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- Ekman, A. -K., et al.
(författare)
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Systemic Up-Regulation of TLR4 Causes Lipopolysaccharide-Induced Augmentation of Nasal Cytokine Release in Allergic Rhinitis
- 2012
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 159:1, s. 6-14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergic rhinitis is a systemic disorder, and it is clinically well recognized that it can be aggravated by infection. Activation of the innate immune system constitutes a critical element in the process. Toll-like receptors (TLRs) comprise a part of the innate immune system, and lipopolysaccharide (LPS)-induced activation of TLR4 represents bacterial-induced interactions in various model systems. The present study examines how TLR2 and TLR4 expression is affected by symptomatic allergic rhinitis, and if LPS added upon allergen affects nasal cytokine release. Methods: In patients with pollen-induced allergic rhinitis and healthy non-allergic volunteers, nasal lavage (NAL), peripheral blood and bone marrow were sampled before and during the pollen season. TLR2 and TLR4 expression was determined flow cytometrically. Changes in the TLR receptor expression pattern were evaluated by a nasal challenge with allergen followed by LPS, or vice versa. Symptoms along with cells and cytokines in NAL were analyzed. Results: TLR4 expression increased in leukocytes in NAL, peripheral blood and bone marrow during symptomatic allergic rhinitis. A similar increase was seen for TLR2 in neutrophils in blood. Nasal challenge with allergen followed by LPS augmented the release of IL-4, IL-5, IL-10, IL-13, IFN-gamma and TNF-alpha. Conclusion: A systemic up-regulation of TLR4 in symptomatic allergic rhinitis may explain why LPS preceded by allergen increases nasal cytokine release. Copyright (C) 2012 S. Karger AG, Basel
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- Virtala, R, et al.
(författare)
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Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor.
- 2012
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222 .- 0954-7894. ; 42:4, s. 590-596
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The existence of a link between inflammation in upper and lower airways is well established. It may therefore be assumed that the nose could be used to study inflammatory events in the lower airways. OBJECTIVE: This study aimed to evaluate a lipopolysaccharide (LPS) nasal challenge model by investigating the effect of the CXCR2 inhibitor AZD8309 on neutrophilic inflammation. METHODS: A total of 18 healthy volunteers were randomized in a placebo-controlled, double-blind, cross-over study. AZD8309 or placebo was dosed for 3 days. Subjects were challenged nasally with LPS (50 μg/nostril), and nasal lavage was performed 6 and 24 h later. Leucocytes, neutrophils and inflammatory mediators were assessed in the lavage fluid. The outcome was compared with data from analogous experiments performed in a model of inhaled LPS followed by induced sputum. This trial was registered in the Current Controlled Trials register (ISRCTN trial number: ISRCTN46666382). RESULTS: The leucocytes in nasal lavage consisted to 99% of neutrophils on average. Treatment with AZD8309 reduced the leucocyte count to 48% of placebo 6 h after the LPS challenge. There was also a reduction in LTB4 levels to 45% of placebo after 6 h and in the neutrophil elastase activity after 24 h. No major adverse events were seen with either AZD8309 or placebo. The nasal LPS model induced only minimal local irritation and no signs of systemic inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: LPS-induced neutrophil recruitment was reduced by inhibition of CXCR2. This outcome mimicked the response previously seen in a lower airway LPS model. Hence, the nasal model offers a convenient and well-tolerated alternative for pharmacological evaluation of anti-inflammatory drugs affecting neutrophilic migration and activity.
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