prostaglandin-d2 and Sinusitis

The relationship between rhinitis and chronic sinusitis is close and complex and may perhaps show many points of view, anatomical and physiological, epidemiological (by comparing the prevalence of an ailment in carriers of another ailment), experimental (by making nasal allergen provocation tests and studying the sinus anomalies induced) and physiopathological (by phenotyping and comparison of the inflammation present with one another and other ailments). If the results of these studies are convincing, there is still lack of formal proof that confirms the fundamental role of nasal inflammation in general and in particular allergic inflammation in the genesis of sinusitis.

Topics: Allergens; Chronic Disease; Cytokines; Eosinophilia; Humans; Leukocytes; Nasal Mucosa; Nasal Polyps; Nasal Provocation Tests; Paranasal Sinuses; Prevalence; Prostaglandin D2; Radiography; Respiratory Hypersensitivity; Rhinitis; Sinusitis

Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease (AERD). With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD.. Patients with nasal polyposis and asthma with AERD (n=20) and without (n=18) were orally challenged with aspirin in a single-blind placebo controlled study. Serum samples and urine were collected before and 6h after placebo and aspirin oral challenges. Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA. The concentrations of 9-alpha, 11-beta prostaglandin F2, and leukotriene E4 (uLTE4) were measured in urine samples by ELISA. The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges.. AERD patients showed significantly higher baseline levels of s-IL-5R-alpha, uLTE4 and percentage of CD4(+)CD25(+)CD127(pos) and CD4(+)CD45RA(-)CD45RO(+) but decreased levels of TGF-β1 and number of CD4(+)CD25(+)CD127(neg) cells. Aspirin challenge induced the release of uLTE4, IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects. Further, IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction (bronchial and nasal).. AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease. Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma, Aspirin-Induced; Chronic Disease; Cytokines; Female; Humans; Immunoenzyme Techniques; Inflammation Mediators; Leukotriene E4; Male; Middle Aged; Nasal Polyps; Prostaglandin D2; Rhinitis; Single-Blind Method; Sinusitis; T-Lymphocyte Subsets

Numerous open trials have demonstrated the beneficial clinical effects of aspirin desensitization (AD) in patients with aspirin-induced asthma (AIA). These beneficial effects might be attributable to aspirin's potent anti-inflammatory properties, but that supposition requires further corroboration.. We sought to compare the clinical and biochemical responses to chronic oral AD in 20 patients with AIA and 14 patients with aspirin-tolerant asthma (ATA). All of the patients had chronic rhinosinusitis and nasal polyposis, and these responses were investigated in a pilot, double-blind, placebo-controlled study.. Twelve patients with AIA and 6 patients with ATA were randomly assigned to receive 624 mg of aspirin, and 8 patients with AIA and 8 patients with ATA received placebo. Both aspirin and placebo were administered once daily for 6 months. Nasal symptoms, Sino-Nasal Outcome Test (SNOT20) scores, peak nasal inspiratory flows, Asthma Control Questionnaire scores, spirometric parameters, peak expiratory flows, blood eosinophilia, and corticosteroid doses were assessed on a monthly basis. Levels of urinary leukotriene E4 and the stable plasma prostaglandin (PG) D2 metabolite 9α,11β-PGF2 were evaluated at baseline and after 1, 3, 5, and 6 months.. Only the patients with AIA subjected to AD reported improvements in smell and reductions in sneezing and nasal blockade. The SNOT20 and Asthma Control Questionnaire scores of these patients decreased, and their peak nasal inspiratory flows increased. The dosages of inhaled corticosteroids were reduced. There were no changes in leukotriene E(4) or 9α,11β-PGF(2) levels after AD.. The clinically beneficial effects of AD on nasal and bronchial symptoms occurred only in the patients with AIA.

Topics: Administration, Oral; Adult; Aged; Allergens; Aspirin; Asthma; Asthma, Aspirin-Induced; Chronic Disease; Desensitization, Immunologic; Dinoprost; Double-Blind Method; Eosinophils; Female; Follow-Up Studies; Humans; Leukotriene E4; Male; Middle Aged; Nasal Polyps; Pilot Projects; Prostaglandin D2; Rhinitis; Sinusitis; Spirometry; Treatment Outcome

Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD).. We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD.. Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation.. Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells.. Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Topics: Adult; Aged; Asthma, Aspirin-Induced; Cells, Cultured; Cytokines; Eosinophilia; Female; Humans; Leukocyte Count; Male; Mast Cells; Middle Aged; Nasal Polyps; Prostaglandin D2; Prostaglandins D; Rhinitis; Sinusitis; Thymic Stromal Lymphopoietin; Young Adult

Topics: Aspirin; Asthma; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprostone; Homeostasis; Humans; Nasal Polyps; Prostaglandin D2; Sinusitis

Treatment with acetylsalicylic acid (ASA) after desensitization may be a therapeutic option in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD). The mechanisms that lead to improvement in rhinosinusitis and asthma symptoms remain unknown.. To attribute the documented clinical effects of ASA treatment of chronic rhinosinusitis and/or asthma to the release of eicosanoid metabolites in urine.. Fourteen patients with NERD were successfully desensitized, and, eventually, eight patients were treated with 650 mg of ASA daily for 3 months. In addition to clinical assessments, nuclear magnetic resonance imaging and smell test were performed before and after treatment with ASA. Venous blood and urine were collected before desensitization and after 1 and 3 months of treatment. The levels of urinary leukotrienes (LT) (cysteinyl LT and LTE4) and tetranor PGDM (metabolite of prostaglandin D2) were measured by enzyme-linked immunosorbent assay.. Treatment with ASA after desensitization alleviated symptoms of rhinosinusitis, improved nasal patency (mean, 50% decrease in peak nasal inspiratory flow) and sense of smell (fourfold increase in smell test score) in as early as 4 weeks. Clinical improvements were not accompanied by any change in sinonasal mucosa thickness as assessed with nuclear magnetic resonance. Urinary cysteinyl LTs, LTE4, and prostaglandin D2 metabolite remained relatively stable during ASA treatment and did not correlate with clinical improvements. Desensitization was associated with a progressive decrease of urinary creatinine.. Clinical improvement in rhinosinusitis and/or asthma after ASA desensitization was not related to concentrations of urinary eicosanoid metabolites. A decrease of urinary creatinine requires further study to determine the renal safety of long-term treatment with ASA after desensitization.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Creatine; Desensitization, Immunologic; Drug Hypersensitivity; Eicosanoids; Humans; Leukotrienes; Prostaglandin D2; Respiratory Tract Diseases; Sinusitis

Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD2, is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD2 and its metabolite, but not PGE2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD2-dependent, rather than PGE2-dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD2, as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS.

Topics: Adult; Aged; Animals; Chronic Disease; Eosinophils; Female; Humans; Inflammation; Killer Cells, Natural; Leukocyte Count; Male; Middle Aged; Nasal Mucosa; Prostaglandin D2; Sinusitis

Prostaglandin D(2) (PGD(2)) participates in airway inflammation. We reported that levels of hematopoietic-type PGD(2) synthase (h-PGDS) in sinonasal tissues may play an important role in the pathophysiology of chronic rhinosinusitis (CRS). Two PGD(2) receptors have been isolated, DP and CRTH2, but whether they participate in CRS remains unclear. We sought to determine the expression and characterization of DP and CRTH2 in CRS.. Expression of DP and CRTH2 in nasal polyps (NP) and uncinate process mucosae (UPM) was examined by in situ hybridization and immunohistochemistry and evaluated by real-time quantitative PCR. h-PGDS, IL-5, eotaxin and RANTES expression was also determined. In addition, the effect of PGD(2) on the expression of both receptors in UPM was assessed.. DP was widely expressed, not only in infiltrating inflammatory cells but also in constitutive cells such as vascular endothelial cells and ciliated columnar epithelia. CRTH2 was selectively expressed in inflammatory cells and some glands. Significantly greater levels of DP mRNA and conversely decreased levels of CRTH2 mRNA were observed in NP compared with UPM. DP and CRTH2 mRNA levels were not only positively and inversely correlated with levels of h-PGDS but also with eotaxin, respectively. Furthermore, addition of PGD(2) significantly increased DP expression and conversely reduced CRTH2 expression in UPM.. These results suggest that distinct expression of DP and CRTH2 is associated with the pathophysiology of CRS, including NP formation, and the expression of these receptors may be regulated by h-PGDS and PGD(2).

Topics: Adolescent; Adult; Aged; Chronic Disease; Eosinophils; Female; Gene Expression Regulation; Humans; Inflammation; Intramolecular Oxidoreductases; Lipocalins; Male; Middle Aged; Nasal Mucosa; Nasal Polyps; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Perennial; RNA, Messenger; Sinusitis; Young Adult

The prevalence of patients with chronic rhinosinusitis (CRS) refractory to traditional therapy appears to be on the increase. In these cases, CRS tends to be associated with bronchial asthma (BA), especially, aspirin-intolerant asthma (AIA). On the other hand, arachidonic acid metabolites have been extensively investigated in the pathogenesis of BA. We sought to assess the role of prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)) in the recalcitrant pathophysiology of CRS.. Samples were prepared from the nasal polyps and mucosa of 40 patients undergoing endoscopic sinus surgery (ESS) at our hospital. The nasal polyp specimens obtained from the patients with CRS were divided into three groups, as follows: the CRS-AIA group, consisting of specimens obtained from patients with CRS complicated by AIA, the CRS-ATA group, consisting of specimens obtained from patients with CRS associated with aspirin-tolerant asthma (ATA), and the CRS-NA group, consisting of specimens obtained from CRS patients without BA. PGD(2) and PGE(2) were extracted from the specimens and quantified.. The concentrations of PGD(2) were significantly higher in the nasal polyps of the CRS-ATA group. The concentrations of PGE(2) were lowest in the nasal polyps of the CRS-AIA group. The PGD(2)/PGE(2) ratio was highest in the CRS-AIA group.. It has previously been reported that CRS complicated by AIA is most likely to be characterized by repeated remissions and relapses, and is thus the most intractable. We may therefore say that the PGD(2)/PGE(2) ratio reflects the intractable nature of CRS.

Topics: Adult; Aged; Aspirin; Asthma; Cell Extracts; Chronic Disease; Dinoprostone; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Nasal Polyps; Paranasal Sinuses; Prostaglandin D2; Rhinitis; Sinusitis

Although many studies have assumed that the overproduction of cysteinyl- leukotrienes (cys-LTs) and an imbalance of arachidonic acid metabolism may be plausible causes for the pathogenesis of aspirin-intolerant asthma (AIA), there has been little experimental evidence to substantiate this notion in lower airways of patients with AIA.. The purpose of this study was to compare the eicosanoid concentrations in sputum and urine from patients with AIA.. The concentrations of sputum cys-LTs, prostaglandin E2 (PGE2), PGF2alpha, PGD2 and thromboxane B2 were measured to assess local concentrations of eicosanoids in patients with AIA and in those with aspirin-tolerant asthma (ATA). The concentrations of two urinary metabolites, leukotriene E4 (LTE4) and 9alpha11betaPGF2, were also measured to corroborate the relationship between the eicosanoid biosynthesis in the whole body and that in lower airways.. The concentration of PGD2 in sputum was significantly higher in patients with AIA than in those with ATA (median, 5.3 pg/mL vs. 3.1 pg/mL, P < 0.05), but there was no significant difference in the concentration of the corresponding metabolite, 9alpha11betaPGF2, between the two groups. No differences were noted in the concentrations of other prostanoids in sputum between the two groups. The sputum cys-LT concentrations showed no differences between the two groups, in spite of the observation that the concentration of urinary LTE4 was significantly higher in patients with AIA than in those with ATA (median, 195.2 pg/mg-cre vs. 122.1 pg/mg-cre, P < 0.05). There was a significant correlation among the concentration of cys-LTs, the number of eosinophils and the concentration of eosinophil-derived neurotoxin (EDN) in sputum.. The urinary concentration of LTE4 does not necessary reflect cys-LT biosynthesis in lower airways. A significantly higher concentration of PGD2 in sputum from patients with AIA suggests the possible ongoing mast cell activation in lower airways.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Case-Control Studies; Drug Hypersensitivity; Eicosanoids; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Humans; Leukocyte Count; Leukotriene E4; Male; Middle Aged; Prostaglandin D2; Rhinitis; Ribonucleases; Sinusitis; Sputum

Chronic sinusitis is a recurrent disorder commonly found in atopic individuals, yet few studies have explored the role of inflammatory mediators in sinusitis. Sinus lavage fluid from ten patients with chronic sinusitis obtained during endoscopic surgery was analyzed for total cell counts and then assayed for histamine, immunoreactive leukotriene C4/D4/E4 (LTC4/D4/E4), and prostaglandin D2 (PGD2). All ten patients had been unresponsive to medical treatment, including oral corticosteroids in most cases. High concentrations of histamine, LTC4/D4/E4 and PGD2 were found in sinus fluid and were comparable to levels seen in nasal secretions of allergic rhinitis patients following allergen challenge. In the sinus fluid, inflammatory cells were predominantly neutrophils with only low percentages of mast cells, basophils or eosinophils. On the basis of the histamine and PGD2 concentrations in sinus fluid, we conclude that mast cell/basophil activation does occur in chronic sinusitis and may contribute to the persistent inflammation present in sinusitis.

Topics: Adolescent; Adult; Aged; Basophils; Body Fluids; Cell Count; Cell Degranulation; Child; Chronic Disease; Female; Histamine; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Mast Cells; Middle Aged; Prostaglandin D2; Sinusitis; Therapeutic Irrigation