leukotriene-b4 and Nasal-Polyps

To characterize gene expression in sinonasal polyps and to gain insight into change in expression after oral corticosteroid treatment.. Nasal polyps were obtained before and after oral corticosteroid treatment and gene expression was analyzed with a focused gene array technique.. Pretreated sinonasal polyps demonstrated high gene expression for chemokine and leukotriene receptor genes (CCR2, CCR5, CX3CL1, and LTB4R) in all patients. After treatment, the global effects of corticosteroids were evident on gene expression.. Gene array techniques hold promise as a research method in sinonasal polyposis. The potential benefits, as well as the potential challenges, in using these research methods will be discussed.

Topics: Administration, Oral; Anti-Inflammatory Agents; Biopsy; Chemokine CCL2; Chemokine CX3CL1; Chemokines, CX3C; Down-Regulation; Endoscopy; Female; Gene Expression; Glucocorticoids; Humans; Leukotriene B4; Male; Membrane Proteins; Methylprednisolone; Nasal Polyps; Oligonucleotide Array Sequence Analysis; Paranasal Sinus Diseases; Polyps; Receptors, CCR2; Receptors, CCR5; Receptors, Chemokine; Receptors, Leukotriene B4

Prostaglandins and leukotrienes are implicated in conditions of both the upper and lower airways. In the former they are deranged in nasal polyposis, intrinsic rhinitis and allergic rhinitis while in the latter they are involved in the pathogenesis of asthma. The aim of the present study was to measure mucosal eicosanoid levels in the three types of rhinitis and compare with controls. In addition, the effect of topical steroids on eicosanoid levels in rhinitis was examined. The levels of prostaglandins E(2) (PGE(2)) and D(2) (PGD(2)) and of leukotrienes E(4) (LTE(4)) and B(4) (LTB(4)) were measured in nasal biopsies from the inferior turbinates of patients suffering from perennial rhinitis and a control group. Rhinitis patients were classified into three categories: perennial allergic rhinitis (PAR), non-allergic rhinitis with eosinophilia (NARES) and noneosinophilic non-allergic rhinitis (NENAR) on the basis of symptoms, secretion eosinophilia, nasal resistance and allergy testing. Patients with rhinitis were randomized into two groups. One received fluticasone propionate nasal spray (FPANS) and the other a placebo (PNS) over a period of six weeks prior to the biopsies. One hundred and one patients with PAR, NARES or NENAR were recruited sequentially and the control group consisted of 21 patients with no evidence of rhinitis but with nasal obstruction due to septal deviation. Untreated rhinitics had significantly lower levels of PGE(2), PGD(2) and LTE(4) than non-rhinitic controls. Six-weeks' treatment with FPANS significantly increased the levels of those eicosanoids in patients with PAR and NARES but they were still significantly below normal. Levels of LTB(4) in all three rhinitis groups were not significantly different from controls and treatment with topical steroids had no effect. Their findings are contrary to current thinking that increased levels of eicosanoids, in particular cysteinyl-leukotrienes, play an important role in the pathogenesis of chronic, non-infective upper airway inflammation.

Topics: Airway Resistance; Androstadienes; Anti-Inflammatory Agents; Chronic Disease; Dinoprostone; Double-Blind Method; Eosinophils; Fluticasone; Humans; Leukocyte Count; Leukotriene B4; Leukotriene E4; Leukotrienes; Nasal Mucosa; Nasal Polyps; Prostaglandin D2; Prostaglandins; Rhinitis; Rhinitis, Allergic, Perennial

Nasal polyposis, a chronic inflammatory disease affecting the upper airways, is a valuable and accessible model to investigate the mechanisms underlying chronic inflammation. The main objective of this study was to investigate a potential involvement of the unfolded protein response (UPR) in the context of oxidative stress and inflammation in nasal epithelial cells from nasal polyps (NP).. Epithelial cells from NP (n = 20) and normal mucosa (Controls, n = 15) in primary culture were analyzed by global proteomic approach and cell biology techniques for the glucose-regulated protein 78 (GRP78), the spliced X-box-binding protein 1 (sXBP-1), the glucose-regulated protein 94 (GRP94), and the calreticulin (immunoblot, mass spectrometry, immunocytochemistry).. Proteomics analysis of human nasal epithelial cells in culture revealed the activation of the unfolded protein response in NP. Systematic cell biology and biochemical analysis of two markers (GRP78, sXBP-1) in the presence and absence of oxidative stress in NP showed a susceptibility of the unfolded protein response to oxidative stress compared to controls at least partially linked to an abnormal redox state of the protein disulfide-isomerase 4. This unfolded protein response was correlated with mitochondrial depolarization and secretion of interleukin 8 (IL-8) and leukotriene B4 (LTB4) and was prevented by mitochondrial antioxidant.. We show the existence of UPR in nasal epithelial cells that is linked to oxidative stress leading to IL-8 and LTB4 secretions. These mechanisms may participate in chronic inflammation in nasal polyposis.

Topics: Antioxidants; Cells, Cultured; Endoplasmic Reticulum Chaperone BiP; Epithelial Cells; Gene Expression Regulation; Humans; Inflammation; Interleukin-8; Leukotriene B4; Nasal Mucosa; Nasal Polyps; Oxidative Stress; Proteome; Proteomics; Unfolded Protein Response

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

The mechanism of action of H1-blockers requires elucidation because they may possess properties unrelated to the blockage of histamine at its receptor level. A study was performed with enzymatically dispersed cells obtained from nasal polyps to examine the effect of terfenadine (0.1-10 mumol) on the release of leukotrienes (LT) (LTC4/D4 and LTB4) after stimulation by anti-IgE, and on the spontaneous release of cytokines (granulocyte/macrophage-colony stimulating factor [GM-CSF] and tumor necrosis factor-alpha [TNF-alpha]) released from cells cultured for 6 h. Terfenadine inhibited significantly, and in a dose-dependent manner, the release of LTC4/D4, LTB4, TNF-alpha, and GM-CSF. IC50 values were determined for LTC4/D4 (8 mumol), LTB4 (9.9 mumol), TNF-alpha (6.1 mumol), and GM-CSF (4 mumol). Terfenadine was found to possess new antiallergic properties with a novel in vitro model which mimics more closely inflammatory cells of allergic rhinitis or asthma.

Topics: Adolescent; Adult; Cells, Cultured; Cytokines; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine H1 Antagonists; Humans; Inflammation Mediators; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotrienes; Male; Middle Aged; Nasal Polyps; Terfenadine; Tumor Necrosis Factor-alpha

It has been suggested that hyperosmolarity may be one of the stimuli that provoke exercise-induced asthma and rhinitis. We investigated whether changes in osmolarity could result in increased levels of mediator release from nasal cells. Cells were dispersed from nasal polyps by enzymatic digestion and were incubated for 15 minutes with solutions of varying osmolarity obtained by the addition of mannitol to Hanks' balanced salt solution. After incubation was performed, cell supernatants were removed, and the release of 15-hydroxyeicosatetraenoic acid, prostaglandin2 leukotriene B4, and fibronectin was measured. Lactate dehydrogenase was measured to assess cell viability. Epithelial cells made up 40% to 60% of cells and mononuclear cells 40% to 65%. At 900 mOsm/kg H2O, which has been suggested as the osmolarity of the fluid lining the airways during exercise, we observed a significant increase (Wilcoxon W test) in the release of 15-hydroxyeicosatetraenoic acid (p < 0.008), leukotriene B4 (p < 0.008), and prostaglandin2 (p < 0.008), but no significant increase in the release of fibronectin was seen. No significant increase was seen between lactate dehydrogenase and 15-hydroxyeicosatetraenoic acid release, suggesting that the increase in mediator levels was not caused by cell death. These results show that hyperosmolar solutions can induce activation of nasal cells, which may at least partly explain rhinitis caused by exercise.

Topics: Adolescent; Adult; Cell Separation; Cell Survival; Dinoprostone; Epithelium; Female; Fibronectins; Humans; Hydroxyeicosatetraenoic Acids; Hypertonic Solutions; Inflammation Mediators; L-Lactate Dehydrogenase; Leukotriene B4; Male; Middle Aged; Nasal Polyps; Osmolar Concentration

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