the perfused hydronephrotic kidney, the peptide-stimulated arachidonic acid metabolism, which appears to be a marker of macrophage function in this model, was enhanced by aspirin treatment.
Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Bradykinin; Chromatography, Thin Layer; Dinoprostone; Disease Models, Animal; Endotoxins; Hydronephrosis; Kidney Cortex; Macrophages; Male; Mechlorethamine; Microsomes; Prostaglandins E; Rabbits; Thromboxane B2; Time Factors
PubMed: 6434790
DOI: 10.1038/ki.1984.127 -
Annals of Surgery Aug 1979Essential fatty acid deficiency (EFAD) has been commonly and readily diagnosed during fat-free total parenteral nutrition (TPN), with only vague awareness of possible...
Essential fatty acid deficiency (EFAD) has been commonly and readily diagnosed during fat-free total parenteral nutrition (TPN), with only vague awareness of possible functional and clinical derangements secondary to essential fatty acid deficiency. Arachidonic acid is known to be a precursor for prostaglandin (PG) synthesis. Prostaglandins are known to be intermediaries between stimulus and cellular response in a variety of physiologic and pathologic processes; one would suspect therefore that EFAD would result in PG deficiency with resultant multiple derangements in functions regulated by PG. We tested this hypothesis by serially measuring intraocular pressure (IOP) in patients before and during fat-free TPN and after supplementing these patients with fat. In the eye as well as in various other organs PG are believed to act as mediators of adrenergic neurotransmission by a negative feedback mechanism. As catecholamines are potent ocular hypotensive agents, decreased levels of PG due to EFAD will cause increase in catecholamine turnover with a reduction in IOP. Two groups of patients matched as to their age, sex, nutritional status and diseases were studied. One group (control) was receiving a normal diet or fat-containing TPN while the other group was receiving fat-free TPN. IOP in the fat-free TPN group dropped from 13.7 +/- 0.4 mmHg pre-TPN to 9.3 +/- 0.5 mmHg during the first week of fat-free TPN. Within two weeks after supplementation of fat or return to normal oral diet IOP returned to 13.9 +/- 0.3 mmHg. Prostaglandin levels, which were 0.025 +/- 0.004 ng/ml pre-TPN or in control patients decreased to 0.012 +/- 0.002 ng/ml (p < 0.001) during fat-free TPN, to return to normal after fat was added to TPN regime or patients returned to normal oral diet. During fat-free TPN linoleic acid levels decreased to 40% of its initial value with a mild increase upon the addition of fat, while eicosatrienoic acid and the triene:tetraene ratio increased to 6.5 times their initial values. Arachidonic acid levels did not change during fat-free TPN or after repletion with fat. Intraocular pressure determination seem to be a simple, harmless, inexpensive, reliable and sensitive indicator of EFAD. Moreover, IOP determination represent a functional derangement which in a clinical setting lends functional credence to the biochemical changes of EFAD whose entire significance has not yet been determined. Similarly, serial IOP determinations are sensitive in detecting adequate functional repletion of EFAD. As PG are known to act as intermediaries in a variety of physiological processes it seems reasonable to assume that the change in IOP is only one of many different changes and derangements to occur as a result of PG and EFA deficiency.
Topics: Adult; Aged; Dietary Fats; Fatty Acids, Essential; Female; Humans; Intraocular Pressure; Male; Middle Aged; Neuromuscular Junction; Parenteral Nutrition; Parenteral Nutrition, Total; Prostaglandins; Prostaglandins E; Receptors, Adrenergic; Synaptic Transmission
PubMed: 223507
DOI: 10.1097/00000658-197908000-00003 -
The Journal of Physiology Jan 19801. Experiments were performed to determine the changes in renal function which occur following prostaglandin synthetase inhibition in healthy conscious humans. It was...
1. Experiments were performed to determine the changes in renal function which occur following prostaglandin synthetase inhibition in healthy conscious humans. It was hoped that such experiments could provide information on the mechanism by which renal prostaglandin synthesis influences urinary excretion. 2. In water-diuretic male subjects (receiving a slow saline infusion) the renal excretion of sodium and water was reduced following I.V. acetylsalicylic acid (1 g) administration, while the effective renal plasma flow (p-aminohippurate clearance), and glomerular filtration rate (inulin clearance) remained unaltered. 3. In normally hydrated female subjects on an unrestricted diet, the mean urinary prostaglandin E output was 8.5 ng/hr. The renal excretion of sodium, water and urinary prostaglandin E were significantly reduced (P less than 0.05) following oral acetylsalicylic acid (1.2 g) administration. 4. In normally hydrated female subjects on an unrestricted diet the renal excretion of sodium and water was reduced following oral paracetamol (1.5 g) administration. 5. It is concluded that following renal prostaglandin synthetase inhibition in conscious humans, the excretion of sodium and water can be reduced without measurable changes in the glomerular filtration rate or effective renal plasma flow. It is suggested that in conscious healthy humans, the kidney may continually synthesize prostaglandin which might help to maintain sodium and water excretion by a direct action on the renal tubule without influencing renal blood flow. The relevance of this hypothesis to the intrarenal location of prostaglandin synthetase is discussed.
Topics: Acetaminophen; Adolescent; Adult; Aspirin; Cyclooxygenase Inhibitors; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Osmolar Concentration; Prostaglandins E; Regional Blood Flow; Sodium; Urination
PubMed: 6767025
DOI: 10.1113/jphysiol.1980.sp013088 -
Journal of Lipid Research May 2010Levuglandins and their stereo- and regio-isomers (termed isolevuglandins or isoketals) are gamma-ketoaldehydes (IsoK) that rapidly react with lysines to form stable...
Levuglandins and their stereo- and regio-isomers (termed isolevuglandins or isoketals) are gamma-ketoaldehydes (IsoK) that rapidly react with lysines to form stable protein adducts. IsoK protein adduct levels increase in several pathological conditions including cardiovascular disease. IsoKs can induce ion channel dysfunction and cell death, potentially by adducting to cellular proteins. However, IsoKs also adduct to phosphatidylethanolamine (PE) in vitro, and whether PE adducts form in cells or contribute to the effects of IsoKs is unknown. When radiolabeled IsoK was added to HEK293 cells, 40% of the radiolabel extracted into the chloroform lower phase suggesting the possible formation of PE adducts. We therefore developed methods to measure IsoK-PE adducts in cells. IsoK-PE was quantified by LC/MS/MS after hydrolysis to IsoK-ethanolamine by Streptomyces chromofuscus phospholipase D. In HEK293 and human umbilical vein endothelial cells (HUVEC), IsoK dose-dependently increased PE adduct concentrations to a greater extent than protein adduct. To test the biological significance of IsoK-PE formation, we treated HUVEC with IsoK-PE. IsoK-PE dose dependently induced cytotoxicity (LC(50) 2.2 muM). These results indicate that cellular PE is a significant target of IsoKs, and that formation of PE adducts may mediate some of the biological effects of IsoKs relevant to disease.
Topics: Animals; Cell Line; Cell Survival; Cytotoxins; Endothelial Cells; Humans; Phosphatidylethanolamines; Phospholipase D; Prostaglandins E; Streptomyces
PubMed: 19965577
DOI: 10.1194/jlr.M001040 -
Postgraduate Medical Journal Nov 1977Evidence exists implicating prostaglandins as mediators of asthma and of chronic inflammation in the lung. In addition to their spasmogenic effects, PGs are also potent...
Evidence exists implicating prostaglandins as mediators of asthma and of chronic inflammation in the lung. In addition to their spasmogenic effects, PGs are also potent in vitro regulators of mediator secretion by basophils, mast cells, or lymphocytes. These regulatory effects of E-series PGs may have considerable significance in drug design and evaluation in both asthma and chronic inflammation.
Topics: Asthma; Humans; Lung; Pneumonia; Prostaglandins E
PubMed: 593987
DOI: 10.1136/pgmj.53.625.652 -
The Journal of Investigative Dermatology Jul 1986To extend our observation that recombinant gamma interferon (r-IFN-gamma) induces the synthesis and expression of HLA-DR antigen we have investigated 2 major areas...
To extend our observation that recombinant gamma interferon (r-IFN-gamma) induces the synthesis and expression of HLA-DR antigen we have investigated 2 major areas including the modulation of r-IFN-gamma-induced HLA-DR expression and the possible immunologic consequences of keratinocyte HLA-DR expression in vitro. The induction of keratinocyte HLA-DR expression was greater for continuous compared with pulse dosage (0.5-24 h) of r-IFN-gamma and was markedly decreased after trypsinization of attached monolayers into single cell suspensions. The r-IFN-gamma caused induction of HLA-DR and this was not influenced by either pretreatment with irradiation, PGE2, or indomethacin. Both HLA-DR+ and HLA-DR- cultured keratinocytes induced RNA synthesis and gamma interferon production by allogeneic peripheral blood mononuclear leukocytes (PBMLs) indicating mononuclear cell activation. However, this activation was not followed by significant mitogenesis and only slightly increased levels of [3H]thymidine incorporation (maximal = 5800 cpm) by the PBMLs was observed. Cultured keratinocytes apparently inhibit both lectin-driven and mixed-lymphocyte reactions by producing a soluble mediator which is not dialyzable, or inhibited by pretreatment with indomethacin or anti-alpha, -beta, -gamma interferon antibodies. These results suggest that lymphocyte-keratinocyte reactions in vitro are complex and may be mediated by a variety of cytokines, lymphokines, and prostaglandins.
Topics: Cell Division; Cell Survival; Concanavalin A; Dinoprostone; Epidermis; HLA-DR Antigens; Histocompatibility Antigens Class II; Humans; In Vitro Techniques; Indomethacin; Interferon-gamma; Lymphocyte Culture Test, Mixed; Lymphocytes; Prostaglandins E; Thymidine; Trypsin
PubMed: 2941488
DOI: 10.1111/1523-1747.ep12523513 -
International Journal of Dermatology Mar 1986Numerous investigations support the theory that arachidonic acid metabolites play a critical role in dictating the progression of chronic immune reactions. With regard... (Review)
Review
Numerous investigations support the theory that arachidonic acid metabolites play a critical role in dictating the progression of chronic immune reactions. With regard to macrophage-mediated inflammatory responses, enzymatic oxygenation of arachidonic acid via the lipoxygenase or cyclooxygenase pathway can result in the production of compounds that may potentiate or suppress the inflammatory lesion. We recently have presented data demonstrating that lipoxygenase derived leukotriene B4 and C4 can induce the release of IL-1 by macrophages, while PGE2 and PGI2 can suppress the production of IL-1. Macrophages are central to the induction of immune responses and the progression of chronic inflammatory reactions. Therefore, an understanding of the role that macrophage-derived arachidonic acid metabolites play in the initiation, maintenance, and resolution of chronic immune responses is essential. As shown in Figure 3, there are a number of chemical signals that occur between macrophages and lymphocytes that are critical for immune cell communication. The investigations described above have demonstrated that the macrophage may regulate the production and expression of any or all of these signals, such that the inflammatory response is potentiated, sustained, suppressed, or resolved. A better comprehension of the activity of these potent arachidonate derivates will undoubtedly aid in the therapeutic manipulation of inflammatory disease.
Topics: Animals; Arachidonic Acids; B-Lymphocytes; Mice; Phagocytes; Phospholipids; Prostaglandins E; Prostaglandins F; T-Lymphocytes
PubMed: 3516896
DOI: 10.1111/j.1365-4362.1986.tb04543.x -
The Journal of Experimental Medicine Aug 1979Hemopoietic colony-forming cells committed to macrophage differentiation (M-CFC) are selectively and differentially inhibited by prostaglandin E (PGE). A hierarchy of...
Hemopoietic colony-forming cells committed to macrophage differentiation (M-CFC) are selectively and differentially inhibited by prostaglandin E (PGE). A hierarchy of sensitivity was observed among murine CFC stimulated by colony-stimulating factors (CSF) which differ in their ability to initiate proliferation of morphologically distinct colony types, or stimulated by CSF provided by macrophage feeder layers. Inhibition of macrophage colony formation to 50 percent levels occurred with PGE concentrations between 10(-8) and 10(-9) M, and was still evident at 10(-10) -10(-11) M PGE concentrations. The growth of mixed colonies containing both macrophages and neutrophils was less sensitive to the inhibitory effects of PGE, however, the monocytoid component of these colonies was reduced in the presence of PGE. Neutrophil progenitor cell proliferation was not influenced by PGE concentrations below 10(-6) M, regardless of time of addition of PGE, whereas clonal macrophage expansion, as well as clone size, was sensitive to inhibition by PGE when added as late as 3 d after culture initiation. Prostaglandin F(2alpha), was not inhibitory to colony formation. Experimental evidence for a selective role of macrophage PGE in the regulation of macrophage colony formation was directly provided by utilizing resident peritoneal macrophages as a source of CSF for bone marrow target cell overlays. Simultaneous morphological analysis of colonies proliferating in bilayer culture in response to increasing concentrations of macrophages, and direct measurements of PGE synthesized by an identical number of macrophages maintained in liquid culture demonstrate that a specific decline in macrophage colony formation occurs coincident with a linear increase in macrophage PGE synthesis. Inhibition of macrophage PGE synthesis by indomethacin results in the specific enhancement of macrophage colony formation. Furthermore, macrophage PGE synthesis is induced by CSF preparations with the selective capacity to differentially stimulate macrophage proliferation, but not by those which preferentially stimulate granulocyte colony formation. In comparison to the effects of PGE on M-CFC, polymorphonuclear granulocyte-derived lactoferrin (LF) reduces macrophage production of colony-stimulating activities for macrophage, mixed macrophage- neutrophil and neutrophil colony formation. The ability of LF to reduce macrophage PGE synthesis, presumably by decreasing CSF production, suggests that LF and PGE can interact in the control of macrophage and granulocyte proliferation.
Topics: Animals; Ascitic Fluid; Bone Marrow Cells; Cell Division; Colony-Stimulating Factors; Female; Granulocytes; Lactoferrin; Macrophages; Mice; Prostaglandins E
PubMed: 313430
DOI: 10.1084/jem.150.2.277