leukotriene-d4 and Edema

Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C4, LTD4, and LTE4), and prostaglandin (PG) E2 are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators.. We sought to determine the role of LTD4-PGE2 crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro.. Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD2 and macrophage inflammatory protein 1β generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA.. LTD4 plus PGE2 potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit(W-sh) mice. Furthermore, LTD4 plus PGE2, through cysteinyl leukotriene receptor 1 (CysLT1R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1β secretion, COX-2 upregulation, and PGD2 generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE2-potentiated effects are partially sensitive to CysLT1R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo.. Our results unravel a unique LTD4-PGE2 interaction affecting mast cells through CysLT1R and EP3 involving Gi, protein kinase G, and Erk and contributing to vascular inflammation in vivo. Furthermore, current results also suggest an advantage of targeting both CysLT1R and EP3 in attenuating inflammation.

Topics: Animals; Capillary Permeability; Cell Line; Cell Line, Tumor; Dinoprostone; Edema; Humans; Inflammation; Leukotriene D4; Mast Cells; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Leukotriene; Receptors, Prostaglandin E, EP3 Subtype

The cysteinyl leukotrienes (cys-LTs) are a family of potent lipid mediators of inflammation derived from arachidonic acid. Activation of certain cell types results in the biosynthesis and export of leukotriene (LT) C(4), which then undergoes extracellular metabolism to LTD(4) and LTE(4). LTE(4), the most stable cys-LT, is only a weak agonist for the defined type 1 and type 2 cys-LT receptors (CysLT(1)R and CysLT(2)R, respectively). We had recognized a greater potency for LTE(4) than LTC(4) or LTD(4) in constricting guinea pig trachea in vitro and comparable activity in eliciting a cutaneous wheal and flare response in humans. Thus, we hypothesized that a vascular permeability response to LTE(4) in mice lacking both the CysLT(1)R and CysLT(2)R could establish the existence of a separate LTE(4) receptor. We now report that the intradermal injection of LTE(4) into the ear of mice deficient in both CysLT(1)R and CysLT(2)R elicits a vascular leak that exceeds the response to intradermal injection of LTC(4) or LTD(4), and that this response is inhibited by pretreatment of the mice with pertussis toxin or a Rho kinase inhibitor. LTE(4) is approximately 64-fold more potent in the CysLT(1)R/CysLT(2)R double-deficient mice than in sufficient mice. The administration of a CysLT(1)R antagonist augmented the permeability response of the CysLT(1)R/CysLT(2)R double-deficient mice to LTC(4), LTD(4), and LTE(4). Our findings establish the existence of a third receptor, CysLT(E)R, that responds preferentially to LTE(4), the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention.

Topics: Animals; Capillary Permeability; Edema; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Mice; Mice, Knockout; Receptors, Leukotriene

The effect of fat-rich diets on the acute inflammatory response was examined. Male Wistar rats aged 21 days were fed, for 6 weeks, with a control diet (4% fat content), or a control diet supplemented with coconut or soybean oils (15% fat content). Carrageenan-induced paw oedema and pleurisy were evaluated. Prostaglandin (PG) E2 and leukotriene (LT) C4/D4 concentrations were determined in the pleural exudate (ELISA). Pleural samples were tested for their effect on cutaneous vascular permeability of control rats and the effect of a LTD4 receptor antagonist (L660-711; 10 mg/kg; i.v.) examined. Relative to controls, rats fed both fat-rich diets presented a significant reduction in protein leakage and oedema formation without affecting the number of migrating leukocytes. Production of LTC4/D4 in pleural exudate was significantly increased from 1.8 +/- 0.2 ng/ml in controls to 2.8 +/- 0.2 and 3.0 +/- 0.3 ng/ml in animals fed coconut and soybean oil enriched diets, respectively, without changes in PGE2 production. The activity of these samples on cutaneous vascular permeability was 50% reduced, returning to control values after treatment of testing animals with a LTD4 receptor antagonist. Rats fed fat-rich diets presented a reduced inflammatory response due, at least in part, to the LTC4/D4 mediated vasoconstrictor effect.

Topics: Acute-Phase Reaction; Animals; Capillary Permeability; Carrageenan; Coconut Oil; Dietary Fats; Dinoprostone; Edema; Enzyme-Linked Immunosorbent Assay; Exudates and Transudates; Hindlimb; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Male; Plant Oils; Pleural Effusion; Pleurisy; Propionates; Quinolines; Rats; Rats, Wistar; Skin; Soybean Oil

Loratadine (CAS 79794-75-5) was effective in inhibiting the contractions of the ileum induced by histamine in guinea pigs. The drug also caused an anti-acetylcholine, anti-serotonin and anti-leukotriene D4 (LTD4) effect. In addition, loratadine inhibited the synthesis of leukotrienes more potently than ketotifen. On the other hand, in in vitro studies of histamine release from rat peritoneal mast cells induced by compound 48/80 or lung fragments in actively sensitized guinea, pigs, loratadine elicited a significant inhibition at a concentration of 5 mumol/l. In ex vivo studies, the drug inhibited histamine release from lung fragments induced by concanavalin A, and significant effect lasted for 24 h when the drug was administered at a dose of 20 mg/kg. The drug inhibited LTD4 release as well as histamine from lung fragments in actively sensitized guinea pigs. Loratadine inhibited not only 45Ca uptake into the rat peritoneal mast cells but also Ca2+ release from the intracellular Ca store induced by compound 48/80 or A23187. Loratadine increased cAMP content in rat lung preparation while decreasing cGMP content. Loratadine caused no significant change in order parameter and phospholipase A2 activity. The drug was more potent than ketotifen and terfenadine in inhibiting antigen-induced increase in airway resistance in guinea pigs. In addition, the effect of loratadine on airway resistance was sustained for 12 h. Loratadine inhibited an increase in dye leakage into the nasal cavity in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Animals; Edema; Granuloma; Guinea Pigs; Histamine; Histamine Release; Hypersensitivity, Delayed; In Vitro Techniques; Leukotriene D4; Leukotrienes; Loratadine; Lung; Male; Mast Cells; Muscle Contraction; Muscle, Smooth; Rats; Rats, Wistar; Serotonin

Propolis is a natural product produced by the honey bee. The extract contains amino acids, flavanoids, terpenes and cinnamic acid derivatives. In various in vitro models propolis extract was shown to inhibit platelet aggregation and to inhibit eicosanoid synthesis, suggesting that it might have potent antiinflammatory properties. A 13% aqueous extract was tested orally in three dose levels (1, 5 and 10 ml/kg) on the carrageenan rat paw oedema model and on adjuvant-induced arthritis in rats. In both models, the extract showed potent dose-related antiinflammatory activity, which compared well with that of diclofenac (as a reference standard). The extract was then tested on an isolated sensitized guinea pig lung preparation to study its effect on the release of prostaglandins, leukotrienes and histamine. It is concluded that propolis extract has potent antiinflammatory properties in vivo. Its activity can be well correlated with its effects on the release of various mediators of inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Diclofenac; Dinoprostone; Dose-Response Relationship, Drug; Edema; Guinea Pigs; Histamine Release; In Vitro Techniques; Inflammation; Leukotriene D4; Lung; Male; Propolis; Prostaglandins; Rats