Proinflammatory effects of phospholipase A2 (PLA2) in several in vitro and in vivo systems.
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Animals↗
Biomedical subjects
J Chang
Publications and source records attributed to J Chang.
The effect of temperature on the formation of ethanol by Candida albicans in blood.
The effect of temperature on microbial fermentation in blood was studied. Specimens of human blood from a blood bank were inoculated with Candida albicans, an organism capable of causing fermentation. A preservative was added to a portion of the inoculated specimens. These inoculated specimens, as well as uninoculated blood, were stored under various temperature conditions. Production of ethyl alcohol was monitored over a period of six months. Fermentation was found to be highly temperature dependent, with refrigeration proving to be most effective at inhibiting ethanol formation.
Alcoholism↗
The use of bone marrow cells grown in long-term culture for autologous bone marrow transplantation in acute myeloid leukaemia: an update.
Eleven patients with acute myeloid leukaemia have been transplanted with autologous marrow grown in long-term bone marrow culture. In the high risk group (six patients who had all previously relapsed) the procedure induced a remission in two patients who were in florid relapse at the time of the transplant. Five patients were transplanted in first remission and they remain well and disease-free between 150 and 12 weeks after their autologous transplant.
Adolescent↗
Long-term bone marrow cultures: their use in autologous marrow transplantation.
When cultured together, hemopoietic cells and marrow stromal cells can support hemopoiesis in vitro in the absence of added growth factors. The continued production of stem cells, progenitor cells, and mature cells within these "long-term bone marrow cultures" (LTBMC) requires their physical association with the stromal cells. For reasons that are not well understood, leukemic cells often fail to survive in such cultures. We and others have undertaken studies to examine whether LTBMC can be exploited as a way of purging the bone marrow of leukemia patients prior to autologous marrow transplantation.
Bone Marrow Cells↗
Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]membrane sulfonamide), an orally active leukotriene antagonist: effects on arachidonic acid metabolism in various inflammatory cells.
The LTD4 antagonist, Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide), was assessed for its ability to modulate arachidonic acid metabolism in several inflammatory cells. In A23187-stimulated rat neutrophils, Wy-48,252 effectively inhibited the conversion of exogenous [14C]arachidonic acid to radiolabeled 5-hydroxyeicosatetraenoic acid (5-HETE) and thromboxane B2 (TxB2) (IC50 = 2 and 9.1 microM, respectively). Synthesis of immunoreactive leukotriene B4 (LTB4) (IC50 = 4.6 microM) and TxB2 (IC50 = 3.3 microM) from endogenous substrate by these cells in the absence of [14C]arachidonic acid was similarly reduced. Wy-48,252 also reduced leukotriene C4 (LTC4) and PGE2 synthesis by zymosan-activated mouse peritoneal macrophages (IC50 = 4.4 and 4.3 microM, respectively). 5-Lipoxygenase (5-LO) catalyzed reactions in human neutrophils, lung mast cells and basophils activated by various stimuli were dose dependently inhibited by Wy-48,252 while PGD2 synthesis by lung mast cells was inhibited at 100 microM. By contrast, 12-LO, 15-LO, phosphodiesterase activity and histamine release from mast cells and basophils were unaffected by Wy-48,252. These data suggested that the LTD4 antagonist, Wy-48,252, also inhibited the synthesis of eicosanoids, a feature that may contribute to its pharmacological actions in vivo.
Animals↗
Interleukin-1 activates phospholipase A2 in human synovial cells.
Interleukin-1 (IL-1) treatment of synovial cells from rheumatoid arthritis and osteoarthritis patients resulted in a dose-dependent secretion of phospholipase A2 (PLA2). IL-1 also stimulated prostaglandin E2 and plasminogen activator synthesis, in parallel with PLA2 activation; all 3 were detectable within 6 hours of IL-1 treatment and peaked by 24 hours. Synovial cell PLA2 required calcium (5 mM) and a neutral pH (7.5) for maximal activity and appears similar to the PLA2 in synovial fluid, which has been described previously. We conclude that PLA2 can be induced by IL-1, and its secretion may contribute significantly to the inflammatory actions of IL-1.
Arthritis, Rheumatoid↗
Effects of cisplatin on parathyroid hormone- and human lung tumor-induced bone resorption.
We have previously shown that dichlorodiamine platinum (DDP), or cisplatin, a cancer chemotherapeutic agent, is effective in the treatment of malignancy-associated hypercalcemia. In the present studies, we evaluated its effects on bovine parathyroid hormone (PTH)- or tumor-induced bone resorption in vitro in the neonatal mouse calvarial bone resorption assay. PTH alone or tumor extract (TE) of a human squamous cell lung cancer alone caused a significant increase in the bone resorption and in the number of osteoclasts in the calvaria. The addition of 3 and 10 micrograms/ml DDP inhibited the PTH- or TE-induced bone resorption. Lower doses of 1 and 2 micrograms/ml DDP, although not effective in inhibiting the PTH-induced bone resorption, were effective in lowering the TE-induced bone resorption. The number of osteoclasts was also reduced by DDP treatment. We therefore conclude that DDP is effective in the treatment of malignancy-associated hypercalcemia by virtue of its inhibitory effects on osteoclast numbers and on bone resorption.
Animals↗
Possible antiestrogenic activity of lindane in female rats.
During chronic peroral (PO) treatment of weanling, female Fischer 344 rats with daily injections (0.069 mmol/kg) of either 1,1'-(2,2,2-trichloroethylidene) bis [4-chlorobenzene] (p,p'-DDT), 2,4-dichlorophenoxy acetic acid (2,4-D), or gamma-hexachlorocyclohexane (lindane), the lindane treatment induced a significant 20% increase in body weight after 110 days. Further investigation with 0, 5, 10, 20, and 40 mg/kg lindane confirmed a significant increase in average body weight gain at the two highest doses after ten weeks of treatment. Significantly greater food consumption was observed, and the Lee index indicated that lindane treatment induced obesity. In addition to obesity, lindane caused a delay in vaginal opening, disrupted estrous cycling, reduced pituitary and uterine weight, and elevated food consumption during proestrus (when appetite is normally suppressed by estradiol). These responses suggest that, by inducing alterations in the reproductive function of the female rat and by interfering with hormonal regulation of energy balance, lindane may be antiestrogenic rather than estrogenic as previously proposed.
Animals↗
Effect of a novel leukotriene D4 antagonist with 5-lipoxygenase and cyclooxygenase inhibitory activity, Wy-45,911, on leukotriene-D4-and antigen-induced bronchoconstriction in the guinea pig.
Wy-45,911 (4-[hydroxy-[3-(2-quinolinylmethoxy)phenyl] amino]-4-oxabutanoic acid, methyl ester) was found to inhibit competitively leukotriene D4 (LTD4)-induced contractions of the isolated guinea pig trachea but not those of leukotriene C4 (LTC4), even in the presence of a gamma-glutamyltranspeptidase inhibitor, reduced glutathione (GSH). Tracheal contractions induced by histamine or pilocarpine were also not significantly altered by Wy-45,911. The drug inhibited the tracheal contractions induced by antigen, even in the presence of GSH. This latter effect resulted from inhibition of 5-lipoxygenase (5-LO), as the synthesis of 5-LO products by rat polymorphonuclear leukocytes and by mouse macrophages was markedly reduced by Wy-45,911. The drug inhibited both LTD4-induced and antigen-induced bronchoconstriction when injected intraduodenally or intragastrically into intact guinea pigs though it was more potent against LTD4-induced bronchoconstriction. We conclude that Wy-45,911 is a novel, orally active LTD4 antagonist in the guinea pig, with some 5-LO inhibitory activity.
Animals↗
Mediastinoscopy: its changing role.
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Carcinoma, Bronchogenic↗
Acute toxicity of helenalin in BDF1 mice.
The acute toxicity of helenalin, a sesquiterpene lactone isolated from Helenium microcephalum, was examined in male BDF1 mice. The 14-day LD50 for a single ip dose of helenalin in male mice was 43 mg/kg. A single ip injection of 25 mg helenalin/kg increased serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), urea nitrogen (BUN), and sorbitol dehydrogenase within 6 hr of treatment. Multiple helenalin exposures, ip injection of 25 mg helenalin/kg for 3 days, increased differential polymorphonuclear leukocyte counts and decreased lymphocyte counts. Serum ALT, BUN, and cholesterol levels were also increased by multiple helenalin exposures at 25 mg helenalin/kg/day. Helenalin significantly reduced liver, thymus, and spleen relative weights and histologic evaluation revealed substantial effects of multiple helenalin exposures on lymphocytes of the thymus, spleen, and mesenteric lymph nodes. No helenalin-induced histologic changes were observed in the liver or kidney. Multiple helenalin exposures (25 mg/kg/day) significantly inhibited hepatic microsomal enzyme activities (aminopyrine demethylase and aniline hydroxylase) and decreased microsomal cytochromes P-450 and b5 contents. Three concurrent days of diethyl maleate (DEM) pretreatment (3.7 mmol DEM/kg, 0.5 hr before helenalin treatment) significantly increased the toxicity of helenalin exposure. The present studies indicate that the hepatic microsomal drug metabolizing system and lymphoid organs are particularly vulnerable to the effects of helenalin. In addition, helenalin toxicity is increased by DEM pretreatments which have been shown to decrease glutathione concentrations.
Animals↗
The antiinflammatory action of guanabenz is mediated through 5-lipoxygenase and cyclooxygenase inhibition.
Guanabenz (2,6-dichlorobenzylidene amino guanidine acetate), an alpha 2-agonist, possesses antiinflammatory activity. Since leukotrienes (LT) and prostaglandins (PG) are proinflammatory substances, the effect of guanabenz on LT and PG synthesis by inflammatory cells was investigated. Guanabenz, but not clonidine, B-HT 920 or B-HT 933 inhibited zymosan-induced LTC4 (IC50 = 13 microM) and PGE2 (IC50 = 10.9 microM) synthesis with no concomitant reduction in zymosan phagocytosis or cell viability. Similarly, guanabenz reduced LTB4 (IC50 = 37.4 microM) and PGE2 (IC50 = 13.8 microM) synthesis by A23187-stimulated rat glycogen elicited neutrophils. Furthermore, guanabenz did not inhibit platelet 12-lipoxygenase or phospholipase A2. In vivo, guanabenz was orally active against rat carrageenan paw edema and adjuvant arthritis (ED50s = 9 and 10 mg/kg, respectively). Topically applied guanabenz reduced arachidonic acid (AA)- or tetradecanoyl phorbol acetate (TPA)-induced ear inflammation (ED50s: AA-induced ear edema, 1.4 mg/ear; PMA-induced ear edema, 0.013 mg/ear). Therefore, the antiinflammatory activity of guanabenz may be due to its ability to inhibit the formation of 5-lipoxygenase and cyclooxygenase products.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Phospholipase A2: function and pharmacological regulation.
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Animals↗
Inhibition of phospholipase A2 (PLA2) activity by nifedipine and nisoldipine is independent of their calcium-channel-blocking activity.
The effects of several calcium antagonists on phospholipase A2 (PLA2) activity were examined. Nifedipine and nisoldipine inhibited a cell-free preparation of PLA2 in a dose-dependent manner with maximal inhibition of 71-77% observed at 100 microM. More potent or equipotent dihydropyridine calcium antagonists such as nitrendipine and felodipine did not inhibit PLA2 activity. In addition, nondihydropyridine calcium antagonists such as diltiazem, verapamil, and cinnarazine failed to reduce PLA2 activity markedly. Nifedipine and nisoldipine also reduced PLA2 activity in intact mouse peritoneal macrophages where PLA2 activity was monitored by free [14C]arachidonic acid release from [14C]arachidonic acid-prelabeled cells. When levels of PGE2 and LTC4 were measured by radioimmunoassay, it was found that the synthesis of these two metabolites was concomitantly inhibited by nifedipine and nisoldipine. In vivo, nifedipine and nisoldipine inhibited tetradecanoylphorbol acetate (TPA) induced ear edema. UV irradiation of nifedipine and nisoldipine (which destroys the slow calcium-channel-blocking activity of these compounds) did not result in a loss of PLA2 inhibitory activity. In fact, in both instances the UV-irradiated forms of nifedipine and nisoldipine were slightly more potent PLA2 inhibitors than the parent compound alone. We therefore conclude that the ability of nifedipine and nisoldipine to inhibit PLA2 was direct and unrelated to their actions on slow calcium channels.
Animals↗
Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse.
Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.
Animals↗
REV 5901 and Ly 171,883 protect rat gastric mucosa against ethanol-induced damage.
The effect of the leukotriene antagonist, Ly 171,883, or the 5-lipoxygenase inhibitor, REV 5901, on ethanol-induced gastric lesion formation in the rat was investigated. Pretreatment with REV 5901 resulted in a dose dependent decrease in lesion length. Doses of 32 and 64 mg/kg induced nearly complete protection against ethanol, while doses of 1 and 8 mg/kg were much less effective. With Ly 171,883, 32 and 64 mg/kg doses less dramatically reduced lesion length. These findings implicate products of the 5-lipoxygenase pathway in the production of ethanol-induced gastric lesions.
Acetophenones↗
Phospholipase A2 activation by interleukin 1: release and metabolism of arachidonic acid by IL 1-stimulated rabbit chondrocytes.
Treatment of rabbit chondrocytes with natural or recombinant human IL 1 results in a dramatic dose-dependent increase in intracellular phospholipase A2 (PLA2) activity and subsequent secretion of this enzyme into the intracellular millieu. PLA2 activity is detectable as early as 1 hr after IL 1 stimulation and is maximal by 24 hr. In the present study, we have characterized more fully the relationship between PLA2 activation and arachidonate metabolism in these cells. IL 1 treatment of chondrocytes which had been prelabeled with [14C]arachidonic acid resulted in an enhanced release of free arachidonic acid identified by thin-layer chromatography. Moreover, the arachidonic acid liberated was subsequently metabolized exclusively to PGE2; no significant increases in the production of 6-keto PGF1 alpha, LTB4, LTC4, 12-HETE or 15-HETE were observed following IL 1 stimulation.
Animals↗