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| 2. |
- Glader, Pernilla, et al.
(författare)
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Cigarette smoke extract modulates respiratory defence mechanisms through effects on T-cells and airway epithelial cells.
- 2006
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 100:5, s. 818-827
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (CCPD) is a disease primarily caused by cigarette smoking, which in turn has been shown to affect the susceptibility to and progression of airway infections. The question addressed in this study was how components from cigarette smoke could affect the defence mechanisms of T-cells and epithelial cells, and thereby contribute to the development of the COPD pathology. T-cells and monocytes were isolated from buffycoats from healthy donors and T-cell responses studied in response to cigarette smoke extract (CSE). Activation level (CD25 expression), proliferation (BrdU incorporation) and intracellular expression of the cytotoxic markers granzyme-b and TIA-1 were determined using flowcytometry. Normal human bronchial epithelial cells were obtained from Cambrex and differentiated in air-liquid interface cultures. After exposure to CSE barrier function (trans-epithelial electric resistance, TEER), MUC5AC and interleukin-8 production were measured. T-cell activation, proliferation and expression of the cytotoxic proteins granzyme-b and TIA-1 were significantly reduced in response to 0.5-1% of CSE. The epithelial cells were more resistant to CSE and responded at doses 20 times higher than T-cells. The expression of interteukin-8 and MUC5AC was significantly increased after exposure to 15% and 30% CSE and TEER was largely unaffected at 30% CSE but clearly reduced at 40% CSE. This study shows that mechanisms, in both T-cells and airway epithelial cells, involved in the defence against infectious agents are modulated by CSE. (c) 2005 Elsevier Ltd. All rights reserved.
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| 3. |
- Glader, Pernilla, et al.
(författare)
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Systemic CD4+ T-cell activation is correlated with FEV(1) in smokers.
- 2006
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 100:6, s. 1088-1093
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Tidskriftsartikel (refereegranskat)abstract
- The inflammation of the lungs in chronic obstructive pulmonary disease (COPD) is characterised by increased numbers of macrophages, neutrophils and T-cells. Decline in lung function in these patients has been correlated to the number of CD8+ T-cells present in the lung as well as to a decline in the ratio of CD4+/CD8+ T-cells. Although systemic components are likely to be present, circulating lymphocyte populations in COPD patients have not been well characterised. This study aimed at correlating lung function to expression of five different T-cell activation markers on peripheral blood CD4+ and CD8+ T-cells in COPD patients and matched smokers. Furthermore, proportions of lymphocyte populations and degree of systemic T-cell activation in COPD patients were compared to that in smokers and never-smokers. Peripheral blood lymphocytes from six never-smokers, eight smokers and 17 smokers with COPD were analysed using flowcytometry. The number of lymphocytes per millilitre was higher in smokers than in never-smokers. No differences were found between the three groups in regard to proportions of lymphocyte populations, but the number of CD4+ T-cells in smokers was higher than in both never-smokers and COPD patients. The degree of T-cell activation was similar in all patient groups; however, a clear correlation between CD69 expression on CD4+ T-cells and lung function (FEV1% of predicted) was found when examining current smokers, with or without COPD. Elevated numbers of CD69+ CD4+ T-cells in blood thus seem to be protective against airway obstruction in smokers while still exposed to cigarette smoke, the main inducer of COPD.
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| 4. |
- Persdotter, Sofia, et al.
(författare)
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Cooperative inhibitory effects of budesonide and formoterol on eosinophil superoxide production stimulated by bronchial epithelial cell conditioned medium
- 2007
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 143:3, s. 201-210
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Tidskriftsartikel (refereegranskat)abstract
- Background: Improved asthma control by combinations of inhaled glucocorticosteroids (GCs) and long-acting beta(2)-agonists (LABAs) includes a reduced frequency and severity of exacerbations. In view of the association of exacerbations with increased airway inflammation, the question has arisen as to whether LABAs are able to complement the known anti- inflammatory activity of GCs. To address this, we studied the effects of a LABA, formoterol (FORM), and a GC, budesonide (BUD), alone and in combination, on bronchial epithelial cell-mediated eosinophil superoxide production in vitro. Methods: We employed 2 experimental approaches. First, superoxide production by human eosinophils incubated with conditioned medium (CM) from human bronchial epithelial cells cultured for 24 h with vehicle, BUD, FORM or BUD + FORM was measured (Epi/Eos assay). Second, eosinophils were stimulated with vehicle-CM to which the drugs were added (Eos assay). Superoxide production was determined as the superoxide dismutase-inhibitable reduction of ferricytochrome C. Results: CM increased eosinophil superoxide generation (p < 0.01) and epithelial-derived granulocyte macrophage colony-stimulating factor was the mediator responsible. In both assays, FORM dose-dependently inhibited eosinophil superoxide similarly and in the same concentration range as BUD. The BUD + FORM combination was more effective than BUD alone, and it completely inhibited CM-induced superoxide production in the Epi/Eos assay, suggesting complementary effects of both drugs on bronchial epithelial cells and eosinophils. Conclusions: The cooperative, inhibitory effects of BUD and FORM on eosinophils and bronchial epithelial cells, in terms of their effects on eosinophil superoxide production, may represent a possible mechanism for the enhanced anti-inflammatory efficacy of BUD and FORM combination therapy of asthma. Copyright (c) 2007 S. Karger AG, Basel
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| 5. |
- Subramaniyam, Devipriya, et al.
(författare)
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C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways.
- 2006
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Ingår i: International Journal of Biochemistry & Cell Biology. - : Elsevier BV. - 1878-5875 .- 1357-2725. ; 38:4, s. 563-575
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Tidskriftsartikel (refereegranskat)abstract
- alpha 1-Antitrypsin (AAT), a major endogenous inhibitor of serine proteases, plays an important role in minimizing proteolytic injury to host tissue at sites of infection and inflammation. There is now increasing evidence that AAT undergoes post-translational modifications to yield by-products With novel biological activity. One Such molecule, the C-terminal fragment of AAT, corresponding to residues 359-394 (C-36 peptide) has been reported to stimulate significant pro-inflammatory activity in monocytes and neutrophils in vitro. In this study we showed that C-36 peptide is present in human lung tissue and mimics the effects of lipopolysaccharide (LIPS), albeit with lower magnitude, by inducing monocyte cytokine (TNF alpha, IL-I beta) and chemokine (IL-8) release in conjunction with the activation of nuclear factor-kappa B (NF-kappa B). Using receptor blocking antibodies and protein kinase inhibitors, we further demonstrated that C-36, like LPS, utilizes CD14 and Toll-like receptor 4 (TLR4) receptors and enzymes of the mitogen-activated protein kinase (MAPK) signaling pathways to stimulate monocyte TNF alpha release. The specificity of C-36 effects were demonstrated by failure of a shorter peptide (C-20) to elicit biological activity and the failure of C-36 to inhibit M/CD28-stimulated IL-2 receptor expression or proliferation in T-cells which lack TLR4 and CD14. We suggest that C-36 mediates its effects though the activation of LPS signaling pathways. (c) 2005 Elsevier Ltd. All rights reserved.
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