15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Nasal-Polyps

Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D. We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD.. Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis.. Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081).. Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

Topics: Aspirin; Asthma, Aspirin-Induced; Cyclooxygenase Inhibitors; Eicosanoids; Humans; Hydroxyeicosatetraenoic Acids; Immunity, Innate; Lymphocytes; Nasal Mucosa; Nasal Polyps; Prostaglandins; Sinusitis

The mechanism of aspirin sensitivity in patients with asthma and rhinosinusitis has been attributed to arachidonic acid metabolism abnormalities.. We aimed to test whether aspirin-triggered generation of 15-hydroxyeicosatetraenoic acid (15-HETE) in nasal polyp dispersed cells (NPDCs) from aspirin-sensitive patients is associated with activation of inflammatory cells.. Polyps were obtained from 11 aspirin-sensitive and 19 aspirin-tolerant patients with chronic rhinosinusitis. NPDCs were stimulated by aspirin or calcium ionophore. Levels of 15-HETE, leukotriene (LT) C4, eosinophil cationic protein (ECP), and tryptase were measured in NPDC supernatant.. NPDCs from aspirin-sensitive patients contained more eosinophils (14% vs 9%, P < .05) and released 2.4-fold more ECP (P < .01) at baseline. Stimulation with aspirin (200 microM) resulted in a significant increase in 15-HETE generation only in tissue from aspirin-sensitive patients (mean increase, 82%) but did not induce any increase in the release of LTC4, ECP, or tryptase. Preincubation with calcium ionophore resulted in significantly enhanced generation of 15-HETE, ECP, tryptase, and LTC4 in patients from both groups. Incubation of NPDCs with misoprostol inhibited aspirin-induced 15-HETE generation in aspirin-sensitive patients and calcium ionophore-induced 15-HETE, ECP, and tryptase release in both aspirin-sensitive and aspirin-tolerant patients.. Our study demonstrated that aspirin-induced 15-HETE generation in nasal polyps from aspirin-sensitive patients is not associated with activation of mast cells and eosinophils. Misoprostol has a potent inhibitory effect on the activation of cells derived from the site of nasal mucosal inflammation, regardless of sensitivity to aspirin.

Topics: Adult; Aged; Aged, 80 and over; Arachidonate 15-Lipoxygenase; Aspirin; Calcium Ionophores; Drug Hypersensitivity; Eosinophils; Female; Humans; Hydroxyeicosatetraenoic Acids; Male; Mast Cells; Middle Aged; Misoprostol; Nasal Polyps

The mechanism of aspirin (acetylsalicylic acid [ASA]) sensitivity associated with severe asthma and chronic rhinosinusitis with nasal polyps ("aspirin triad") has been attributed to arachidonic metabolism alternations, although the putative biochemical defects have not been elucidated. The aim of this study was assessment of the hypothesis that local production of eicosanoids in the respiratory epithelium in patients with ASA-sensitive asthma/rhinosinusitis (ASARS) differs from that of ASA-tolerant patients with rhinosinusitis (ATRS). Nasal polyps were obtained from 10 patients with ASARS and 15 with ATRS during routine polypectomies, and epithelial cells (ECs) were cultured on bovine collagen type I matrix (Vitrogen 100), in medium supplemented with growth factors. The generation of eicosanoids in supernatants of confluent ECs (6 to 8 d of culture; purity > 98%) was quantified by immunoassays. Unstimulated ECs from ASARS patients generated significantly less prostaglandin E(2)(PGE(2)) compared with ATRS (0.8 +/- 0.3 versus 2. 4 +/- 0.5 ng/microg double-stranded deoxyribonucleic acid [dsDNA], respectively), although a similar relative increase in response to calcium ionophore and inhibition with ASA was observed in both groups. Basal levels of 15-hydroxyeicosatetraenoic acid (15-HETE) were not different between groups, and calcium ionophore enhanced its production to a similar extent. However, cells incubation with 200 microM ASA for 60 min resulted in a significant increase (mean +359%) in 15-HETE generation only in ASARS patients, whereas no effect of ASA on 15-HETE generation in ATRS patients was observed. PGF(2alpha) generation was similar in both groups, and no significant generation of PGD(2) or leukotriene C(4) (LTC(4)) was observed in epithelial cell cultures from either group. Our results indicate that nasal polyps ECs from ASA-sensitive patients have significant abnormality in basal and ASA-induced generation of eicosanoids which may be causally related to the mechanism of ASA sensitivity.

Topics: Adult; Aged; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Aspirin; Asthma; Cattle; Cells, Cultured; Dinoprostone; Drug Hypersensitivity; Female; Humans; Hydroxyeicosatetraenoic Acids; Male; Middle Aged; Nasal Polyps; Prostaglandin D2; Respiratory Mucosa

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

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonate 15-Lipoxygenase; Bronchi; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene A4; Leukotrienes; Lipoxins; Nasal Polyps; Neutrophils

Chopped human nasal polyps and bronchial tissue produced lipoxin A4 and isomers of lipoxins A4 and B4, but not lipoxin B4, after incubation with exogenous leukotriene A4. In addition, these tissues transformed arachidonic acid to 15-hydroxyeicosatetraenoic acid. The capacity per gram of tissue to produce lipoxins and 15-hydroxyeicosatetraenoic acid was 3-5-times higher in the nasal polyps. Neither tissue produced detectable levels of lipoxins or leukotrienes after incubation with ionophore A23187 and arachidonic acid. Co-incubation of nasal polyps and polymorphonuclear granulocytes with ionophore A23187 led to the formation of lipoxins, including lipoxins A4 and B4. The results indicate the involvement of an epithelial 15-lipoxygenase in lipoxin formation in human airways.

Topics: Arachidonate 15-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Bronchi; Calcimycin; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene A4; Leukotrienes; Lipoxins; Nasal Polyps; Neutrophils

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

Nasal polyp tissue is characterized by its frequent infiltration by large numbers of eosinophils. We have studied the metabolism of 14C-labeled arachidonic acid by both nasal polyp tissue and by eosinophils. The major metabolite produced by both is 15-hydroxyeicosatetraenoic acid (HETE) with lesser amounts of 12-HETE. No cyclooxygenase pathway products were found. The 15-lipoxygenase activity of nasal polyps averages 30 times that of normal nasal mucosa or chronically inflamed sinus mucosa. Nasal polyps which contained significant numbers of eosinophils averaged 7 times the 15-lipoxygenase activity of nasal polyps without eosinophilia. Thus, eosinophils appear to be a major source of 15-lipoxygenase activity in nasal polyps.

Topics: Arachidonic Acid; Arachidonic Acids; Eosinophils; Humans; Hydroxyeicosatetraenoic Acids; Nasal Polyps