interleukin-8 and Rhinitis

Topics: Chronic Disease; Humans; Interleukin-8; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis

Apart from ventilatory and bacteriologic aspects, understanding the pathomechanisms of inflammation in chronic sinusitis and nasal polyposis seems crucial for further success in disease treatment. New insights into inflammatory processes became recently possible by investigating the pattern of cytokines and chemokines as well as adhesion molecules in different acute and chronic sinus diseases. The proinflammatory cytokines interleukin (IL)-1 beta, IL-6 and especially the neutrophil-chemoattractant IL-8 play a dominant role in acute sinusitis, as was shown before for viral and allergic rhinitis. In contrast, IL-3 protein dominates the cytokine profile in chronic sinusitis, giving support to a variety of inflammatory cells. The most striking finding was the increased synthesis of IL-5 protein in bilateral nasal polyposis, whereas IL-5 was not found in controls or antrochoanal polyps. As this cytokine is known to enhance eosinophil activation and survival, our data point to IL-5 as a key protein in the pathomechanism of tissue eosinophilia in nasal polyposis. The investigation of cytokine patterns may furthermore help to differentiate between sinusitis subgroups, e.g. in the classification of sinus diseases.

Topics: Acute Disease; Cell Adhesion Molecules; Chemokines; Chemotaxis, Leukocyte; Chronic Disease; Cytokines; Eosinophilia; Eosinophils; Humans; Interleukin-1; Interleukin-3; Interleukin-5; Interleukin-6; Interleukin-8; Maxillary Sinus; Nasal Polyps; Neutrophils; Paranasal Sinus Neoplasms; Polyps; Rhinitis; Sinusitis

Low-dose clarithromycin has been recommended for the treatment of chronic rhinosinusitis without nasal polyps. However, it is uncertain whether a high dose of clarithromycin is more effective than a low dose.. Forty-three chronic rhinosinusitis patients were randomised to low-dose or high-dose clarithromycin groups, and clinical efficacy was evaluated. Pre- and post-treatment measures included: nasal symptom assessment, endoscopic inspection (Lund-Kennedy system), a quality of life questionnaire (the Sino-Nasal Outcome Test 20) and examination of cytokine levels (interleukin-5 and -8) in nasal secretions.. The high dose of clarithromycin was significantly better in terms of clinical efficacy than the low dose for the treatment of chronic rhinosinusitis (p < 0.025). Significant differences in nasal cytokine levels (interleukin-5 and -8) were also observed between the low-dose and high-dose groups after short-term clarithromycin treatment (p < 0.025).. Short-term, high-dose clarithromycin appears to be more effective for the treatment of chronic rhinosinusitis than low-dose clarithromycin.

Topics: Adult; Anti-Bacterial Agents; Biomarkers; Chronic Disease; Clarithromycin; Dose-Response Relationship, Drug; Female; Humans; Interleukin-5; Interleukin-8; Male; Middle Aged; Quality of Life; Rhinitis; Sinusitis; Surveys and Questionnaires; Treatment Outcome

Recent epidemiologic and in vivo studies have suggested that inhaled endotoxin plays an important role in asthma pathogenesis.. The present study examines the effect of nasal allergen provocation on subsequent endotoxin challenge in subjects with atopic asthma.. By using a split-nose randomized crossover design, individual nares of 12 asthmatic subjects underwent challenge and lavage as follows. Immediately after a baseline nasal lavage, one nares received normal saline, and the other received dust mite antigen. Four hours later, both nares were exposed to either saline or endotoxin. Dust mite antigen (Dermatophagoides farinae) and endotoxin (Escherichia coli 026:B6) doses were 100 AU and 1000 ng, respectively. Postchallenge lavages were done at 8 and 24 hours after the initial challenge. The subjects then returned a minimum of 3 weeks later for crossover to the study arm. Nasal lavage fluid was analyzed for total and differential cell counts, IL-8, IL-6, intercellular adhesion molecule 1, GM-CSF, eosinophil cationic protein, myeloperoxidase, and soluble CD14.. A significant increase in the total inflammatory cell count was seen at 8 hours for the dust mite/endotoxin exposure compared with the saline/saline and saline/endotoxin exposures. Differential cell counts revealed a similar neutrophilic and eosinophilic inflammation for the dust mite/endotoxin exposure at 8 hours.. These data demonstrate an interaction between allergen and endotoxin exposure in asthmatic subjects, suggesting that a prior allergen challenge significantly augments the endotoxin-induced inflammation. Moreover, these data provide further evidence that concomitant exposure to allergen and endotoxin may be an important factor in asthma pathogenesis.

Topics: Adult; Asthma; Cross-Over Studies; Endotoxins; Female; Humans; Hypersensitivity, Immediate; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Male; Nasal Lavage Fluid; Nasal Provocation Tests; Rhinitis; Solubility

We sought to determine whether a normal alpha1-antitrypsin (AAT) gene could be expressed in respiratory epithelium and whether local expression would have antiinflammatory effects. In an unblinded study, we delivered a normal AAT gene in a plasmid-cationic liposome complex to one nostril of each of five subjects with AAT deficiency; the other, untreated nostril served as a control. AAT protein concentration in nasal lavage fluid (NALF) increased in the transfected nostril (TN), but not in the control nostril (CN), of every subject, peaking on day 5 at levels about one-third normal (baseline CN, 4.1 +/- 1.2 microg/mg of protein; baseline TN, 4.3 +/- 1.3; day 5 CN, 4.0 +/- 0.5 [p = NS versus baseline]; day 5 TN, 9.0 +/- 1.7 [p < 0.5 versus baseline]); isoelectric focusing identified the transgene-generated protein (M) in the only two patients in whom the measurement was possible. The reverse transcriptase-polymerase chain reaction (RT-PCR), performed on NALF from TN and CN of four of the five subjects, was positive for transgene message in TN in all cases and negative in NALF from CN except for one time point in one subject. Interleukin 8 (IL-8) concentrations in NALF were elevated at baseline (normal [N = 10] = 2.5 +/- 0.5 ng/mg of protein; baseline TN = 5.5 +/- 0.8, p < 0.05 versus normal) and decreased after AAT transfection (TN = 2.9 +/- 0.6, p < 0.05 versus baseline) but not in the control nostril (CN = 6.5 +/- 2.2, p = NS versus baseline). NALF samples taken from four of the patients while receiving intravenous AAT protein showed normal concentrations of AAT, but IL-8 concentrations (10.5 +/- 4.2 ng/mg of protein, p = NS versus baseline) were not decreased from baseline. We conclude that plasmid-cationic liposome delivery of a normal AAT gene to the respiratory epithelium of deficient patients produces potentially therapeutic local AAT concentrations and that AAT gene therapy, unlike AAT protein therapy, is antiinflammatory.

Topics: Administration, Intranasal; Adult; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Anti-Inflammatory Agents, Non-Steroidal; Drug Carriers; Female; Genetic Therapy; Humans; Interleukin-8; Liposomes; Male; Middle Aged; Nasal Lavage Fluid; Nasal Mucosa; Rhinitis; Transfection; Transgenes

Interleukin-8 (IL-8) is a major cytokine in the recruitment of neutrophils (polymorphonuclear leukocytes) to areas of inflammation. It also activates T lymphocytes and cytokine-primed basophils and eosinophils and therefore may be implicated as an effector in allergic inflammation. IL-8 has also been identified as a mediator in such inflammatory pulmonary conditions as cystic fibrosis, allergen challenge, and sarcoidosis. To investigate the bioactivity of IL-8 in humans, we examined the effects of nasal challenge with human recombinant IL-8 in a double-blind placebo-controlled crossover study in which nasal resistance and rhinitic symptoms were monitored for 4 h after challenge. Cellular infiltration was quantified on differentially stained nasal smears obtained at hourly intervals. Cellular responses caused by in vivo priming were assessed by a comparison of atopic and nonatopic patient groups. A significant neutrophilic infiltrate in smear samples was observed in all patients challenged with IL-8 from 12 +/- 4% (mean +/- SEM) at baseline to 60 +/- 6% after 4 h; placebo challenge resulted in an increase in neutrophils to 30 +/- 4% (p < 0.04). Additionally, a significant increase in cumulative eosinophil recruitment occurred over the challenge period. Nasal resistance was significantly increased 10 min after instillation of IL-8 in all subjects compared with placebo, but there was no difference between atopic and nonatopic subjects. Nasal rhinitic symptoms were also increased in all subjects receiving IL-8 compared with placebo. In a further study in 19 subjects, nasal biopsy was performed 3 h after IL-8 or placebo challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Airway Resistance; Biopsy; Cross-Over Studies; Double-Blind Method; Female; Humans; Hypersensitivity, Immediate; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Nasal Mucosa; Nasal Provocation Tests; Recombinant Proteins; Rhinitis; Statistics, Nonparametric; Time Factors

To examine whether and how interleukin (IL)-1α is involved in chronic rhinosinusitis with nasal polyps (CRSwNP).. Nasal polyp (NP) and control tissues were collected from CRSwNP patients and control subjects. The expression of IL-1α and other proinflammatory cytokines (IL-1β, IL-8 and IL-13, etc.), as well as neutrophil and eosinophil accumulation, were examined in sinonasal tissues using immunohistochemical (IHC), immunofluorescent (IF) staining, qPCR, and Luminex, respectively. Moreover, the regulation of IL-1α expression and its effects on other proinflammatory cytokines were evaluated in cultured nasal epithelial cells (NECs).. The mRNA and protein levels of IL-1α were significantly higher in NP tissues compared to that in control tissues. IL-1α in polyp tissues was mainly located in epithelial cells and neutrophils. Polyps IL-1α level was significantly associated with IL-8, IL-1β, IL-6, IL-4 and IL-13 production, as well as tissue neutrophil infiltration. Moreover, poly (I:C), lipopolysaccharides, Flagellin, R848 and cytokines (IL-4, IL-5, and IL-13) significantly increased the expression of IL-1α in cultured NECs in vitro, and recombinant IL-1α significantly promoted production of IL-8 and CXCL1 in cultured NECs.. These findings provided the evidence that IL-1α were significantly increased in NP tissues, which may contribute to tissue neutrophilia in CRSwNP patients in China.

Topics: Chronic Disease; Humans; Interleukin-13; Interleukin-4; Interleukin-8; Nasal Polyps; Rhinitis; Sinusitis

Although metabolomics provides novel insights into disease mechanisms and biomarkers, the metabolic alterations in local tissues affected by chronic rhinosinusitis (CRS) are unknown.. This study aimed to determine the metabolomic profiles of sinonasal tissues associated with different types of CRS and their treatment outcomes.. Untargeted metabolomic profiling was performed on sinonasal tissues obtained from patients with eosinophilic CRS with nasal polyps (CRSwNP), noneosinophilic CRSwNP or CRS without nasal polyps (CRSsNP), and controls. The messenger RNA (mRNA) levels of inflammatory cytokines in nasal tissues were detected by quantitative real-time reverse transcriptase PCR. Nasal polyp tissues were cultured ex vivo and treated with glutathione.. Distinct metabolomic profiles were observed for the CRS subtypes. Eosinophilic CRSwNP had profoundly enhanced unsaturated fatty acid oxidization, which correlated with mucosal eosinophil numbers and IL-5 mRNA levels. Noneosinophilic CRSwNP was characterized by uric acid accumulation. Increased uric acid levels were positively correlated with mucosal neutrophil numbers and IFN-γ, IL-17A, IL-1β, and IL-8 mRNA levels. Disrupted purine metabolism was specifically detected in CRSsNP. Reduced levels of amino acid metabolites were found in eosinophilic CRSwNP and CRSsNP, and were inversely associated with mucosal total inflammatory cell numbers and inflammatory cytokines. Compared to non-difficult-to-treat CRS, difficult-to-treat CRS had higher glutathione disulfide levels, which were positively correlated with IL-8 mRNA levels. Glutathione treatment reduced IL-8 mRNA expression in cultured nasal polyp tissues.. Specific metabolic signatures are associated with different types of CRS, inflammatory patterns, and disease outcomes, which may provide novel insights into pathophysiologic mechanisms, subtype-specific biomarkers, and treatment targets of CRS.

Topics: Biomarkers; Chronic Disease; Cytokines; Glutathione; Humans; Interleukin-8; Nasal Polyps; Rhinitis; RNA, Messenger; Sinusitis; Uric Acid

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammation of the mucosa of the nose and paranasal sinuses with the presence of polyps, affecting between 2.7% and 4.4% of the population. Cytokine analysis has become important in research on inflammatory mechanisms in CRSwNP. Therefore, our aim is to investigate the complex appearance, relative distribution, and interlinks of IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, and Ki-67 in CRSwNP.. Samples of nasal polyps were obtained from 19 patients with previously diagnosed CRSwNP and the recurrence of polyps after previous surgeries. The control group consisted of samples from 17 otherwise healthy individuals with isolated nasal septum deviations. Tissues were stained for previously mentioned cytokines and Ki-67 immunohistochemically.. Polyp samples showed an increased presence of cytokines in subepithelial connective tissue and a decreased appearance in epithelium when compared to controls. There were several very strong, strong, and moderate correlations among factors.. IL-6 strongly correlates with other cytokines as well as with the proliferation marker Ki-67, which suggests significant stimulation of this regulatory cytokine and its possible involvement in the pathogenesis of recurrent nasal polyps. IL-4, IL-7, IL-10, and IL-12 correlate with Ki-67, which suggests the possible involvement of these cytokines in tissue cell proliferation in the case of recurrent nasal polyps.

Topics: Cell Proliferation; Chronic Disease; Cytokines; Humans; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-6; Interleukin-7; Interleukin-8; Ki-67 Antigen; Nasal Polyps; Rhinitis; Sinusitis

Staphylococcus aureus colonization and release of enterotoxin B (SEB) has been associated with severe chronic rhinosinusitis with nasal polyps (CRSwNP). The pathogenic mechanism of SEB on epithelial barriers, however, is largely unexplored.. We investigated the effect of SEB on nasal epithelial barrier function.. SEB was apically administered to air-liquid interface (ALI) cultures of primary polyp and nasal epithelial cells of CRSwNP patients and healthy controls, respectively. Epithelial cell integrity and tight junction expression were evaluated. The involvement of Toll-like receptor 2 (TLR2) activation was studied in vitro with TLR2 monoclonal antibodies and in vivo in tlr2. SEB applied to ALI cultures of polyp epithelial cells decreased epithelial cell integrity by diminishing occludin and zonula occludens (ZO)-1 protein expression. Antagonizing TLR2 prevented SEB-induced barrier disruption. SEB applied in the nose of control mice increased mucosal permeability and decreased mRNA expression of occludin and ZO-1, whereas mucosal integrity and tight junction expression remained unaltered in tlr2. SEB damages nasal polyp epithelial cell integrity by triggering TLR2 in CRSwNP. Our results suggest that SEB might represent a driving factor of disease exacerbation, rather than a causal factor for epithelial defects in CRSwNP. Interfering with TLR2 triggering might provide a way to avoid the pathophysiological consequences of S. aureus on inflammation in CRSwNP.

Topics: Adolescent; Adult; Aged; Animals; Case-Control Studies; Cell Line; Enterotoxins; Female; Humans; In Vitro Techniques; Interleukin-6; Interleukin-8; Male; Mice; Mice, Knockout; Middle Aged; Nasal Mucosa; Nasal Polyps; Occludin; Permeability; Primary Cell Culture; Rhinitis; RNA, Messenger; Sinusitis; Staphylococcus aureus; Tight Junctions; Toll-Like Receptor 2; Young Adult; Zonula Occludens-1 Protein

IL-8 is an important chemokine implicated in the pathogenesis of chronic rhinosinusitis (CRS), but little is known about epigenetic regulation of IL8 in the pathogenesis of CRS.. We sought to investigate the relationship between the DNA methylation level in the IL8 proximal promoter and CRS in Han Chinese subjects.. Patients with chronic rhinosinusitis with nasal polyps (CRSwNP; n = 187), patients with chronic rhinosinusitis without nasal polyps (CRSsNP; n = 89), and control subjects (n = 57) were enrolled in 2 independent cohorts. Purified human nasal epithelial cells from each participant were assessed for percentage DNA methylation of CpG sites in the IL8 proximal promoter by using bisulfite pyrosequencing and for functional aspects of methylation status by using in vitro assays.. DNA methylation of CpG sites 1, 2, and 3, respectively, in the IL8 proximal promoter was significantly decreased in human nasal epithelial cells of patients with CRSwNP compared with that in patients with CRSsNP (P < .001) and control subjects (P < .001). Percentage of DNA methylation of the CpG3 site was correlated negatively with both tissue eosinophilic cationic protein (P < .01) and myeloperoxidase (P < .05) levels. IL-1β (P < .001) and TNF-α (P < .01) significantly increased IL8 expression accompanied by a reduction in methylation at the CpG3 site (P < .001). Electrophoretic mobility shift assays demonstrated that methylation status of CpG3 changed the binding of octamer-binding transcription factor 1 and nuclear factor κB.. Decreased DNA methylation of particularly CpG sites in the IL8 proximal promoter might play a role in the pathogenesis of CRSwNP.

Topics: Adolescent; Adult; Aged; Asian People; Chronic Disease; Cohort Studies; CpG Islands; DNA Methylation; Female; Humans; Interleukin-8; Male; Middle Aged; Nasal Polyps; Promoter Regions, Genetic; Respiratory Mucosa; Rhinitis; Sinusitis; Young Adult

High-mobility group box 1 (HMGB1) mediates various functions according to the location. We tried to investigate the role of HMGB1 in upper airway under hypoxic conditions. We cultured primary normal human nasal epithelium (NHNE) cells under hypoxic conditions and evaluated the movement of HMGB1 by western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level was evaluated to estimate the translocation mechanism of HMGB1. The role of secreted HMGB1 was evaluated by ELISA assay. Furthermore, we collected human nasal mucosa samples and nasal lavage fluids from patients conditioned under hypoxic and non-hypoxic environment, and compared the expression of HMGB1 in human nasal mucosa samples by immunohistochemistry and the levels of HMGB1 in lavage fluids using ELISA assay. Hypoxia induced translocation of HMGB1 into the extracellular area and it was dependent on ROS produced by dual oxidase 2. Secreted HMGB1 was involved in the upregulation of interleukin (IL)-8. In human samples, HMGB1 was translocated from nucleus to the cytoplasm in hypoxic-conditioned nasal mucosa. HMGB1 was increased in nasal lavage samples of chronic rhinosinusitis patients, whose sinus mucosa was supposed to be hypoxic as compared with controls. We suggest that HMGB1 is secreted in hypoxic condition via ROS-dependent mechanism and secreted HMGB1 participates in IL-8 upregulation mediating inflammatory response.

Topics: Adult; Cells, Cultured; Chronic Disease; Dual Oxidases; Female; HMGB1 Protein; Humans; Hypoxia; Interleukin-8; Male; Middle Aged; Nasal Mucosa; Reactive Oxygen Species; Respiratory Mucosa; Rhinitis; Sinusitis; Up-Regulation; Young Adult

Topics: Chronic Disease; Humans; Immunity, Innate; Interleukin-33; Interleukin-8; Rhinitis; Sinusitis

Fibroblasts are major supporting cells in nasal mucosa and can induce inflammatory process with recruitment of inflammatory cells. Airborne fungi have been suggested as an etiologic factor of chronic rhinosinusitis (CRS). The aim of this study was to investigate the interaction between airborne fungi and pattern recognition receptors (PRRs) in nasal fibroblasts.. Primary nasal polyp fibroblasts were cultured with Alternaria and Aspergillus for 48h. To determine the production of chemical mediators interleukine-6 (IL-6), IL-8, granulocyte-macrophage colony stimulating factor (GM-CSF), eotaxin, and regulated on activation normal T expressed and secreted (RANTES) were measured with enzyme immunoassay methods. PRRs for toll-like receptors (TLRs) and protease-activated receptors (PARs) mRNA were determined with reverse transcription polymerase chain reaction (RT-PCR). To determine the role of PRRs, fibroblasts were treated with small interfering RNA (siRNA).. IL-6 and IL-8 productions were significantly increased by 50 and 100μg/ml of Alternaria. However, GM-CSF, eotaxin, and RANTES productions did not change. Aspergillus did not influence the production of chemical mediators from nasal polyp fibroblasts. TLR2 and TLR5 mRNA expressions were significantly increased by fungi and these two TLRs were associated with the production of IL-6 and IL-8.. Alternaria interacts as a pathogen-associated molecular pattern with the PRRs, such as TLR2 and TLR5, which induce the production of inflammatory chemical mediators from nasal polyp fibroblasts. Airborne fungi enhance the innate immune defense mechanism and may be associated with the pathogenesis of nasal inflammatory diseases.

Topics: Adult; Alternaria; Aspergillus; Cells, Cultured; Chemokine CCL5; Chemokines; Chronic Disease; Female; Fibroblasts; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Mycoses; Nasal Polyps; Receptors, Pattern Recognition; Receptors, Proteinase-Activated; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis; RNA, Messenger; RNA, Small Interfering; Sinusitis; Toll-Like Receptors

Topics: Asthma; Comorbidity; Eosinophilia; Humans; Inflammation; Interleukin-8; Phenotype; Prevalence; Pulmonary Disease, Chronic Obstructive; Rhinitis; Syndrome

T-helper 2 (Th2) inflammation is a hallmark of chronic rhinosinusitis with nasal polyps (CRSwNP) although the pathogenesis is poorly understood. P-glycoprotein (permeability glycoprotein, P-gp) is an efflux pump that is capable of regulating cytokine transport and is expressed within sinonasal mucosa. The purpose of this study was to examine if the oversecretion of interleukin 5 (IL-5) and thymic stromal lymphopoietin (TSLP) in CRSwNP could be explained through P-gp-mediated secretory pathways.. Fifteen ethmoid mucosal explants were harvested from patients with CRS (n = 10) and CRSwNP (n = 10) and stimulated with Staphylococcus aureus enterotoxin B (SEB). P-gp was inhibited using zosuquidar trihydrochloride (herein Zosuquidar). P-gp expression was measured using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-5, IL-8, and TSLP secretion were quantified using ELISA.. P-gp protein was overexpressed in CRSwNP (28.32 ± 25.94 ng/mL per mg explant) as compared to CRS (10.74 ± 8.61; p = 0.01, 2-tailed Mann-Whitney U test). There was no difference in messenger RNA (mRNA) expression. SEB induced a significant increase in IL-5 and TSLP but not IL-8 secretion relative to control in the CRSwNP explants only. Subsequent P-gp inhibition significantly reduced IL-5 and TSLP secretion (p = 0.04 for both, 2-tailed Student t test) to control levels. The concentration of IL-5 and TSLP secretion were strongly and significantly correlated to the concentration of P-gp within the same explant (IL-5: r = 0.791, p = 0.001; TSLP: r = 0.687, p = 0.003; 2-tailed Spearman's rank-order correlation).. P-gp protein is expressed at higher concentrations in CRSwNP as compared to CRS. This overexpression directly contributes to the relative hypersecretion of IL-5 and TSLP. These findings suggest a novel mechanism for Th2 skewing in CRSwNP.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Cells, Cultured; Chronic Disease; Cytokines; Dibenzocycloheptenes; Enterotoxins; Humans; Interleukin-5; Interleukin-8; Nasal Mucosa; Organ Culture Techniques; Quinolines; Rhinitis; Sinusitis; Staphylococcus aureus; Thymic Stromal Lymphopoietin

Chronic rhinosinusitis without nasal polyps (CRSsNP) is a common chronic disease and the etiology remains unclear. Thromboxane A2 (TXA2) participates in platelet aggregation and tissue inflammation. In this study, the CXCL1/8 chemokine and TXA2-TP receptor expression in the CRSsNP mucosa was investigated.. Immunohistochemistry, chemokine release assay by ELISA, RT-PCR, Real-time PCR, Western blotting, pharmacological and siRNA knockdown analysis were applied in the CRSsNP tissue specimen and cultured nasal mucosa-derived fibroblasts.. The immunohistochemistry results indicated that CXCL1 and CXCL8 were highly expressed in the CRSsNP mucosa compared with the controls; however, the TP receptors were expressed in both mucosa. Therefore, U46619 and IBOP, a TXA2 analog and TP agonist, were used to explore the role of TP activation in CXCL1/8 expression; both of these induced CXCL1/8 mRNA and protein expression in CRSsNP mucosa-derived fibroblasts. U46619 phosphorylated PI-3K, cyclic AMP (cAMP)/PKA, PKC, and cAMP response element (CREB). Activation of cAMP/PKA, PKC, and CREB was the major pathway for cxcl1/8 gene transcription. Pharmacological and siRNA knockdown analyses revealed that activation of cAMP/PKA and PKCμ/PKD pathways were required for CREB phosphorylation and PKA/C crosstalked with the PI-3K pathway.. Our study provides the first evidence for abundant TP receptor and CXCL1/8 expression in human CRSsNP mucosa and for TXA2 stimulation inducing CXCL1/8 expression in nasal fibroblasts primarily through TP receptor, cAMP/PKA, PKCμ/PKD, and CREB-related pathways.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Bridged Bicyclo Compounds, Heterocyclic; Case-Control Studies; Cells, Cultured; Chemokine CXCL1; Cyclic AMP Response Element-Binding Protein; Fatty Acids, Unsaturated; Fibroblasts; Interleukin-8; Nasal Mucosa; Phosphatidylinositol 3-Kinases; Protein Kinase C; Receptors, Thromboxane A2, Prostaglandin H2; Rhinitis; Second Messenger Systems; Sinusitis; Thromboxane A2

Nasal secretions include cytokines and inflammatory mediators that are involved in the pathogenesis of upper airway inflammation.. We tried to find unknown biomolecules that are involved in the pathogenesis of chronic rhinosinusitis (CRS).. We collected nasal mucosal secretions from patients who were diagnosed as having CRS and who underwent endoscopic sinus surgery. A total of 63 patients who underwent nasal secretion collection were reviewed. Enzyme-linked immunosorbent assay was performed by using nasal lavage samples to evaluate which biomolecules were associated with the severity of inflammation based on the Lund-Mackay score. By using human nasal epithelial cells, we performed Western blot, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay to evaluate the secretory mechanism of heat shock protein (HSP) 70.. We found that the level of interleukin 8 and HSP70 were significantly associated with the Lund-Mackay score and interleukin 17C, C-X-C motif chemokine 10, and HSP27 were not significantly associated. HSP70 was also significantly associated with the surgical outcome of the enrolled patients. Furthermore, we found that exposure to hypoxia and treatment of lipoteichoic acid induced the secretion of HSP70 but that lipopolysaccharide did not induce the secretion of HSP70 in human nasal epithelial cells.. Our findings indicated that HSP70 might play a role in the pathogenesis of CRS and the possibility of HSP70 as a biomolecule that represents the severity of CRS.

Topics: Adolescent; Adult; Aged; Cells, Cultured; Chronic Disease; Female; HSP70 Heat-Shock Proteins; Humans; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Rhinitis; Severity of Illness Index; Sinusitis; Teichoic Acids

Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nose and paranasal sinuses. Staphylococcus aureus is increasingly linked with CRS exacerbations. Little is known about how bacteria activate inflammatory pathways that contribute to CRS.. To develop an in vitro coculture system to explore how infection with S aureus stimulates innate immune responses of sinonasal epithelial cells (SNECs).. Sinonasal epithelial cells were collected from 13 patients during endoscopic sinus surgery and grown in culture at the air-liquid interface from July 2014 through December 2014.. Differentiated SNECs from control individuals, patients with CRS with nasal polyps (CRSwNPs), and patients with CRS without nasal polyps (CRSsNPs) were infected with S aureus at 3 different concentrations for 24 hours.. Growth of S aureus and viability of SNECs were measured. Expression of inflammatory markers and innate immune genes was measured by reverse transcription-polymerase chain reaction. Basal secretion of interleukin 8 was determined by enzyme-linked immunosorbent assay.. Cultured SNECs from patients with CRSsNPs demonstrated a significant increase (P < .05) in expression of interleukin 8 (23-fold to 82-fold) and tumor necrosis factor (11-fold to 61-fold) at all the tested concentrations of S aureus. Control or CRSwNP SNECs demonstrated a significant increase (P < .05) in expression of interleukin 8 (47-fold and 50-fold, respectively) and tumor necrosis factor (106-fold and 58-fold, respectively) at the higher inoculum of S aureus. Basal secretion of inflammatory markers correlated with expression changes. No significant changes in expression were observed for the helper T cell, subtype 2, inflammatory mediators tested.. In this study, we developed a model to study early innate immune-mediated changes in SNECs cocultured at an air-liquid interface with bacteria. We also demonstrated that bacterial burden can be detected by SNECs in the absence of adaptive immune-mediated responses. The CRSsNP SNECs are more sensitive to S aureus burden than control or CRSwNP SNECs. Future studies will further develop this infection model and explore the SNEC innate immune response to bacteria.

Topics: Bacterial Load; Case-Control Studies; Cell Survival; Chronic Disease; Coculture Techniques; Epithelial Cells; Humans; Immunity, Innate; Interleukin-8; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis; Staphylococcus aureus; Tumor Necrosis Factor-alpha

High mobility group box 1 (HMGB1) protein is a chromatin protein that functions as a proinflammatory cytokine when secreted in response to inflammatory stimuli. The purpose of this study was to determine the relationship between the HMGB1 level in nasal secretions and the severity of inflammation in chronic rhinosinusitis.. This was a cross-sectional study.. Nasal secretions were obtained by irrigation of the affected sinonasal cavities with normal saline. Total 63 nasal lavage fluid samples were collected from 38 patients with chronic rhinosinusitis who underwent endoscopic sinus surgery. Levels of HMGB1 and tumor necrosis factor alpha, interleukin (IL)-1β, and IL-8 were determined by enzyme-linked immunoassay. Severity of inflammation was assessed by the Lund-Mackay scoring system, which is based on preoperative computed tomography scans. Concurrent medical disorders, presence of nasal polyps, septal deviation, and allergic rhinitis were also investigated.. The level of HMGB1 in nasal lavage fluid was positively correlated with the Lund-Mackay score. The score was the only factor associated with HMGB1 by univariate and multivariate analysis. Other cytokines, with the exception of IL-8, were not correlated with the Lund-Mackay score.. Our results showed that HMGB1 is secreted into the extracellular area space in the upper airway, and HMGB1 levels in nasal lavage fluid correlate with severity of inflammation, as assessed by the Lund-Mackay staging system for chronic rhinosinusitis. These results provide evidence for HMGB1 as an inflammatory mediator associated with the severity of chronic rhinosinusitis.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; HMGB1 Protein; Humans; Immunohistochemistry; Inflammation; Interleukin-1beta; Interleukin-8; Male; Middle Aged; Nasal Lavage Fluid; Rhinitis; Severity of Illness Index; Sinusitis; Tumor Necrosis Factor-alpha; Young Adult

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP accounts for the majority of CRS cases and is characterized by fibrosis and neutrophilic inflammation. However, the pathogenesis of CRS, especially CRSsNP, remains unclear. Immunohistochemistry of CRSsNP specimens in the present study showed that the submucosa, perivascular areas, and the mucous glands were abundant in fibroblasts. Therefore, we investigated the effects bradykinin (BK), an autacoid known to participate in inflammation, on human CRSsNP nasal mucosa-derived fibroblasts (NMDFs). BK increased CXCL1 and -8 secretion and mRNA expression with EC50 ranging from 0.15~0.35 μM. Moreover, BK enhanced cell proliferation and upregulated the expressions of proinflammatory molecules, including cell adhesion molecules (CAMs) and cyclooxygenase (COX)-1 and -2. These functionally caused an increase in monocyte adhesion to fibroblast monolayer. Using pharmacological intervention and BKR siRNA knockdown, we demonstrated that the BK-induced CXCL chemokine release, cell proliferation and COX and CAM expressions were mainly through the B2 receptor (B2R). Accordingly, the B2R was preferentially expressed in the NMDFs than B1R. The B2R was highly expressed in the CRSsNP than the control specimens, while the B1R and kininogen (KNG)/BK expression slightly increased in the CRSsNP mucosa. Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction. Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.

Topics: Bradykinin; Cell Adhesion; Cell Proliferation; Cells, Cultured; Chemokine CXCL1; Chronic Disease; Fibroblasts; Gene Expression; Humans; Interleukin-8; Nasal Mucosa; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Rhinitis; Sinusitis

Firefighters exposed to World Trade Center (WTC) dust have developed chronic rhinosinusitis (CRS) and abnormal forced expiratory volume in 1 s (FEV1). Overlapping but distinct immune responses may be responsible for the clinical manifestations of upper and lower airway injury. We investigated whether a panel of inflammatory cytokines, either associated or not associated with WTC-LI, can predict future chronic rhinosinusitis disease and its severity.. Serum obtained within six months of 9/11/2001 from 179 WTC exposed firefighters presenting for subspecialty evaluation prior to 3/2008 was assayed for 39 cytokines. The main outcomes were medically managed CRS (N = 62) and more severe CRS cases requiring sinus surgery (N = 14). We tested biomarker-CRS severity association using ordinal logistic regression analysis.. Increasing serum IL-6, IL-8, GRO and neutrophil concentration reduced the risk of CRS progression. Conversely, increasing TNF-α increased the risk of progression. In a multivariable model adjusted for exposure intensity, increasing IL-6, TNF-α and neutrophil concentration remained significant predictors of progression. Elevated IL-6 levels and neutrophil counts also reduced the risk of abnormal FEV1 but in contrast to CRS, increased TNF-α did not increase the risk of abnormal FEV1.. Our study demonstrates both independent and overlapping biomarker associations with upper and lower respiratory injury, and suggests that the innate immune response may play a protective role against CRS and abnormal lung function in those with WTC exposure.

Topics: Biomarkers; Dust; Firefighters; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung Injury; Male; Neutrophils; New York; Occupational Exposure; Respiratory Tract Diseases; Rhinitis; Risk Assessment; Risk Factors; September 11 Terrorist Attacks; Severity of Illness Index; Sinusitis; Tumor Necrosis Factor-alpha

The primary human sinonasal epithelial cell culture (HSNEC) allows for in-vitro modelling of mucosal responses to topical therapy. Cultures grown from healthy donors may underestimate changes in individuals with chronic sinonasal disease thereby yielding inaccurate results with respect to this large patient population. The purpose of this study was to analyse HSNECs derived from patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) to determine whether expected disease dependent variables salient to topical drug delivery persist in culture.. Cultures were grown from patients with CRSwNP. Ciliary beat frequency (CBF) (basal and stimulated), permeability (trans and paracellular), inflammatory response, and glucocorticoid dose response were measured and compared with healthy controls.. Methylcholine stimulated CBF was greater in CRSwNP versus controls (ΔCBF(60 min) 7.25 ± 1.02 vs 0.89 ± 1.04 Hz, respectively). Paracellular permeability was greater in CRSwNP versus controls (basolateral dextran(120 min) 18.97 ± 3.90 vs 11.31 ± 4.35 µg/ml, respectively). Lipopolysaccharide (0.1 mg/ml) stimulated interleukin-6 (IL-6) and IL-8 secretion was increased in CRSwNP versus controls (IL-6 Δbaseline 1738.72 ± 654.82 vs 1461.61 ± 533.51%, respectively; IL-8 Δbaseline 137.11 ± 0.83 vs 111.27 ± 0.67%, respectively). CRSwNP cultures were more sensitive than controls to dexamethasone (1 µg/ml) dependent IL-6 and IL-8 suppression.. HSNECs derived from patients with CRSwNP retained their primary phenotype with respect to ciliary function, epithelial permeability, irritant induced inflammatory cytokine secretion, and glucocorticoid dose response.

Topics: Administration, Topical; Case-Control Studies; Cells, Cultured; Chronic Disease; Cilia; Dexamethasone; Dose-Response Relationship, Drug; Epithelial Cells; Glucocorticoids; Humans; Interleukin-6; Interleukin-8; Models, Biological; Nasal Mucosa; Nasal Polyps; Phenotype; Rhinitis; Sinusitis

The biologic mechanisms involved in airway inflammatory response to air pollution are not clearly understood. The authors conducted a longitudinal study to investigate whether exposure to ambient air pollutants affected inflammatory cells and mediators from nasal lavage in schoolchildren. Study participants were 100 elementary and middle-school students in New Taipei City, Taiwan. A structured respiratory health questionnaire was administered in September 2007, followed by monthly measurement of nasal inflammation from October 2007 to November 2009. During the study period, daily concentrations of air pollutants were obtained from the Environmental Protection Administration monitoring station and the Aerosol Supersite. Mixed-effects models were applied to examine the association between air pollution and nasal inflammatory cells and mediators, including percentages of neutrophils, eosinophils, and monocytes in lavaged cells and interleukin-8. A total of 824 measurements were obtained from 100 participants over a period of 10 months. The level of particulate matter with an aerodynamic diameter of 2.5 μm or less (PM(2.5)) was found to be associated with percentage of neutrophils (β = 3.45%, 95% confidence interval: 0.89, 6.01) and interleukin-8 level (β = 29.98 pg/mL, 95% confidence interval: 3.26, 56.69) in the nasal lavage on the day of exposure. In this longitudinal cohort study of schoolchildren, results indicated that exposure to PM(2.5) might induce nasal inflammation.

Topics: Air Pollution; Asthma; Child; Eosinophils; Female; Follow-Up Studies; Health Surveys; Humans; Inflammation; Inhalation Exposure; Interleukin-8; Longitudinal Studies; Male; Models, Statistical; Monocytes; Nasal Lavage Fluid; Neutrophils; Particulate Matter; Rhinitis; Surveys and Questionnaires; Taiwan

The examination was applied to 81 children aged 5-15 years, including 64 children with diagnosis of rhinosinusitis. The control group consisted of 17 healthy children. The set of laboratory clinical diagnostic techniques was applied to detect the causes of pathology. It is established that children with rhinosinusitis suffered from concurrent bacterial and virus infections. The morphologic presentation of mucous membrane of nasal cavity reflects the etiologic factor and the stage of inflammatory process. The detection of concentration of IL-4, IL-6 and IL-8 of blood serum gives a possibility to diagnose children with combined mechanisms of development of rhinosinusitis.

Topics: Adolescent; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-4; Interleukin-6; Interleukin-8; Nasal Cavity; Rhinitis; Sinusitis

The aim of this study was to elucidate the role of IL-8 for neutrophil recruitment in nonallergic CRS patients.. After coculture of Streptococcus pneumoniae (SP) with the mucosal epithelial cells (MECs) from non-CRS patients, at three different SP/MEC (1/1, 10/1, 100/1) ratios, the expression of IL-8 mRNA and the concentration of IL-8 were measured by RT-PCR and ELISA. The expression of CD11b/CD18 on neutrophils and E-selectin/ICAM-1 on endothelial cells and the adherence between neutrophils and human umbilical vascular endothelial cells (HUVECs) were determined by flow cytometric analysis, ELISA, and RIA, respectively.. IL-8 concentration and IL-8 mRNA expression continued to increase from 3 hours after incubation in SP number-dependent manner. The expression of CD11b/CD18 on neutrophils and E-selectin/ICAM-1 on HUVECs, and the adherence between neutrophils and HUVECs were significantly increased in 10 SP/MEC-CM, and the increments were significantly blocked by anti-IL-8 antibody.. MEC and IL-8 are major factors for neutrophil recruitment in nonallergic CRS.

Topics: Adolescent; Adult; Animals; Bacterial Infections; CD11b Antigen; CD18 Antigens; Cells, Cultured; Chronic Disease; Epithelial Cells; Female; Humans; Interleukin-8; Male; Middle Aged; Nasal Mucosa; Neutrophil Infiltration; Rhinitis; Sinusitis; Young Adult

In patients with chronic fungal sinusitis, concentrations of interleukin-8 (IL-8), immunoglobulin E (IgE), and soluble intercellular adhesion molecule-1 (sICAM-1) were compared in paranasal sinus aspirates and serum. Furthermore, immunological effects of macrolide treatment of our patients with chronic fungal rhinosinusitis were also studied.. In our cohort study, 108 patients with chronic rhinosinusitis undergoing sinus surgery were selected. Sinus aspirates were collected, and used for immunological assasy and cultured for fungal study. All patients were examined for the presence of characteristic allergic mucin of chronic allergic fungal rhinosinusitis and this was confirmed later by measurement of total serum IgE.. Our cases were classified into 3 groups: chronic rhinosinusitis with positive fungal culture and negative allergic mucin, chronic rhinosinusitis with positive fungal culture and positive allergic mucin and chronic rhinosinusitis without fungal growth. A control group was included. We found 57.4% of the patient cultures positive for fungus and 36.4% of the control subjects. Aspergillus ssp. were the most prevalent followed by Bipolaris ssp., and Curvularia. IgE levels were increased in group II compared to group I, III and IV. ICAM-1 and IL-8 levels were increased in groups I, II and III compared to the control group. Erythromycin given in group II decreased the levels of IL-8 and ICAM-1.. Aspergillus species were the most common. These results confirm the role of ICAM-1 and IL-8 in all types of rhinosinusitis. Erythromycin modulated the immune status of the patients.

Topics: Adult; Anti-Bacterial Agents; Chronic Disease; Erythromycin; Female; Humans; Immunoglobulin E; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Paranasal Sinuses; Rhinitis; Sinusitis

Airway angiogenesis may be an important part of structural remodelling in the pathogenesis of asthma. The development of asthma is frequently preceded by rhinitis.. We sought to determine whether the levels of angiogenesis-related factors are elevated in airways of patients with rhinitis or controlled asthma.. We analysed the induced sputum of 18 rhinitis patients, 16 asthmatic patients, and 15 healthy controls. The concentrations of angiogenin, vascular endothelial growth factor (VEGF), IL-8, fibroblast growth factor (bFGF), and TNF-alpha were measured by cytometric bead arrays.. We found significantly increased angiogenin and VEGF concentrations in the induced sputum supernatant of both rhinitis and asthma patients compared with that of the healthy control group (P< or =0.0005). With the exception of TNF-alpha, there was no difference in the other angiogenic factors; TNF-alpha levels were higher in the rhinitis group than in the control group (P=0.02).. These in vivo results suggest increased airway angiogenesis in patients with rhinitis without asthma as well as in corticosteroid-treated and well-controlled asthma patients.

Topics: Adolescent; Adult; Aged; Angiogenesis Inducing Agents; Asthma; Cell Count; Eosinophils; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Lymphocytes; Macrophages; Male; Middle Aged; Neutrophils; Rhinitis; Ribonuclease, Pancreatic; Sputum; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

The impact of Staphylococcus aureus in the pathogenesis of chronic rhinosinusitis is not well understood. Therefore, we investigated primary human nasal epithelial cell cultures for their ability to produce IL-8, growth-related oncogene-alpha, and IL-6 via stimulation with trypsin and culture supernatants of different S. aureus strains and phenotypes. Inhibition of cytokine synthesis was performed using a glucocorticoid, a serine protease inhibitor, and a cysteine protease inhibitor. Finally, signal transduction pathways were analyzed by quantifying phosphorylated forms of MAPKs (PI3K, ERK, and p38) and DNA-binding assays that quantified NF-kappaB and its inhibition using BAY11-7085. In vitro studies showed that the induction of IL-8, growth-related oncogene-alpha, and IL-6 by S. aureus culture supernatants was significantly inhibited by the serine protease inhibitor. In contrast, steroids and the cysteine protease inhibitor had little effect. Activation of NF-kappaB was observed after cell treatment with trypsin and bacterial supernatants, and was inhibited by BAY11-7085 and the serine protease inhibitor. S. aureus serine proteases were identified to modulate chemokine synthesis and activate NF-kappaB in nasal epithelial cells, and may therefore be relevant for the pathophysiology of chronic rhinosinusitis.

Topics: Cells, Cultured; Chemokine CXCL1; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Immunomodulation; Interleukin-6; Interleukin-8; Metalloendopeptidases; Middle Aged; Nasal Mucosa; NF-kappa B; Rhinitis; Serine Proteases; Signal Transduction; Sinusitis; Staphylococcal Infections; Staphylococcus aureus

Chronic rhinosinusitis (CRS) is characterized by persistent mucosal inflammation and frequent exacerbations.. To determine whether innate epithelial responses to cigarette smoke or bacterial or viral pathogens may be abnormal in CRS leading to an inappropriate inflammatory response.. Primary nasal epithelial cells (PNECs) were grown from middle turbinate biopsies of 9 healthy controls and 11 patients with CRS. After reaching 80% to 90% confluence, PNECs were exposed to medium or cigarette smoke extract (CSE) 5% (vol/vol) for 1 hour, washed, then stimulated with staphylococcal lipoteichoic acid, LPS, or double-stranded RNA (dsRNA). After 24 hours, gene expression was quantified by QRT-PCR.. At baseline, PNECs revealed elevated TNF-alpha and growth-related oncogene-alpha (a C-X-C chemokine)/CXCL1 (GRO-alpha) (4-fold increase, P = .02; and 16-fold increase, P = .004, respectively) in subjects with CRS compared with controls with normal levels of IL-1beta, IL-6, IL-8/CXCL8, human beta-defensin-2, monocyte chemoattractant protein 2/CCL8, monocyte chemoattractant protein 3/CCL7, and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5. Immunostaining of nasal biopsies, however, revealed comparable epithelial staining for TNF-alpha, GRO-alpha, and RANTES. There were no differences in mRNA induction by CSE, TNF-alpha, lipoteichoic acid, LPS, or dsRNA alone. The combination of CSE+dsRNA induced exaggerated RANTES (12,115-fold vs 1500-fold; P = .03) and human beta-defensin-2 (1120-fold vs 12.5-fold; P = .05) in subjects with CRS. No other genes were differentially induced. Furthermore, CSE+dsRNA induced normal levels of IFN-beta, IFN-lambda1, and IFN-lambda2/3 mRNA in subjects with CRS.. Cigarette smoke extract plus dsRNA induces exaggerated epithelial RANTES expression in patients with CRS. We propose that an analogous response to cigarette smoke plus viral infection may contribute to acute exacerbations and eosinophilic mucosal inflammation in CRS.

Topics: Adult; Aged; beta-Defensins; Cells, Cultured; Chemokine CCL5; Chemokine CCL7; Chronic Disease; Complex Mixtures; Epithelial Cells; Female; Gene Expression Regulation; Humans; Immunochemistry; Interferon-beta; Interferons; Interleukin-1beta; Interleukin-6; Interleukin-8; Interleukins; Lipopolysaccharides; Male; Middle Aged; Nasal Mucosa; Rhinitis; RNA, Double-Stranded; RNA, Messenger; Sinusitis; Tobacco Smoke Pollution; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha

Bacterial etiology of chronic rhinosinusitis (CRS) still remains controversial. Whereas Staphylococcus aureus enterotoxins have been detected in CRS, the impact of Staphylococcus epidermidis, a major commensal inhabitant of the nose, has not been studied. Among others, serine and cysteine proteases have been identified as factors of virulence in S. epidermidis.. S. epidermidis was examined in tissue biopsies of 30 CRS patients (16 with nasal polyposis) using standard procedures. Primary human nasal epithelial cells from inferior nasal turbinates (HNECs), from nasal polyps (NPECs) and A549 airway epithelial cells were stimulated with S. epidermidis supernatants DSM20044 or ATCC35984 and the IL-8 and GRO-alpha response was quantified by ELISA. Protease-triggered chemokine responses and involvement of NF-kappaB were investigated by addition of protease or NF-kappaB inhibitors. Activation of NF-kappaB was demonstrated by quantitative DNA binding assay.. S. epidermidis was the most frequently isolated bacteria in the majority of CRS patients. HNECs and NPECs revealed no different IL-6 and IL-8 synthesis following stimulation with DSM20044 or ATCC35984. Stimulation of HNECs and A549 cells with S. epidermidis supernatants resulted in increased IL-8 and GRO-alpha expression which could be suppressed by the serine protease inhibitor AEBSF and the NF-kappaB inhibitor BAY 11 but not by the cysteine protease inhibitor E64. Results obtained for A549 cells were similar to HNECs.. S. epidermidis was present in the majority of CRS specimens. Proinflammatory impact of S. epidermidis supernatants on nasal epithelial cells was demonstrated by serine protease-triggered and NF-kappaB-dependent chemokine responses.

Topics: Cell Line; Cells, Cultured; Chemokine CXCL1; Chronic Disease; Epithelial Cells; Humans; Interleukin-6; Interleukin-8; Nasal Mucosa; Nasal Polyps; NF-kappa B; Nitriles; Rhinitis; Serine Proteinase Inhibitors; Sinusitis; Staphylococcus epidermidis; Sulfones

The effects of protease-activated receptor-2 (PAR-2) stimulation on inflammation mechanisms of chronic rhinosinusitis (CRS) are still unknown.. PAR-2 receptor expression was investigated by immunohistochemistry and Taqman mRNA analysis in the mucosa of different rhinosinusitis entities. In primary nasal epithelial cell cultures, the function of PAR-2 and its ability to produce CXC, CC chemokines, and IL-6 were measured by calcium mobilization and stimulation tests. Inhibition tests were performed using cortisone, serine protease inhibitors, cysteine protease inhibitors, Pertussis toxin (PTX) and nuclear transcription factor (NF-kappaB) inhibition (BAY 11-7085). Signal transduction pathways were analysed by electromobility shift assays (EMSA) and NF-kappaB binding studies.. The expression of PAR-2 was found to be increased in CRS specimens. The activation of PAR by trypsin or PAR-2-specific activating peptide (AP) caused an increase in cytosolic calcium, as well as the release of the CXC chemokines IL-8 and growth-related oncogene (GRO)-alpha, but not the release of CC chemokines or IL-6. AP-induced CXC chemokine was sensitive to PTX and activation of NF-kappaB was inhibited by BAY11-7085. Furthermore, a serine protease inhibitor significantly inhibited chemokine synthesis stimulated by trypsin and culture supernatants of staphylococci, whereas steroids and cysteine protease inhibitors had little effect.. PAR-2 plays a role in serine protease-mediated regulation - staphylococcal and non-staphylococcal origin - of IL-8 and GRO-alpha in nasal epithelial cells, but not in the regulation of CC chemokines. PAR-2 may therefore be involved in the pathophysiology of CRS and NP at different sites of activation, namely (i) proteases, (ii) the PAR-2 receptor itself or (iii) the application of novel agents that block NF-kappaB/IkappaB-alpha signalling.

Topics: Acute Disease; Adult; Aged; Bacterial Proteins; Calcium; Case-Control Studies; Cells, Cultured; Chemokine CCL11; Chemokine CCL17; Chemokine CCL5; Chemokine CXCL1; Chemokines, CC; Chemokines, CXC; Chronic Disease; Culture Media, Conditioned; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Nasal Mucosa; Nasal Polyps; NF-kappa B; Nitriles; Peptides; Pertussis Toxin; Receptor, PAR-2; Rhinitis; RNA, Messenger; Serine Endopeptidases; Serine Proteinase Inhibitors; Signal Transduction; Sinusitis; Staphylococcus aureus; Sulfones; Trypsin

The pathophysiological mechanism of non-allergic rhinitis is not clear and there is a lack of models in healthy volunteers. It has previously been shown that swine dust exposure is an excellent method for inducing inflammatory changes in the lower airways. We have shown earlier that exposure to swine dust increases the histamine sensitivity of the nasal mucosa as measured by rhinostereometry. In this study the aim was to investigate the effects of swine dust exposure on nasal symptoms as well as the microcirculation. Furthermore, the effect on nasal lavage was investigated.. Seventeen subjects were exposed to swine dust during a three-hour period of work in a swine house. Nasal symptoms and the nasal mucosal response to histamine before and after exposure to swine dust were evaluated by laser Doppler flowmetry and nasal lavage.. Exposure to swine dust increased nasal symptoms and levels of neutrophils, IL-8 and albumin. The increase in nasal symptoms and the microcirculation were modified by nasal lavage. CMBC correlated inversely with an increase in albumin (p = 0.018, R = -0.95).. Swine dust exposure is a useful model for inducing nasal inflammation in healthy volunteers. Furthermore, nasal lavage modifies subjective as well as objective parameters, which should be considered when designing studies. Nasal lavage may be useful in the treatment of workers in a swine dust environment.

Topics: Albumins; Animals; Disease Models, Animal; Dust; Humans; Inhalation Exposure; Interleukin-8; Laser-Doppler Flowmetry; Microcirculation; Nasal Lavage Fluid; Nasal Mucosa; Neutrophils; Rhinitis; Swine

The aim of this study was to evaluate the effects of Staphylococcus aureus exotoxin B (SE-B) on proinflammatory cytokine/chemokine releases in primary nasal epithelial cell cultures (NECC) of subjects with and without chronic rhinosinusitis (CRS).. NECC (CRS: n = 14;. n = 11) were stimulated with SE-B. Protein concentrations of interleukin-(IL)-1beta, IL-6, and IL-8 levels were measured in NECC supernatants by ELISA before (T0) and after 24 hr stimulation with SE-B (T1).. T0: supernatants of the NECC of CRS patients contained significant lower levels of IL-8 (2.1 ng/ml) compared to CONTROLS (IL-8: 6.2 ng/ml; P < 0.01). T1: SE-B induced a significant increase of IL-6 in NECC (P < 0.001). IL-1beta was not detectable.. This is the first study evaluating the effects of exotoxins on NECC. SE-B showed proinflammatory effects on NECC.. Our data suggest that resident NECC are involved in immunological responses to Staphylococcus aureus toxins, supplementing the so-called "superantigen hypothesis" in CRS.

Topics: Cells, Cultured; Chronic Disease; Culture Media, Serum-Free; Epithelial Cells; Exotoxins; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Nose; Rhinitis; Sinusitis; Staphylococcus aureus; Superantigens

While various microorganisms have been recovered from patients with chronic rhinosinusitis, the inflammatory impact of virulence factors, in particular proteases from Staphylococcus aureus and coagulase negative staphylococci on the nasal epithelium, has not yet been investigated. Expression of CXC chemokines was determined in the epithelium of patients with chronic rhinosinusitis by immunohistochemistry. In a cell culture system of A549 respiratory epithelial cells, chemokine levels were quantified by enzyme-linked immunosorbent assay (ELISA) after stimulation with supernatants originating from three different staphylococcal strains or with trypsin, representing a serine protease. Inhibition experiments were performed with prednisolone, with the serine protease inhibitor 4-(2-aminoethyl)-benzenesulphonylfluoride (AEBSF) and with the nuclear transcription factor (NF)-kappaBeta inhibitor (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulphonyl]-2-propenenitrite (BAY) 11-7085. Electromobility shift assays (EMSA) were used to demonstrate NF-kappaB-dependent protein synthesis. CXC chemokines interleukin (IL)-8, growth-related oncogene alpha (GRO-alpha) and granulocyte chemotactic protein-2 (GCP-2) were expressed in the patients' epithelium whereas epithelial cell-derived neutrophil attractant 78 (ENA-78) was rarely detected. In A549 cells, chemokines IL-8, ENA-78 and GRO-alpha but not GCP-2 were induced by trypsin and almost equal levels were induced by staphylococcal supernatants. IL-8, GRO-alpha and ENA-78 synthesis was suppressed almost completely by AEBSF and BAY 11-7085, whereas prednisolone reduced chemokine levels differentially dependent on the supernatant added. CXC chemokines were detectable in the epithelium of patients with chronic rhinosinusitis. Staphylococcal serine proteases induced CXC chemokines in A549 cells, probably by the activation of proteases activated receptors, and thus might potentially be involved in neutrophilic inflammation in chronic sinusitis.

Topics: Adult; Aged; Cell Line; Chemokine CXCL1; Chemokine CXCL5; Chemokines, CXC; Chronic Disease; Epithelial Cells; Female; Humans; Immunity, Mucosal; Immunoenzyme Techniques; Intercellular Signaling Peptides and Proteins; Interleukin-8; Male; Metalloendopeptidases; Middle Aged; Nasal Mucosa; Neutrophil Infiltration; NF-kappa B; Nitriles; Prednisolone; Rhinitis; Serine Proteinase Inhibitors; Signal Transduction; Sinusitis; Sulfones; Trypsin

The aetiology of chronic rhinosinusitis (CRS) remains unclear. The purpose of this study was to investigate neutrophil-attracting chemokine patterns in CRS without nasal polyposis.. The biological activity of the chemokines was identified using a two-step high-performance liquid chromatography (HPLC) technique combined with a bioassay in extracts from 55 CRS patients, and in the turbinate mucosa (TM) of patients (N=51) undergoing septumplasty. The biologic activity of each chemokine was assessed using blocking antibodies to chemokines. Immunolocalization of detected neutrophil chemokines was performed by quantitative evaluation of immunohistochemistry. Besides, PCR analysis was performed to quantify neutrophil chemokine mRNA.. In CRS, the chemokines primarily detected by two-step HPLC were growth-related oncogene-alpha (GRO-alpha) and the granulocyte chemotactic protein-2 (GCP-2). Blocking of GCP-2 and GRO-alphad each resulted in chemotaxis inhibition rates of 43.3% and 35.9%, respectively, whereas anti-IL-8 and anti-ENA-78 had no effect. Both GCP-2 and GRO-alphad were generally synthesized by the surface epithelium and mucosal glands while GRO-alpha in particular was synthesized by endothelial cells, as shown by immunohistochemistry. The concentrations of the chemokines IL-8 and epithelial cell-derived neutrophil attractant-78 (ENA-78) were low in CRS and TM.. It appears that both GRO-alpha and GCP-2 contribute to neutrophil chemotaxis in CRS, whereas IL-8 and ENA-78 appear to be of secondary importance for the chemotaxis of neutrophils in this condition. The expression of chemokines in mucosal gland cells is the main phenomenon involved in constitutive neutrophil chemotaxis in the TM.

Topics: Adult; Chemokine CXCL1; Chemokine CXCL5; Chemokine CXCL6; Chemokines, CXC; Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Male; Nasal Mucosa; Neutrophil Activation; Neutrophils; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis; Sinusitis

To determine the role of interleukin (IL)-4, IL-4 receptor (R), IL-6, IL-8, IL-11, and transforming growth factor (TGF)-beta in chronic rhinosinusitis (CRS) and chronic rhinosinusitis with nasal polyposis (CRS/NP).. Sinus tissue from patients undergoing endoscopic sinus surgery for CRS and CRS/NP was collected. Sinus tissue was then analyzed using reverse-transcription polymerase chain reaction (RT-PCR) to detect transcription of IL-4R, IL-6, IL-8, and IL-11. Sinus tissue samples were also cultured in vitro, treated with IL-4 for 24 hours, and real-time PCR was used to quantify the transcription of TGF-beta.. Twenty patients were evaluated, 9 with CRS/NP and 11 with CRS alone. The mean age was 43 (20-74) years, with 13 females and 7 males. IL-4R, IL-6, IL-8, and IL-11 were identified by RT-PCR in all 20 patients. The transcription of TGF-beta was found to be 3.2 times greater in patients with CRS/NP than in patients with CRS alone (P = .047).. IL-6, IL-8, and IL-11 are nonspecific markers of sinus inflammation being transcribed in patients with CRS and patients with CRS/NP. However, patients with CRS/NP demonstrate increased transcription of TGF-beta in response to IL-4 treatment, suggesting an IL-4 mediated mechanism for stromal proliferation in the formation of nasal polyposis.

Topics: Adult; Aged; Biomarkers; Cell Proliferation; Chronic Disease; Endoscopy; Female; Humans; Interleukin-11; Interleukin-4; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Nasal Polyps; Receptors, Interleukin-4; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis; Sinusitis; Transforming Growth Factor beta

The characteristic feature of chronic rhinosinusitis with nasal polyposis (CRSwNP) is eosinophilic inflammation of the sinus mucosa; a type of inflammation also seen in asthmatic airways. Similar histopathologic findings of airway remodelling are present in both diseases. Remodelling is tightly controlled by matrix metalloproteinases (MMP). Increase of collagenase-2 (MMP-8) expression in the bronchial epithelial cells has been described in asthmatic patients, but it has not been studied in CRSwNP.. The concentrations and degree of activation of MMP-8 were analysed by immunofluorometric assay and Western blotting, respectively, in sinus mucus samples from CRSwNP patients and in nasal lavages from healthy controls in relation to inductive cytokines interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha).. Significantly elevated levels of MMP-8 and IL-8 but not TNF-alpha were found in CRSwNP patients relative to controls. In particular, the activation of mesenchymal-type MMP-8 but not polymorphonuclear-type MMP-8 was associated with elevated IL-8 levels.. The IL-8 and MMP-8 seemingly form an inductive cytokine-proteinase cascade in CRSwNP pathogenesis. Together they provide a target for novel therapies and a diagnostic tool for monitoring CRSwNP treatment.

Topics: Aged; Chronic Disease; Female; Humans; Interleukin-8; Male; Matrix Metalloproteinase 8; Middle Aged; Nasal Mucosa; Nasal Polyps; Paranasal Sinuses; Rhinitis; Sinusitis; Tumor Necrosis Factor-alpha; Up-Regulation

To investigate the correlation between nuclear factor-kappa B (NF-kappaB) activity and cytokine expression in nasal mucosa of chronic sinusitis.. IL-5, IL-6 and IL-8 levels in nasal mucosa were assayed by the method of ELISA in 52 cases of chronic sinusitis [concomitant with allergic rhinitis (AR group), without allergic rhinitis (NAR group)] and 12 normal subjects. Semi-quantitative RT-PCR and immunohistochemical staining were used to examine P50 and P65 subunits of NF-KB expressions and activation in nasal mucosa. The correlation between activities of NF-KB P50 and P65 subunits and cytokine expression was evaluated.. IL-5, IL-6 and IL-8 levels in both AR and NAR groups were significantly increased (all P < 0.01 for AR group; P < 0.05, 0.05, 0.01, respectively, for NAR group, as compared with normal group), and the levels were much higher in AR group than that in NAR group (P < 0.01, 0.05, 0.01, respectively). The levels of P50 and P65 mRNA in both AR and NAR groups were enhanced (all P < 0.01 for AR group; all P < 0.01 for NAR group, as compared with normal group), and AR group had markedly greater P50 and P65 mRNA levels in comparison with NAR group (both P < 0.05). Immunohistochemical study revealed that nucleus-present rates of P50 and P65 in both AR and NAR groups were significantly higher than those of control group (all P < 0.01), and they were much greater in AR group as compared with NAR group (all P < 0.01). Pearson correlation analysis demonstrated that P50 and P65 nucleus-present rates were closely correlated with IL-6 and IL-8 levels, but not IL-5. The correlation coefficient was 0. 49 for P50 and IL-6, 0. 54 for P50 and IL-8, 0. 61 for P65 and IL-6, and 0.66 for P65 and IL-8 (all P < 0.01).. Activation of P50 and P65 subunits of NF-kappaB might be one of the mechanisms for induction of IL-6 and IL-8 expression in chronic sinusitis. Concomitance of allergic rhinitis with chronic sinusitis further increased activities of NF-kappaB subunits, and further elevated IL-6 and IL-8 expression. IL-5 expression was independent of NF-kappaB pathway in chronic sinusitis.

Topics: Adult; Chronic Disease; Female; Humans; Interleukin-5; Interleukin-6; Interleukin-8; Male; Middle Aged; Nasal Mucosa; NF-kappa B p50 Subunit; Rhinitis; RNA, Messenger; Sinusitis; Transcription Factor RelA

Patients with obstructive sleep apnea treated with nasal continuous positive airway pressure (CPAP) often complain of nasal side effects. We studied patients before and after initiation of nasal CPAP to see how treatment affected nasal function and markers of nasal inflammation. We searched for pretreatment findings that might help to predict noncompliance.. Nasal symptom scores, nasal flow by anterior rhinomanometry, mediator levels (intercellular adhesion molecule-1, interleukin-6, interleukin-8 and interleukin-13), and nasal scrapes for cytology were obtained at baseline and monthly for up to 3 months of nasal CPAP therapy. Compliance was assessed from the patient's report and by recording hours of usage for up to 19 months of follow-up.. Thirty-eight patients with newly diagnosed obstructive sleep apnea were classified as having no rhinitis (42%), allergic rhinitis (37%), or nonallergic rhinitis (21%). There was no significant difference in compliance in patients with and without rhinitis. Compliant and noncompliant patients showed no significant differences in their baseline nasal symptom scores, nasal flow, and mediator levels. Nasal neutrophil counts before treatment were greater in noncompliant than in compliant patients (p = .004) and greater in those discontinuing because of nasal symptoms than in patients who quit for other reasons (p = .05). There was a positive correlation between neutrophil counts and nasal bacterial scores, both before and after treatment with nasal CPAP.. Patients with increased neutrophil counts in the nasal scrape before beginning nasal CPAP are at increased risk of discontinuing therapy. They appear to have subclinical nasal inflammation that cannot be identified from clinical assessment, nasal symptom scores or rhinomanometry.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Continuous Positive Airway Pressure; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-13; Interleukin-6; Interleukin-8; Male; Middle Aged; Nasal Cavity; Neutrophils; Predictive Value of Tests; Rhinitis; Rhinomanometry; Sleep Apnea, Obstructive; Treatment Refusal

The etiology and classification of chronic rhinosinusitis with and without nasal polyps still remain unclear. Based on investigations of inflammation type in biopsies from patients with nasal polyposis and chronic non-polypous rhinosinusitis, we tried to determine whether there is a need for further classification of chronic rhinosinusitis into two disease entities.. Biopsies of diffuse nasal polyposis (n= 37) and chronic rhinosinusitis without nasal polyps (n= 41) were examined for eosinophil and neutrophil tissue infiltration, degree of inflammation, and involved cytokines in inflammation mechanisms.. Neutrophil elastase positive neutrophils and CD38-positive lymphocytes were characterized in nasal polyposis and chronic non-polypous rhinosinusitis by immunohistochemistry. Using a monoclonal antibody against eosinophilic cationic protein (ECP) activated eosinophils were identified. In tissue homogenates, albumin was quantified as a marker for inflammation vascular permeability. In addition, interleukin (IL)-8 and IL-5 were determined by means of quantitative ELISA measurements in homogenates.. Significantly increased numbers of eosinophils and neutrophils were detected in nasal polyposis. In chronic rhinosinusitis without nasal polyps, tissue infiltration was dominated by lymphocytes and neutrophils. The concentration of albumin and IL-5 was significantly higher in nasal polyps than in chronic rhinosinusitis without nasal polyps. IL-8 protein levels did not differ significantly between the two tissue types. In addition, patients' durations of illness did not differ significantly.. Different types and quantities of inflammatory cells as well as different levels of inflammation support our hypothesis that there is need for further subdivision of chronic rhinosinusitis into two disease entities.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adult; Albumins; Antigens, CD; Blood Proteins; Chronic Disease; Eosinophil Granule Proteins; Eosinophils; Female; Humans; Inflammation Mediators; Interleukin-5; Interleukin-8; Leukocyte Elastase; Lymphocytes; Male; Membrane Glycoproteins; Middle Aged; Nasal Polyps; Neutrophils; Rhinitis; Ribonucleases; Sinusitis; Tomography, X-Ray Computed

To examine work associated upper airway inflammation in 31 waste handlers, and to correlate these findings with personally monitored exposure to different bioaerosol components.. Cell differentials, interleukin 8 (IL-8), myeloperoxidase (MPO), and eosinophilic cationic protein (ECP) were examined in NAL (nasal lavage), and swelling of the nasal mucosa was determined by acoustic rhinometry before work start on Monday and the following Thursday. Bioaerosol exposure was determined by personal full shift exposure measurements on Monday, Tuesday, and Wednesday and analysed for total bacteria, fungal spores, endotoxin, and beta(1-->3)-glucans.. The increased percentage of neutrophils from Monday (28%) to Thursday (46%) correlated with increases in ECP (r(S) = 0.71, p < 0.001) and MPO (r(S) = 0.38, p < 0.05), and showed a close to significant correlation with nasal swelling (r(S) = -0.55, p = 0.07). The Thursday levels of neutrophils, MPO, and IL-8 were associated with the exposure to fungal spores (range 0-2.0 x 10(6)/m(3)) and endotoxin (range 4-183 EU/m(3)) measured the day before, and the median exposure to beta(1-->3)-glucans (range 3-217 ng/m(3)), respectively (r(S) = 0.47-0.54, p < 0.01). Swelling of the nasal mucosa was associated with the fungal spore and beta(1-->3)-glucan exposure (r(S) = 0.58-0.59, p < 0.05).. These results are based on a relatively small population, and conclusions must be drawn with care. The results suggested that a moderate exposure to fungal spores, endotoxins, and beta(1-->3)-glucans during waste handling induced upper airway inflammation dominated by neutrophil infiltration and swelling of the nasal mucosa.

Topics: Adolescent; Adult; Aerosols; Air Pollutants, Occupational; Blood Proteins; Dust; Edema; Endotoxins; Enzyme-Linked Immunosorbent Assay; Eosinophil Granule Proteins; Eosinophils; Female; Humans; Inhalation Exposure; Interleukin-8; Male; Middle Aged; Nasal Lavage Fluid; Nasal Mucosa; Occupational Exposure; Peroxidase; Refuse Disposal; Rhinitis; Ribonucleases; Spores, Fungal

Long-term, low-dose macrolide therapy is effective in the treatment of chronic rhinosinusitis. The mechanism of its anti-inflammatory effect and how this differs from corticosteroids remains unclear. The effect of clarithromycin and prednisolone on interleukin-5, interleukin-8, and granulocyte-macrophage colony-stimulating factor production by cultured chronic sinusitis nasal mucosa was examined in the study.. Nasal mucosa was obtained from 11 patients with chronic sinusitis. This tissue was cultured for 24 hours in the presence of clarithromycin or prednisolone at a variety of concentrations. Cytokine levels were determined by enzyme-linked immunoassay.. Clarithromycin and prednisolone each produced significant reductions in interleukin-5, interleukin-8, and granulocyte-macrophage colony-stimulating factor production. There was no significant difference between the effects of clarithromycin and prednisolone.. Macrolide antibiotics are capable of inhibiting pro-inflammatory cytokine production in vitro and are as potent as prednisolone. This mechanism is likely to be at least partly responsible for the clinical efficacy of macrolide antibiotics in chronic rhinosinusitis.

Topics: Adult; Anti-Bacterial Agents; Anti-Inflammatory Agents; Chronic Disease; Clarithromycin; Culture Techniques; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Glucocorticoids; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-5; Interleukin-8; Male; Middle Aged; Nasal Mucosa; Prednisolone; Rhinitis; Sinusitis

In rhinologic disorders such as polyposis or rhinitis, nasal cytology allows differentiation between patients according to the degree of eosinophilia in nasal secretions. The egress of eosinophil and/or neutrophil polymorphonuclears from the underlying mucosa might correlate with the release of soluble mediators of cell activation such as the chemokine IL-8, and such molecules of the innate immunity as the LPS-receptor CD14 or lysozyme. We assayed the levels of these three molecules in nasal secretions in correlation with cytologic findings and especially the degree of eosinophilia.. Fifty-four patients from a prospective study of nasal secretions were enrolled in this work. They constituted two groups of 27 patients each, respectively, with or without more than 20% eosinophils in nasal secretions. Nasal secretions were collected by aspiration, weighed and diluted in a fixed amount of buffer. Classic cytologic analyses were performed on the pelleted cells and IL-8, sCD14, and lysozyme levels were assayed in the cell-free supernatants.. Cytologic analyses included cell-enumeration in Neubauer's chambers, and differentials performed on May-Grünwald Giemsa-stained cytospins. ELISA tests were used to assay the levels of IL-8 and sCD14. Lysozyme concentrations were assayed in immuno-nephelometry.. Significantly lower levels of IL-8 and sCD14 were observed in patients with eosinophilia than in patients with a predominance of neutrophils, whereas no difference was observed in lysozyme concentrations.. These data show that the egress of neutrophils in nasal secretions is associated with high levels of IL-8 and sCD14.

Topics: Adolescent; Adult; Aged; Eosinophilia; Female; Humans; Inflammation Mediators; Interleukin-8; Leukocyte Count; Lipopolysaccharide Receptors; Male; Middle Aged; Muramidase; Nasal Lavage Fluid; Nasal Mucosa; Nasal Polyps; Neutrophils; Reference Values; Rhinitis; Sinusitis

The epidemiological evidence that ambient exposure, including particulate matter (PM) is related to adverse health outcomes continues to mount. Inflammation and disease of the upper respiratory tract are commonly suggested as effects of ambient exposure. Therefore we studied both ambient exposure and nasal effects in a 4-months cross-sectional survey in Nordrhein-Westfalen (Germany). At 4 locations in 3 different cities ambient exposure to TSP (total suspended particles), O3, NOx and SO2 was derived from compliance measurements by governmental offices, and 884 subjects (501 mothers and 383 children, 6-7 years old) were screened using nasal lavage, with success rates of 90 and 75%, respectively. No differences in total cell counts or percentage of neutrophils were found between mothers or children from the 4 different locations, despite small but significant differences in ambient exposure to TSP, SO2, O3, and NOx during this period. A higher epithelial cell count in mothers and children from one city might be related to general higher ambient pollution in that location. Interestingly, total cells and interleukin-8 levels in children were higher than in mothers and possibly reflect their increased susceptibility to effects of air pollution. Future analysis will concentrate on temporal relations between inflammation and exposure, including individual risk factors such as allergy, smoking and the presence of disease.

Topics: Adult; Air Pollutants; Child; Cross-Sectional Studies; Environmental Exposure; Epidemiologic Studies; Epithelial Cells; Female; Germany; Humans; Interleukin-8; Male; Particle Size; Rhinitis

Polymorphonuclear neutrophils (PMNs) infiltrate tissue in response to chemoattractants, including interleukin 8 (IL-8). Infiltrating PMNs clear microorganisms but also cause tissue damage. We previously reported the presence in human bronchial lavage of a peptide that inhibits PMN functions. The current project assessed (1) effects of a synthetic analog of this peptide (synthetic neutrophil inhibitor peptide, SNIP) on IL-8-induced nasal inflammation in humans, (2) effects of SNIP on PMN apoptosis and chemotaxis, (3) specific binding of SNIP to PMNs, and (4) evidence of larger molecules with the SNIP sequence. Results show that SNIP attenuates IL-8-induced nasal inflammation, inhibits in vitro PMN chemotaxis to IL-8, and accentuates PMNs apoptosis. PMNs contain specific SNIP-binding sites and the integrin CR3 (CD11b/CD18), or a CR3-associated molecule, is one SNIP-binding molecule. Chemotaxis to IL-8 is most potently inhibited by SNIP in the presence of fibrinogen, a CR3 ligand. Antiserum against the SNIP sequence recognizes a 70-kDa protein in bronchoalveolar lavage and an anti-SNIP immunoaffinity column binds a 70-kDa protein in U937 cell culture supernatant. U937 cell mRNA contains a 1.8-kb transcript detected with degenerate oligonucleotides designed from the SNIP sequence. These studies demonstrate that a synthetic inhibitor peptide can attenuate in vivo nasal inflammation through downregulatory effects on PMNs.

Topics: Analysis of Variance; Apoptosis; Carrier Proteins; Down-Regulation; Female; Humans; In Vitro Techniques; Interleukin-8; Macrophage-1 Antigen; Male; Neutrophil Infiltration; Neutrophils; Peptides; Protein Binding; Rhinitis; Sequence Analysis, Protein

To clarify whether occupational exposure to paper-dust is associated with an increased risk of non-infectious rhinitis.. Thirty-seven workers exposed to paper-dust in a soft-paper mill were compared with 36 unexposed controls. The study was performed under normal working conditions during the non-pollen season. Medical and occupational history was taken down in a comprehensive questionnaire and nasal symptoms were scored on a visual analogue scale (VAS). Pulmonary and nasal function was assessed by spirometry, acoustic rhinometry and peak nasal inspiratory flow. Nasal lavage was analysed for interleukin-8 (IL-8) and nasal transit time was monitored with the saccharine test. Concentrations of inhalable dust for each exposed subject during the day of the clinical study were measured with personal sampling devices.. There was an increased prevalence of nasal blockage and crust formation among the exposed workers. However, there was no difference with regard to acoustic rhinometry, nasal transit time or nasal peak inspiratory flow. In the whole population, IL-8 in nasal lavage was higher among men than among women, 193 ng/l vs 132 ng/l, P = 0.006. There was also a positive trend (P = 0.01) with increasing nasal IL-8 going from non-smokers (122 ng/l), ex-smokers (126 ng/l) to current smokers (235 ng/l).. We have found that occupational exposure to paper-dust is associated with symptoms of nasal blockage and nasal crusting. We find no objective signs of nasal inflammation, even among the subgroup with the highest current exposure.

Topics: Adult; Case-Control Studies; Dust; Female; Humans; Interleukin-8; Male; Middle Aged; Occupational Exposure; Odds Ratio; Paper; Prevalence; Rhinitis; Smoking; Sweden

Exposure to microbial agents in the composting industry may cause work related airway inflammation. Nasal lavage (NAL) has been proposed as a noninvasive method to assess such effects in population studies.. Pre- and post-shift NAL were performed in the workers of a compost plant visited in 1995 (n = 14) and 1996 (n=15), of whom only four participated in both surveys. Total cells, cytokines and other inflammation markers were measured in NAL fluid, and pre-shift levels and post/pre concentration ratios were compared with NAL results obtained in the same periods in 10 and 9 controls, respectively, and with levels of airborne exposure to microbial agents endotoxin and beta(1,3)-glucan as measured in personal air samples.. Job-title specific exposure levels in the first survey ranged from 75 to 527 EU/m(3) for endotoxin and from 0.54 to 4.85 microg/m(3) for beta(1,3)-glucan. In the second survey these values were lower, 29-285 EU/m(3) and 0.36-4.44 microg/m(3), respectively. In the first survey pre-shift NAL concentrations of total cells, MPO, IL-8, NO and albumin were significantly (1.1-4.8 fold) higher in compost workers than in controls. Post/pre ratios for various markers were significantly (1.2-3.2 fold) higher in compost workers in both surveys. NAL cells were mainly neutrophils, while eosinophils were only incidentally observed. A weak relation with exposure was found for pre-shift levels of MPO, uric acid and urea in the first survey.. Occupational exposure of compost workers may cause acute and possibly (sub-)chronic inflammatory reactions in the upper airways, presumably induced by non-allergenic pro-inflammatory agents like endotoxins and beta(1, 3)-glucans.

Topics: Adult; Aerosols; Air Microbiology; Air Pollutants, Occupational; Albumins; beta-Glucans; Blood Proteins; Endotoxins; Eosinophil Granule Proteins; Eosinophils; Follow-Up Studies; Glucans; Humans; Immunologic Factors; Inflammation Mediators; Interleukin-8; Male; Nasal Lavage Fluid; Nitric Oxide; Occupational Diseases; Occupational Exposure; Peroxidase; Population Surveillance; Rhinitis; Ribonucleases; Statistics as Topic; Urea; Uric Acid; Waste Products

Epithelial hyperplasia and mucosal infiltration of leukocytes are common features of chronic rhinosinusitis. The epithelium can produce chemoattractant cytokines that may contribute to leukocyte infiltration in rhinosinusitis.. We sought to determine whether mucosal IL-8 gene expression is increased in chronic rhinosinusitis and to relate IL-8 gene expression to disease severity.. We used both a noncompetitive and a quantitative, competitive reverse transcription-polymerase chain reaction to examine IL-8 gene expression in samples of sinus mucosal tissue obtained during surgery from 22 patients with chronic rhinosinusitis and 9 normal control subjects. IL-8 gene expression was related to disease severity assessed by sinus computed tomography (CT) scores and to symptom scores assessed by means of a questionnaire.. Sinus mucosal IL-8 gene expression was not detected in any of the control subjects but was present in 12 of 22 (55%) patients with rhinosinusitis. Sinus CT scores and symptom scores were both significantly higher in patients with positive mucosal IL-8 gene expression than in subjects with no detectable IL-8 gene expression. Positive IL-8 gene expression was not predicted by history of prior surgery nor by atopic or asthmatic status. In 9 subjects with positive IL-8 gene expression, levels of mRNA expression, assessed by competitive reverse transcription-polymerase chain reaction, correlated significantly (rho = 0.72, P <.05) with sinus CT scores.. Sinus mucosal expression of the gene for IL-8 is increased in patients with chronic rhinosinusitis, and the level of IL-8 gene expression correlates with disease severity.

Topics: Adult; Aged; Asthma; Chronic Disease; Epithelial Cells; Female; Gene Expression; Humans; Hypersensitivity, Immediate; Interleukin-8; Male; Middle Aged; Mucous Membrane; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis; RNA, Messenger; Sinusitis; Tomography, X-Ray Computed

Epoxy resin compounds (ERC) include a large number of chemicals, such as epoxy resins (ER), reactive diluents and hardeners. Many hardeners, e.g., aliphatic polyamines, are well-known sensitizers. Another type of ER hardeners are the phthalic anhydrides, such as methylhexahydrophthalic anhydride (MHHPA) and methyltetrahydrophthalic anhydride (MTHPA), which have been reported as causing immunologically-mediated respiratory diseases and contact urticaria, but not allergic contact dermatitis. Here, we present a horizontal boring-machine worker who developed allergic contact dermatitis, as well as allergic rhinitis and an immediate contact skin reaction from MHHPA. Patch testing with a dilution series of MHHPA in pet. elicited the following results: 2%, 1% and 0.5%, +2; 0.25% and 0.125%, + (3- to 6-day readings). An immunohistochemical and electron microscopic study also indicated that the patch test reactions were conventional-delayed allergic reactions. Interleukin 8 was observed in the epidermal cells, whereas interleukin 4 immunoreactivity was detected in the dermal cells. Immunoreactivity to-interleukin 5, granulocyte/macrophage-colophony stimulating factor (GM-CSF) or eosinophil cationic protein was not seen. In conclusion, the patient developed both Type I and Type IV allergy to MHHPA. The clinical data, patch test results, immunohistochemical and electron microscopic observations indicated that the MHHPA allergy detected by the patch test reaction was a conventional delayed-type hypersensitivity reaction. The patient also had an allergic patch test reaction to para-phenylenediamine and diaminodiphenylmethane, possibly representing occupational sensitization.

Topics: Allergens; Aniline Compounds; Blood Proteins; Dermatitis, Allergic Contact; Dermatitis, Occupational; Eosinophil Granule Proteins; Eosinophils; Epidermis; Epoxy Resins; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Immunohistochemistry; Inflammation Mediators; Interleukin-4; Interleukin-5; Interleukin-8; Male; Microscopy, Electron; Middle Aged; Patch Tests; Phenylenediamines; Phthalic Anhydrides; Respiratory Hypersensitivity; Rhinitis; Ribonucleases; Skin; Urticaria

The ability of the nasal mucosa to produce various cytokines has been shown to correlate closely with the capacity to regulate an inflammatory condition in the nasal cavity. Immune senescence is characterized by a dysregulation of the immune system. This change is reflected by the altered production of cytokines during aging. We measured the in vivo production and gene expression of IL-8-like cytokines (GRO/CINC-1) in nasal lavages and mucosa from young (2- to 4-week-old and 11- to 15-week-old) and older (81-to 98-week-old) rats by using enzyme-linked immunosorbent assays and reverse transcription-polymerase chain reactions. Significant increases of GRO/CINC-1 levels were found in unstimulated nasal lavages of the older rats compared to that of the 2- to 4-week-old animals. GRO/CINC-1 showed time-dependent production with lipopolysaccharide (LPS) stimulation in nasal lavages. The GRO/CINC-1 production reached a plateau by 4 h with LPS in any group. However, the manner of the initial time course showed no significant differences among these three groups. At the time of peak production of GRO/CINC-1, messenger RNA for the GRO/CINC-1 was found to be induced in the nasal mucosa. These findings may be important for understanding the mechanisms of the altered immune response and inflammation in the nasal cavity associated with aging.

Topics: Aging; Animals; Chemokine CXCL1; Chemokines; Chemokines, CXC; Chemotactic Factors; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Growth Inhibitors; Growth Substances; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lipopolysaccharides; Male; Nasal Cavity; Nasal Mucosa; Polymerase Chain Reaction; Rats; Rats, Wistar; Rhinitis; RNA, Messenger; Therapeutic Irrigation; Time Factors; Transcription, Genetic

Epithelial cells potentially contribute to airways inflammation by antigen presentation and the production of proinflammatory cytokines. This study investigated the immunocytochemical localization of interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor (IL-1R Type I), tumor necrosis factor-alpha receptor (TNF-alpha R; 55kD), and human leukocyte antigen-DR (HLA-DR) on epithelial cells obtained by nasal brushing from 10 patients with allergic rhinitis in season and 15 healthy, nonallergic subjects. Six of the 15 nonallergic asymptomatic subjects had macroscopic evidence of nasal mucosal inflammation, and their brushings contained more than 10% neutrophils ("subclinical inflammation"). In normal control subjects, 8 +/- 7.5% of epithelial cells stained for HLA-DR, approximately one quarter stained for IL-8 and GM-CSF, and about one third stained positive for IL-1R and TNF-alpha R. The findings in subjects with allergic rhinitis in season and with subclinical neutrophilia were similar, and the numbers of cells staining for HLA-DR expression correlated with both neutrophil and lymphocyte content. These findings further support the conclusion that epithelial cells can contribute to inflammatory processes in the nasal mucosa. The findings emphasize the need to identify asymptomatic nasal mucosal inflammation in studies of the nasal mucosa.

Topics: Adolescent; Adult; Eosinophils; Epithelium; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-DR Antigens; Humans; Interleukin-8; Keratins; Leukocyte Count; Macrophages; Middle Aged; Nasal Mucosa; Neutrophils; Receptors, Interleukin-1; Receptors, Tumor Necrosis Factor; Rhinitis; Rhinitis, Allergic, Seasonal; T-Lymphocytes, Helper-Inducer; Tumor Necrosis Factor-alpha

Allergic diseases such as allergen-induced rhinitis represent an inflammatory reaction that is characterized by the chemotaxis and activation of various cell populations. A high degree of cell-to-cell communication is needed to orchestrate this inflammatory immune response. A variety of cytokines and adhesion receptors seem to play an important role in the allergic late phase reaction. Here we demonstrate that proinflammatory cytokines such as interleukin(IL)-1, IL-8 and TNF-alpha (tumor necrosis factor-alpha) can be detected in nasal secretions and mucosa by enzyme-linked immunosorbent assay and immunohistochemistry. The increased expression of adhesion receptors in mucosa specimens of patients with seasonal allergic rhinitis points to their role in regulating the cellular migration and probably represents a key event in allergic inflammation. We established an in vitro model using freshly taken nasal mucosa to study the induction of adhesion receptors by proinflammatory cytokines. E-selectin, an endothelial receptor, was strongly upregulated by IL-1 beta, TNF-alpha and allergen. The induction due to allergen exposure of the mucosa was markedly inhibited by soluble cytokine receptors (sIL-1R, TNF-BP) or by a receptor antagonist (IL-1ra) and prednisolone, These findings indicate that proinflammatory cytokines may be key factors for the upregulation of adhesion processes in human nasal mucosa and the activation of various cell populations involved in the allergic inflammation. They therefore represent a main target for new therapeutic strategies.

Topics: Cell Adhesion Molecules; Cell Communication; Chemotaxis; E-Selectin; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-8; Lymphocyte Function-Associated Antigen-1; Membrane Glycoproteins; Nasal Mucosa; Receptors, Immunologic; Respiratory Hypersensitivity; Rhinitis; Rhinitis, Allergic, Seasonal; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

We studied the cytokines IL(interleukin)-1 beta, IL-4, IL-6 and IL-8 in nasal lavage samples from 20 patients with naturally acquired viral rhinitis and 5 healthy controls without nasal complaints. IL-1 beta, IL-6 and IL-8 levels in lavage fluid from the viral rhinitis patients were significantly elevated when compared to control subjects. IL-4 was not measurable in any of the samples. The cytokine levels in secretions from the healthy controls remained stable intraindividually on 5 consecutive sampling days. We suggest that cytokines such as IL-1 beta, IL-6 and IL-8, but not IL-4, are involved in the pathophysiology of the common cold.

Topics: Adult; Case-Control Studies; Common Cold; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1; Interleukin-4; Interleukin-6; Interleukin-8; Male; Nasal Lavage Fluid; Rhinitis

Plasma interleukin-8 (IL-8) concentrations were measured in patients with atopic dermatitis. Plasma IL-8 was not detected in 25 controls (0/25), in allergic rhinitis (0/20), or in bronchial asthma during remission (0/13), while low concentrations of IL-8 were detectable in a few patients with urticaria (1/19), contact dermatitis (4/17), and bronchial asthma at the time of attack (6/16). In contrast, IL-8 was detectable in most cases of atopic dermatitis (41/52). Moreover, IL-8 concentrations were significantly higher in severe than in mild or moderate atopic dermatitis. IL-8 concentrations decreased as atopic dermatitis was improved by treatment, and IgE production in vitro was also decreased while serum IgE concentrations remained unchanged. IL-8 measurement may be a useful tool for the study of the pathogenesis and clinical course of atopic dermatitis.

Topics: Adolescent; Asthma; Cells, Cultured; Child; Child, Preschool; Dermatitis, Atopic; Dermatitis, Contact; Female; Humans; Immunoglobulin E; Infant; Interleukin-1; Interleukin-6; Interleukin-8; Male; Rhinitis; Urticaria