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| 2. |
- 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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| 4. |
- Andersson, Cecilia K, et al.
(författare)
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Novel Site-Specific Mast Cell Subpopulations in the Human Lung.
- 2009
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Ingår i: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 64, s. 297-305
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lung mast cells are stereotypically divided into connective tissue (MCTC) and mucosal (MCT) mast cells. This study tests the hypothesis that each of these subtypes can be divided further into site-specific populations created by the microenvironment within each anatomic lung compartment. METHODS: To study mast cells under non-inflamed conditions surgical resections and bronchial and transbronchial biopsies from non-smoking individuals were obtained to investigate morphometric and molecular characteristics of mast cell populations in multiple lung structures by immunohistochemistry and electron microscopy. RESULTS: MCT and MCTC coexisted at all compartments with MCT being the prevailing type in bronchi, bronchioles and the alveolar parenchyma. MCTC were more abundant in pulmonary vessels and the pleura. Each of the MCTC and MCT phenotypes could be further differentiated into site-specific populations. MCTC was of significantly larger size in pulmonary vessels than in small airway walls (p<0.001) while a reversed pattern was observed for MCT (p<0.001). Within each MCTC and MCT population there was also distinct site-specific expression pattern of the IgE-receptor, IL-9 receptor, renin, histidine decarboxylase, VEGF, FGF, 5-Lipoxygense, and LTC4-synthase; e.g. bronchial MCT consistently expressed more histidine decarboxylase than alveolar MCT (p<0.004). Renin content was high among vascular MCTC but markedly reduced among MCTC in other compartments (p<0.0002). Notably, for both MCTC and MCT IgE-receptor was highly expressed in conducting airways but virtually absent in alveolar parenchyma. CONCLUSION: Our findings demonstrate novel site-specific sub-populations of lung MCTC and MCT. This observation is suggested to have important implications in unravelling the recently proposed role of mast cells in a variety of pulmonary diseases.
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| 5. |
- Andersson, Cecilia, et al.
(författare)
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Mice Lacking 12/15-Lipoxygenase have Attenuated Airway Allergic Inflammation and Remodeling.
- 2008
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 39:6, s. 648-656
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Tidskriftsartikel (refereegranskat)abstract
- Arachidonate 15-lipoxygenase (LO)-1 has been implicated in allergic inflammation and asthma. The overall effect of 15-LO in allergic inflammation in vivo is, however, unclear. This study investigates systemic allergen sensitization and local allergic airway inflammation and remodeling in mice lacking the murine 12/15-LO, the ortholog to human 15-LO-1. Upon systemic sensitization with intraperitoneal ovalbumin, 12/15 LO(-/-) mice produced elevated levels of allergen-specific IgE compared to wild type (Wt) controls. However, when challenged with repeated aerosolized allergen sensitized 12/15 LO(-/-) mice had an impaired development of airway allergic inflammation compared to Wt controls, as indicated by reduced BAL fluid leukocytes (eosinophils, lymphocytes macrophages) and Th2 cytokines (IL-4, IL-5, IL-13) as well as tissue eosinophils. Allergen-induced airway epithelial proliferation was also significantly attenuated in 12/15 LO(-/-) mice whereas goblet cell hyperplasia was unaffected. However, 12/15 LO(-/-) mice had significantly reduced luminal mucus secretions compared to Wt controls. The repeated allergen challenges resulted in a dramatic increase of alpha-smooth muscle-actin positive alveolar cells in the peripheral airways, a phenomenon that was significantly less developed in 12/15 LO(-/-) mice. In conclusion, our data suggest that 12/15 LO(-/-) mice, although having a fully developed systemic sensitization, did not establish a fully developed allergic airway inflammation and associated manifestations of central and peripheral airway remodeling. These data suggest that 12/15-LO derived metabolites play an important pathophysiological role in allergen-induced inflammation and remodeling. Hence, pharmacologic targeting of the human 15-LO-1 may represent an attractive therapeutic strategy to control inflammation and remodeling in asthma.
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| 6. |
- Andersson Sjöland, Annika, et al.
(författare)
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Fibrocytes are associated with vascular and parenchymal remodelling in patients with obliterative bronchiolitis.
- 2009
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 10:Oct 30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the present study was to explore the occurrence of fibrocytes in tissue and to investigate whether the appearance of fibrocytes may be linked to structural changes of the parenchyme and vasculature in the lungs of patients with obliterative bronchiolitis (OB) following lung or bone marrow transplantation. METHODS: Identification of parenchyme, vasculature, and fibrocytes was done by histological methods in lung tissue from bone marrow or lung-transplanted patients with obliterative bronchiolitis, and from controls. RESULTS: The transplanted patients had significantly higher amounts of tissue in the alveolar parenchyme (46.5 +/- 17.6%) than the controls (21.7 +/- 7.6%) (p < 0.05). The patients also had significantly increased numbers of fibrocytes identified by CXCR4/prolyl4-hydroxylase, CD45R0/prolyl4-hydroxylase, and CD34/prolyl4-hydroxylase compared to the controls (p < 0.01). There was a correlation between the number of fibrocytes and the area of alveolar parenchyma; CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.05) and CD34/prolyl 4-hydroxylase (p < 0.05). In the pulmonary vessels, there was an increase in the endothelial layer in patients (0.31 +/- 0.13%) relative to the controls (0.037 +/- 0.02%) (p < 0.01). There was a significant correlation between the number of fibrocytes and the total area of the endothelial layer CXCR4/prolyl 4-hydroxylase (p < 0.001), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). The percent areas of the lumen of the vessels were significant (p < 0.001) enlarged in the patient with OB compared to the controls. There was also a correlation between total area of the lumen and number of fibrocytes, CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). CONCLUSION: Our results indicate that fibrocytes are associated with pathological remodelling processes in patients with OB and that tissue fibrocytes might be a useful biomarker in these processes.
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| 7. |
- Egesten, Arne, et al.
(författare)
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The proinflammatory CXC-chemokines GRO-α/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids
- 2007
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 22:12, s. 1421-1427
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Tidskriftsartikel (refereegranskat)abstract
- Background Ulcerative colitis is characterized by relapsing mucosal inflammation where the lesions include tissue-damaging granulocytes. In addition, T cells and natural killer (NK) cells play important pathophysiologic roles. Chemokines are a large family of peptides that play key roles in the regulation of inflammation. The CXC-chemokines, growth-related oncogene (GRO)-α/CXCL1 and interleukin (IL)-8/CXCL8, both recruit neutrophils and possess mitogenic properties, whereas the interferon-dependent CXC-chemokines monokine induced by gamma-interferon (MIG)/CXCL9, interferon-γ inducible protein of 10 kD/CXCL10, and IFN-inducible T cell alpha chemoattractant/CXCL11 recruit and activate T cells and NK cells. Materials and methods The expression of CXC-chemokines was studied in eight controls and in 11 patients suffering from ulcerative colitis in the distal part of the colon, before and during topical treatment with corticosteroids. Perfusates (obtained before, after 7 days, and after 28 days of treatment) and pinch biopsies (obtained before and after 28 days of treatment) were collected by colonoscopy. The rectal release of GRO-α and MIG was determined by enzyme-linked immunosorbent assay (ELISA), and tissue expression of the chemokines was detected in colonic tissue by immunohistochemistry. Results In perfusates, high levels of GRO-α, IL-8, and MIG were detected compared with controls (p = 0.02, 0.005, and p = 0.03, respectively). During treatment with corticosteroids, both GRO-α and MIG decreased. In clinical nonresponders, characterized by sustained inflammation, the levels of GRO-α and MIG remained elevated. Both epithelial cells and granulocytes, present in the submucosa, expressed GRO-α and MIG as detected by immunohistochemistry. Conclusions CXC-chemokines are likely to be important in the pathophysiology of ulcerative colitis and may become targets for novel treatment strategies. In addition, GRO-α may serve as a marker of disease activity.
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| 9. |
- Fransson, Mattias, et al.
(författare)
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Expression of Toll-like receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis.
- 2007
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Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Allergic rhinitis is an inflammatory disease of the upper airway mucosa that also affects leukocytes in bone marrow and peripheral blood. Toll-like receptor 9 (TLR9) is a receptor for unmethylated CpG dinucleotides found in bacterial and viral DNA. The present study was designed to examine the expression of TLR9 in the nasal mucosa and in leukocytes derived from different cellular compartments during symptomatic allergic rhinitis. METHODS: The study was based on 32 patients with seasonal allergic rhinitis and 18 healthy subjects, serving as controls. Nasal biopsies were obtained before and after allergen challenge. Bone marrow, peripheral blood and nasal lavage fluid were sampled outside and during pollen season. The expression of TLR9 in tissues and cells was analyzed using immunohistochemistry and flow cytometry, respectively. RESULTS: TLR9 was found in several cell types in the nasal mucosa and in different leukocyte subpopulations derived from bone marrow, peripheral blood and nasal lavage fluid. The leukocyte expression was generally higher in bone marrow than in peripheral blood, and not affected by symptomatic allergic rhinitis. CONCLUSION: The widespread expression of TLR9 in the nasal mucosa along with its rich representation in leukocytes in different compartments, demonstrate the possibility for cells involved in allergic airway inflammation to directly interact with bacterial and viral DNA.
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| 10. |
- Fransson, Mattias, et al.
(författare)
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Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis
- 2005
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:100
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. METHODS: 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. RESULTS: mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. CONCLUSION: The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation.
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