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- Hasela, H, et al.
(författare)
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Ketotifen induces primary necrosis of human eosinophils
- 2005
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Ingår i: Journal of Ocular Pharmacology and Therapeutics. - : Mary Ann Liebert Inc. - 1080-7683 .- 1557-7732. ; 21:4, s. 318-327
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils are considered essential in the pathogenesis of allergy. Reduced eosinophil apoptosis is considered to be a key element in the formation of eosinophilia in allergic conditions. Antihistamines are widely used in the treatment of allergic disorders, but their effects on eosinophil apoptosis are poorly understood. The histamine HI-receptor antagonist, ketotifen, is available orally and as eye drops for the treatment of allergic symptoms. The aim of our study was to investigate the possible effect of ketotifen on constitutive eosinophil apoptosis and on interleukin (IL)-5-mediated eosinophil survival. Isolated peripheral blood eosinophils were cultured with or without the survival-prolonging cytokine IL-5 and ketotifen. Apoptosis was assessed by measuring the relative DNA content and by morphological analysis. Ketotifen was found to reverse eosinophil survival induced by interleukin-5. However, the flow cytometry histogram of DNA in propidium iodide-stained cells was not typical to apoptosis. Morphological analysis of the eosinophils by bright-field microscopy suggested that the effect of ketotifen was due to the induction of primary necrosis rather than apoptosis. Histological assessment of eosinophil ultrastructure by transmission electron microscopy confirmed signs of advanced necrosis. In summary, our results suggest that at clinically relevant drug concentrations, ketotifen induces primary necrosis in IL-5-treated human eosinophils.
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| 2. |
- Erjefält, Jonas, et al.
(författare)
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Acute allergic responses induce a prompt luminal entry of airway tissue eosinophils.
- 2003
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 29:4, s. 439-448
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Tidskriftsartikel (refereegranskat)abstract
- Traditionally, traffic and activation of eosinophils in asthmatic airways are thought to take place during the late-phase allergic reaction. The present study tests the hypothesis that when eosinophils are present in the tissue before allergen exposure, as in chronically inflamed asthmatic airways, acute anaphylactic reactions initiate an eosinophil response. Using a guinea-pig allergic model, where eosinophilia is present at baseline conditions, the traffic of resident eosinophils was examined in vivo immediately after allergen challenge. By 2 min after challenge, eosinophils had moved up to apical epithelial positions. Within 10 min, a marked migration of eosinophils into the airway lumen was demonstrated. Along with the allergen-induced egression of eosinophils, acute luminal entry of plasma proteins and eotaxin occurred. Eosinophil egression was effectively inhibited by the antiexudative drug formoterol, whereas the proexudative drug bradykinin could in naive animals evoke a prompt luminal entry of eosinophils. In conclusion, the present study demonstrates that acute allergic reactions initiate a prompt transepithelial migration of resident eosinophils. Our data further suggest that this response in part is initiated by the plasma exudation response, which may alter the transepithelial gradient of eosinophil chemoattractants including eotaxin. We propose that prompt eosinophil response is a significant component of the acute phase of allergic reactions when occurring in airways where these cells are already present in the mucosa.
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| 3. |
- Erjefält, Jonas, et al.
(författare)
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Rapid and efficient clearance of airway tissue granulocytes through transepithelial migration.
- 2004
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Ingår i: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 59:2, s. 136-143
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clearance of tissue granulocytes is central to the resolution of airway inflammation. To date the focus has been on apoptotic mechanisms of cell removal and little attention has been given to alternative processes. The present study explores transepithelial migration as a mechanism of cell clearance. Method: Guinea pig tracheobronchial airways where eosinophils are constitutively present in the mucosal tissue were studied. A complex topical stimulus (allergen challenge) was applied and the fate of the eosinophils was determined by selective tracheobronchial lavage and histological examination of the tissue. Results: Within 10 minutes of the allergen challenge, massive migration of eosinophils into the airway lumen occurred together with a reduction in tissue eosinophil numbers. Cell clearance into the lumen continued at high speed and by 30 and 60 minutes the tissue eosinophilia had been reduced by 63% and 73%, respectively. The marked transepithelial migration (estimated maximal speed 35 000 cells/min x cm2 mucosal surface) took place ubiquitously between epithelial cells without affecting epithelial integrity as assessed by transmission and scanning electron microscopy. Eosinophil apoptosis was not detected but occasional cytolytic eosinophils occurred. Conclusion: This study shows that luminal entry has a remarkably high capacity as a granulocyte elimination process. The data also suggest that an appropriate stimulus of transepithelial migration may be used therapeutically to increase the resolution of inflammatory conditions of airway tissues.
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| 4. |
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| 5. |
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| 6. |
- Malm-Erjefält, Monika, et al.
(författare)
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Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation
- 2001
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 24:3, s. 352-359
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophil degranulation is a characteristic feature of asthma and allergic rhinitis. However, degranulated eosinophils have not been convincingly demonstrated in the common mouse models of these airway diseases. This study uses eosinophil peroxidase (EPO) histochemistry and transmission electron microscopy (TEM) analysis to assess eosinophil degranulation in the airways of ovalbumin (OVA)-sensitized and challenged BALB/c and C57BL/6 mice. Using TEM we also examined mouse and human blood eosinophils after in vitro incubation with formyl-Met-Leu-Phe (fMLP) or phorbol myristate acetate (PMA). Although OVA exposure induced significant nasal and lung eosinophilia, we did not observe any of the known cellular processes by which eosinophils release their granule products, i.e., eosinophil cytolysis, piecemeal degranulation, and exocytosis. The occurrence of other allergen-induced degranulation events was ruled out because no difference in granule morphology was observed between lung-tissue eosinophils and blood or bone-marrow eosinophils from control animals. Accordingly, there was no detectable extracellular EPO in lung tissues of allergic mice. Similarly, mouse blood eosinophils remained nondegranulated in vitro in the presence of fMLP and PMA, whereas the same treatment of human eosinophils resulted in extensive degranulation. This investigation indicates that OVA-induced airway inflammation in the present mouse strains does not involve significant eosinophil degranulation. It is speculated that this dissimilarity from the human disease may be due to a fundamental difference in the regulation of mouse and human eosinophils.
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| 9. |
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| 10. |
- Greiff, Lennart, et al.
(författare)
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Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo
- 1997
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 160:4, s. 387-391
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Tidskriftsartikel (refereegranskat)abstract
- Platelet activating factor (PAF) has been reported to produce a variety of airway effects including epithelial damage and increased airway-lung absorption of hydrophilic tracers. The present study examines effects of PAF on the guinea-pig tracheobronchial mucosa in vivo. Vehicle with and without PAF (4.0 and 8.0 nmol) was superfused onto the tracheobronchial mucosa. The levels of 125I-albumin, previously given intravenously, were determined in tracheobronchial lavage fluids as an index of mucosal exudation of plasma. The mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA (a low molecular weight, 492 Da, hydrophilic tracer) was superfused onto the mucosal surface through an oro-tracheal catheter, together with vehicle or PAF (8.0 nmol). A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of mucosal absorption. PAF produced dose-dependent mucosal exudation of plasma up to 20-fold greater than control (P < 0.001). However, PAF did not damage the epithelium and the absorption ability of the airway mucosa was unaffected. The results, in contrast to previous reports, suggest that PAF may not readily damage the airway mucosa even at large exudative doses of the agent. The present finding support the view that the plasticity of the epithelial junctions allows the creation of valve-like paracellular pathways for unidirectional clearance of extravasated plasma into the airway lumen. We suggest that endogenous PAF may participate in first line respiratory defence reactions by causing lumenal entry of bulk plasma without harming the epithelium.
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