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Laryngo-Rhino-Otologie 10/2012; · 0.97 Impact Factor
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B.A. Stuck,
C. Bachert,
P. Federspil,
W. Hosemann,
L. Klimek,
R. Mösges,
O. Pfaar, C. Rudack,
H. Sitter,
M. Wagenmann,
K. Hörmann
HNO 04/2012; 55(10):758-777. · 0.40 Impact Factor
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B A Stuck,
C Bachert,
P Federspil,
W Hosemann,
L Klimek,
R Mösges,
O Pfaar, C Rudack,
H Sitter,
M Wagenmann,
R Weber,
K Hörmann
HNO 12/2011; 60(2):141-62. · 0.40 Impact Factor
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ABSTRACT: Nasal polyposis (NP) is considered a subgroup within chronic rhinosinusitis. NP can be further subdivided into aspirin sensitive- and aspirin tolerant types (ASNP/ ATNP). Although the true etiology of NP has not been identified so far, it is agreed that NP represents an inflammatory disease of the nasal mucosa. Alterations of cellular kinase activities including that of IKK-2 might play a role in this inflammatory process.
Paraffin sections of ASNP, ATNP and controls were immunostained with Phospho-IkB-α antibody that detects the direct IKK-2 product (IkB-α. Intensity of epithelial staining was analysed semi-quantitatively by two independent observers. In cultured nasal polyp epithelial cells (NPECs) epithelial derived cytokines IL-8 and GRO α were induced by TNF-α or Staphylococcal supernatants and subsequently repressed by IKK-2 inhibitor TPCA-1.
Significant Phospho-IkB-α staining was observed in the nasal epithelium of ASNP compared to ATNP and controls suggesting strong IKK-2 activation in patients with ASNP in vivo. In vitro, pro-inflammatory cytokines IL-8 and GRO-α in NPECs were significantly repressed by TPCA-1.
IKK-2 activity is increased in the subgroup of ASNP. IL-8 and GRO-α responses were repressed by IKK-2 inhibitor TPCA-1 in vitro. IKK-2 inhibitors might represent a potential target for anti-inflammatory intervention in ASNP.
Rhinology 06/2011; 49(2):168-73. · 1.32 Impact Factor
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ABSTRACT: This study evaluated the efficacy and safety of mometasone furoate nasal spray (MFNS) in patients with chronic sinusitis.
In this double-blind, placebocontrolled, multicenter, parallel-group study, 60 patients with persistent sinusitis symptoms were randomized to receive either MFNS 200 μg twice daily or placebo, for 16 weeks (112 days). Eventually, 53 patients terminated the study in regular course.
Total Symptom Scores (TSS) in patients receiving MFNS changed by a mean of -7.27 (95% CI -9.71, -4.84), versus -5.35 (95% CI -6.73, -3.96) in the placebo group (P=0.51). MFNS reduced nasal congestion and discharge scores, and improved patients' olfactory function. There were few side effects. Considerably more patients in the MFNS group were satisfied with the treatment than those who had received placebo (P<0.05). Also, more patients would take the medication again in the event of symptoms, compared with those who had taken placebo (P<0.05). Furthermore, the MFNS patients would recommend it to others.
The positive patient assessment and few side effects are reflected in the efficacy evaluation performed by the physicians. The endoscopic results under MFNS were always numerically more favorable than those under placebo, and the overall difference reached statistical significance (P<0.01). MFNS offers an effective and safe treatment for chronic rhinosinusitis.
Advances in Therapy 02/2011; 28(3):238-49. · 2.11 Impact Factor
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ABSTRACT: Staphylococcus aureus has been associated with chronic rhinosinusitis with nasal polyps (CRSwNP) pathogenesis but its role is still controversially discussed. Here, we demonstrate S. aureus detection in the mucosa of CRSwNP. In addition, intracellular residency of S. aureus in nasal polyp epithelial cells (NPECs) and its capability to induce TH-2 cytokines were analyzed in vitro.
Staphylococcus aureus detection in CRSwNP (n = 25), CRS without polyps (CRSsNP, n = 5), and turbinate mucosa (TM, n = 10) was performed by peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH) and microbial cultivation from tissue biopsies. Intracellular residency was examined by intracellular persistence assay and electron microscopy. IL-6 and IL-13 responses to S. aureus infection and supernatants were quantified by ELISA.
Peptide nucleic acid-fluorescence in situ hybridization positive bacterial cells were significantly increased in the epithelium of CRSwNP (17/25) compared to CRSsNP (0/5) and TM (1/10). Good concordance of PNA-FISH results and S. aureus cultivation was found applying Cohen's κ for CRSwNP (κ = 0.841) and TM (κ = 1.0). Intracellular persistence assay with S. aureus strain Newman and its corresponding small-colony variant mutant strain III33 demonstrated intracellular survival and replication of S. aureus within NPECs. Both S. aureus strains significantly induced IL-6 but not IL-13 in infected NPECs and in NPECs challenged with corresponding staphylococcal supernatants.
Invasion of the epithelium by S. aureus was a phenomenon seen predominantly in CRSwNP. Regardless of an intra- or extracellular localization in the epithelium, S. aureus is capable to induce IL-6 synthesis in vitro and thus may contribute to the TH-2 cytokine pattern in CRSwNP.
Allergy 04/2010; 65(11):1430-7. · 6.27 Impact Factor
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ABSTRACT: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nasal mucosa. Recent studies suggest that S. aureus enterotoxins may play an etiologic role in the development of CRS. Apart from surgery and repeated courses of steroids, macrolide antibiotics have been reported to exert anti-inflammatory effects in CRS. Similar effects have been reported for fluoroquinolones on various cell types. Since these effects have poorly been characterized in CRS, we examined anti-inflammatory effects of ciprofloxacin on human nasal epithelial cells (HNECs).
Inflammation was induced in HNECs cultured from nasal turbinate mucosa with supernatants of S. aureus Newman for 12 hours. Subsequently, HNECs were coincubated with S. aureus Newman and ciprofloxacin (1.5 x 10-5 M), clarithromycin (10-6 M) or prednisolone (10-5 M) for another 12 hours. IL-8 synthesis was quantified after 12 and 24 hours by ELISA.
Stimulation with S. aureus Newman supernatants was associated with an increase of IL-8 synthesis after 12 hours in all experiments. During the second 12 hours, IL-8 synthesis decreased and this effect was independent from any stimulus or inhibitor. However, coincubation of HNECs with ciprofloxacin was associated with a more extensive decrease of IL-8 synthesis. Similarly, addition of clarithromycin was associated with a reduction of IL-8 synthesis although this effect was not significant. Coincubation with prednisolone resulted in a significant reduction of IL-8 levels.
Ciprofloxacin exerts anti-inflammatory effects in S. aureus Newman driven nasal inflammation. Inhibitory effects were comparable to those of prednisolone and clarithromycin.
Journal of Inflammation 02/2008; 5:11. · 2.26 Impact Factor
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ABSTRACT: 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.
International Archives of Allergy and Immunology 02/2008; 145(1):24-32. · 2.40 Impact Factor
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B A Stuck,
C Bachert,
P Federspil,
W Hosemann,
L Klimek,
R Mösges,
O Pfaar, C Rudack,
H Sitter,
M Wagenmann,
K Hörmann
HNO 11/2007; 55(10):758-60, 762-4, 766-77. · 0.40 Impact Factor
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ABSTRACT: 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.
Clinical & Experimental Allergy 08/2007; 37(7):1009-22. · 5.03 Impact Factor
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C Rudack
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ABSTRACT: Early and appropriate treatment of allergic rhinitis is of great importance, since the condition may be associated with such comorbidities as bronchial asthma and rhinosinusitis. The pharmacotherapeutic concept is determined by the new and further development of pharmacological substance classes, such as the antihistaminics and glucocorticosteroids. In recent years, specific immunotherapy--the sole causal treatment of AR--has also been improved by new approaches to the nature and form of its application. In future, a tablet against grass pollen allergy for sublingual application will be available for adults in whom the subcutaneous route is not feasible. The spectrum of therapeutic agents also includes mast cell stabilizers, systemic and topical antihistaminics as well as glucocorticosteroids and beta sympathomimetics.
MMW Fortschritte der Medizin 03/2007; 149(7):32-4.
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Clinical and Experimental Allergy - CLIN EXPERIMENT ALLERGY. 01/2007; 37(7):1009-1022.
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ABSTRACT: Endogenous nitric oxide (NO) production by the inducible NO-synthase is enhanced in the nasal respiratory epithelium of patients with allergic rhinitis. Recent experimental data suggest endogenous NO to be strongly involved in the regulation of ciliary activity, the driving force of the mucociliary transport system.
In this study, we investigated the effect of endogenous NO on mechanical stimulation of ciliary activity in a nasal mucosa explant model.
Cultures of nasal mucosa explants were incubated with TNF-alpha and bacterial lipopolysaccharides (LPS) to enhance endogenous NO production. Direct in vitro NO imaging was performed by the fluorescent NO-indicator DAF-2 DA and laser scanning confocal microscopy. Ciliary beat frequency (CBF) was determined using a photoelectric technique. Mechanical stimulation was performed by two consecutive flow increments in a closed perfusion chamber. Endogenous NO-synthesis was blocked by l-NAME before the second flow stimulation.
Under control conditions the mean rise of CBF relative to baseline was 30.2% during the first flow increment and 30.7% during the second flow increment. Blocking of the endogenous NO synthesis in TNF-alpha/LPS-stimulated cultures reduced baseline CBF by 10.6+/-2.1% (P<0.05) but the effect of mechanical ciliostimulation on CBF remained unchanged (36.0% vs. 38.2%).
In conclusion, endogenous NO- and Ca(2+)-dependent mechanical stimulation of ciliary activity probably use independent intracellular signalling pathways. The combination of both effects on ciliary activity is likely to improve the local defence against inhaled allergens in patients with nasal allergies.
Clinical & Experimental Allergy 10/2006; 36(10):1254-9. · 5.03 Impact Factor
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ABSTRACT: 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.
Clinical & Experimental Allergy 07/2006; 36(6):748-59. · 5.03 Impact Factor
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ABSTRACT: 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.
Clinical & Experimental Immunology 07/2006; 144(3):534-42. · 3.36 Impact Factor
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ABSTRACT: CXC chemokines are thought to play an important role at sites of inflammation. Because ELR(+) CXC chemokines are expressed in different types of tonsillitis we investigated the role of the surface/crypt epithelium of human tonsils in producing ELR(+) CXC chemokines: interleukin (IL)-8 (CXCL8), ENA-78 (CXCL5), GRO-alpha (CXCL1) and GCP-2 (CXCL6). Tonsillar tissue was obtained from patients undergoing tonsillectomy and chemokine expression was investigated by means of immunohistochemistry. A549 cells were used as a model to study kinetics of chemokine expression in epithelial cells. Cells were stimulated with tumour necrosis factor (TNF)-alpha, lipopolysaccharide (LPS) and supernatants derived from aerobic/anaerobic Staphylococcus aureus strains. Chemokine expression was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We observed epithelial expression of IL-8, GRO-alpha and GCP-2 in different types of tonsillitis, whereas ENA-78 was rarely expressed. In A549 cells abundant expression of ENA-78 was detected. IL-8 and GCP-2 are expressed in an acute type of tonsillitis whereas GRO-alpha was frequently detectable both in chronically and acutely inflamed tonsils. ENA-78 does not seem to play a pivotal role in tonsillitis in vivo.
Clinical & Experimental Immunology 06/2005; 140(2):293-300. · 3.36 Impact Factor
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ABSTRACT: Angioedema of the upper airways associated with angiotensin-converting enzyme inhibitors (ACEI) represent a rare but serious problem. We present two cases from our hospital in order to illustrate the therapeutic consequences resulting from angioedema associated with the intake of ACEIs. Surgical airway management should be considered early if medical treatment fails.
HNO 06/2005; 53(5):459-61. · 0.40 Impact Factor
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ABSTRACT: In the industrialized countries, the last 15 years have seen an increasing rate of cases of tuberculosis. However, upper cervical spine tuberculosis involving a cold retropharyngeal abscess is extremely rare. We report on a 58 year old female from Sri Lanka presenting with unspecific neck pain and stiffness. She was diagnosed as having extensive tubercular osteodestruction of the second cervical spine body, including epidural and large retropharyngeal abscesses.
HNO 10/2004; 52(9):820-3. · 0.40 Impact Factor
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ABSTRACT: Trotz der in den westlichen Industrielndern seit 15 Jahren wieder hufiger zu beobachtenden Tuberkuloseinfektionen stellt die Manifestation einer tuberkulsen Spondylitis im Bereich der oberen Halswirbelsule (C1–C3) mit Ausbildung eines kalten Abszesses des Retropharyngealraumes weiterhin eine Raritt dar. Wir berichten ber eine 58Jahre alte, aus Sri Lanka stammende Patientin mit ausgedehnter tuberkulser Osteodestruktion des 2.Halswirbelkrpers sowie einer epiduralen als auch retropharyngealen Abszedierung, die sich mit unspezifischen Nackenschmerzen und einer Nackensteife vorstellte.In the industrialized countries, the last 15years have seen an increasing rate of cases of tuberculosis. However, upper cervical spine tuberculosis involving a cold retropharyngeal abscess is extremely rare. We report on a 58year old female from Sri Lanka presenting with unspecific neck pain and stiffness. She was diagnosed as having extensive tubercular osteodestruction of the second cervical spine body, including epidural and large retropharyngeal abscesses.
HNO 08/2004; 52(9):820-823. · 0.40 Impact Factor
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C Rudack
Laryngo-Rhino-Otologie 06/2004; 83 Suppl 1:S54-86. · 0.97 Impact Factor
