thromboxane-b2 and Nasal-Polyps

In this study the effects of antihistamines on the release of eicosanoids and the pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha) were compared. Enzymatically dispersed cells from human nasal polyps served as an in vitro model of chronic respiratory mucosal inflammation. Nasal polyp cells (2 x 10(5)/ml) were sensitized with human IgE pre-incubated azelastine (CAS 58581-89-8), terfenadine (CAS 50679-08-8), levocabastine (CAS 79516-68-0) or cetirizine (CAS 83881-51-0), and stimulated with anti-human immunoglobulin E (IgE). Thromboxane B2 (TBX2) and leukotriene C4 (LTC4) were measured by radioimmunoassay (RIA), TNF alpha by enzyme-linked immunosorbent assay (ELISA). Data represent mean values of % inhibition estimated from the untreated positive control or mean IC50 (n = 5). Azelastine and terfenadine inhibited TNF alpha release with IC50 values of 6.2 mumol/l and 4.3 mumol/l, respectively. Terfenadine reduced TXB2 release by 37 +/- 15%, and LTC4 release was decreased by azelastine and terfenadine very potently by 86% and 100%, respectively. Azelastine shows anti-inflammatory properties in therapeutically relevant concentrations as assessed by its ability to reduce TNF alpha release as well as its ability to inhibit LTC4 production in allergically stimulated human nasal polyp cells.

Topics: Cytokines; Eicosanoids; Epithelial Cells; Histamine Antagonists; Humans; Immunoglobulin E; Leukotriene C4; Leukotrienes; Nasal Polyps; Thromboxane B2; Tumor Necrosis Factor-alpha

The mechanisms of action of cyclosporin A require further elucidation since this drug includes anti-inflammatory properties unrelated to its previously documented effect of T cells. A study was performed using enzymatically dispersed cells from nasal polyps of 7 subjects to examine the effects of cyclosporin A on the release of histamine, leukotriene C4/D4 (LTC4/D4) and thromboxane (TxB2) following stimulation by anti-IgE. Cells were resuspended and preincubated with cyclosporin A (0.1, 1 and 10 microM) or 0.1% DMSO (the vehicle used to dissolve cyclosporin A) for 20 min prior to challenge with 10 microgram/ml epsilon-chain-specific anti-IgE for 45 min at 37 degrees C. Histamine, LTC4/D4 and TxB2 were measured using EIA. Cyclosporin A significantly inhibited the release of histamine, LTC4/D4, and TxB2 in a concentration-dependent manner. IC30 values, histamine (5.1 microM), LTC4/D4 (7.8 microM) and TxB2 (6.2 microM), were determined. These data demonstrate new antiallergic properties of cyclosporin A using a novel in vitro model which mimics more closely allergic inflammation.

Topics: Cells, Cultured; Cyclosporine; Histamine Release; Humans; Immunosuppressive Agents; Leukotriene C4; Nasal Polyps; Thromboxane B2

A role of prostaglandins (PGs) and leukotrienes (LTs) in the pathogenesis of nasal polyps has been recently suggested. Cyclooxygenase (CO) products (thromboxane B2, PGE2 and 6-keto PGF1 alpha) and lipoxygenase (LO) products (LTB4 and LTC4) were investigated by radioimmunoassay in polyps, hypertrophic turbinates and nasal mucosa from 14 patients with non-allergic (n = 6), allergic chronic rhinitis (n = 6) and aspirin-sensitive asthma (ASA) (n = 2), who underwent polypectomy. In all tissues CO metabolite levels were found higher than LO products (P < 0.01). Nasal polyps showed a significantly lower (P < 0.05) arachidonic acid (AA) metabolism in comparison to nasal mucosa. In polyps of allergic patients significantly higher LTB4 levels (P < 0.001) and a tendency to produce higher amounts of CO products in comparison to non-allergic subjects were observed, whereas in turbinates of non-allergic patients LT levels were significantly higher in comparison to those of allergic ones (P < 0.01). In ASA patients a decreased CO/LO ratio was found supporting the hypothesis of an imbalance of AA metabolism in this syndrome. These findings seem to indicate that the occurrence of nasal polyps may represent the result of different chronic inflammatory stimuli, regulated in part by AA metabolites.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Asthma; Dinoprostone; Humans; Leukotriene B4; Leukotriene C4; Lipoxygenase; Middle Aged; Nasal Mucosa; Nasal Polyps; Prostaglandin-Endoperoxide Synthases; Rhinitis; Thromboxane B2; Turbinates

In order to clarify the influence of inflammatory mediators of the arachidonic acid cascade in the mechanism of nasal polyp growth, peptido-leukotriene (pLT), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) synthesis was investigated. In addition to several stimuli, functionally intact human biopsy specimens of polypous and normal tissue were incubated. Especially remarkable was the significantly increased release of pLT by polypous tissue upon arachidonic acid stimulation, in contrast to only slightly elevated PGE2 release compared to normal tissue. Basic release of pLT and PGE2 was similar for polypous and normal tissue. Examining TXB2 release, no significant difference was observed with regard to the origin of tissues. These data support an altered pattern of the lipoxygenase and cyclo-oxygenase pathways when tissue becomes irritated and suggest their involvement in the aetiopathogenesis of nasal polyps.

Topics: Biopsy; Case-Control Studies; Dinoprostone; Humans; Immunoenzyme Techniques; Leukotrienes; Nasal Mucosa; Nasal Polyps; Radioimmunoassay; Thromboxane B2

Arachidonic acid metabolites (AAMs) are known to be involved in inflammation. It is suggested that AAMs play an important role in the pathogenesis of nasal polyp. We have measured the levels of prostaglandin E2, 6-keto prostaglandin F1 alpha, thromboxane B2, leukotriene B4 and a mixture of leukotriene C4, D4 and E4 in both nasal polyp and maxillary sinus mucosa by radioimmunoassay. Our results showed that arachidonic acid metabolism in nasal polyps from allergic patients was more active than that from non-allergic patients. The arachidonic acid metabolism in nasal polyp was more active than in maxillary sinus mucosa among allergic patients. On the other hand, arachidonic acid metabolism in maxillary sinus mucosa was more active than that in nasal polyps among non-allergic patients. On the basis of these results, we hypothesized the causal mechanisms of nasal polyps as follows: The nasal polyp in allergic patients is caused by primary inflammation of the nasal mucosa, and sinusitis occurs secondarily. In non-allergic patients, the primary side of inflammation is located in the maxillary sinus mucosa, leading to the secondary formation of nasal polyp.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Arachidonic Acids; Child; Dinoprostone; Female; Humans; Leukotriene B4; Leukotriene E4; Male; Maxillary Sinus; Middle Aged; Mucous Membrane; Nasal Polyps; Respiratory Hypersensitivity; Rhinitis; SRS-A; Thromboxane B2

Prostaglandins (PGs) and leukotrienes (LTs) are known to play an important role in allergic inflammatory reactions. The triad of aspirin sensitivity, nasal polyposis, and asthma led us to suspect that PGs, LTs and other arachidonic acid metabolites may be involved in the pathogenesis of nasal polyps. The purpose of this study was to determine arachidonic acid metabolites and to measure concentrations of PGs and LTs in nasal polyps and nasal mucosa. Samples of nasal polyps and nasal mucosa were obtained at the time of polypectomies and nasal procedures. Metabolites of arachidonic acid in tissue were determined by incubation of tissue-homogenates with 14C-arachidonic acid and analyses with thin-layer chromatography and high performance liquid chromatography (HPLC). Levels of PGE2, 6-keto-PGF1 alpha, thromboxane (Tx)B2, 15-hydroxyeicosatetraenoic acid (HETE), LTC4, LTB4 were measured by radioimmunoassay. The predominant arachidonic acid metabolite in both nasal polyps and mucosa with 15-HETE. The HPLC analysis showed that the predominant metabolite in nasal polyp was 15-HETE, especially in polyps from aspirin sensitive patients. Levels of 15-HETE and PGE2 were higher in polyps from patients with a history of allergy than from nonallergic patients. Levels of LTC4 and LTB4 in nasal polyps were determined. The findings of this study will help to explain biochemical basis of the pathogenesis of aspirin-sensitive nasal polyps and to develop better medical treatment for them.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Nasal Mucosa; Nasal Polyps; Prostaglandins; Prostaglandins E; Radioimmunoassay; SRS-A; Thromboxane B2