| 1. |
- Johansson, Anna-Karin, 1974, et al.
(författare)
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Allergen-induced traffic of bone marrow eosinophils, neutrophils and lymphocytes to airways
- 2004
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Ingår i: Eur J Immunol. ; 34:11
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated whether bone marrow (BM) inflammatory cells have capacity to traffic into the airways following allergen exposure in a mouse model of allergen-induced airway inflammation. We also evaluated the effect of IL-5 overexpression on (i) the production of eosinophils in BM, (ii) the accumulation of eosinophils, neutrophils and lymphocytes in blood and airways and (iii) the changes in CD34(+) cell numbers in BM, blood and airways. Bromodeoxyuridine (BrdU) was used to label cells produced during the exposure period. Furthermore, CD3 splenocytes were adoptively transferred to investigate the BM inflammatory response. Allergen exposure induced traffic of BM eosinophils, neutrophils and lymphocytes to the airways and increased the number of BrdU(+) eosinophils, neutrophils, lymphocytes and CD34(+) cells in BALf. IL-5 overexpression enhanced the eosinophilopoiesis and increased the presence of BrdU(+) eosinophils and CD34(+) cells in airways and enhanced the number of CD34(+) cells in BM and blood after allergen exposure. Adoptive transfer of CD3 lymphocytes overexpressing IL-5 caused increased BM eosinophilia. In conclusion, allergen exposure induces traffic of not only newly produced eosinophils but also newly produced neutrophils and lymphocytes into the airways.
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| 2. |
- Sergejeva, Svetlana, 1972, et al.
(författare)
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A synthetic VIP peptide analogue inhibits neutrophil recruitment in rat airways in vivo
- 2004
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 117:2, s. 149-54
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Tidskriftsartikel (refereegranskat)abstract
- Currently, there is no effective pharmacotherapy against exaggerated mobilisation of neutrophils in human airway diseases such as chronic obstructive pulmonary disease and asthma. We evaluated the effect of two synthetic vasoactive intestinal peptide (VIP)-like analogues on cytokine-induced neutrophil recruitment in airways in vivo. Recombinant interleukin (IL)-1 beta was administered intratracheally (i.t.) to intubated, spontaneously breathing Sprague-Dawley rats. The rats were pretreated either with a VIP synthetic peptide analogue, a pituitary adenylate cyclase-activating peptide (PACAP)-1-27 synthetic analogue, the beta(2)-adrenoceptor agonist salbutamol or vehicle, systemically or locally. Differential cell counts were performed on bronchoalveolar lavage fluid (BALf) cytospins. Effects on mean arterial blood pressure (MAP) were monitored in separate experiments. Systemic administration of the VIP analogue, the PACAP analogue and salbutamol attenuated the cytokine-induced increase in BALf neutrophil number. Local administration of the VIP analogue and salbutamol, but not the PACAP analogue, also decreased the neutrophil number in BALf. Local administration of the VIP analogue and salbutamol caused a transient decrease in MAP. Systemic or local administration of a synthetic VIP peptide analogue inhibits cytokine-induced neutrophil recruitment in airways in vivo. This action is exerted without severe, sustained cardiovascular side effects, and deserves to be further evaluated in obstructive pulmonary diseases in human.
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| 3. |
- Sergejeva, Svetlana, 1972, et al.
(författare)
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Allergen exposure-induced differences in CD34+ cell phenotype: relationship to eosinophilopoietic responses in different compartments
- 2004
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Ingår i: Blood. ; 103:4, s. 1270-7
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that the allergen-induced increased number of airway eosinophils results from increased recruitment of eosinophils from bone marrow (BM) and local development of CD34(+) cells into eosinophils. We also assumed that the phenotype of airway eosinophils depends on whether these cells have differentiated within BM or airway. C57BL/6 mice were sensitized and subsequently exposed to ovalbumin (OVA) on 5 consecutive days. Newly produced cells were labeled with a thymidine analog. Clonogenic activity and interleukin 5 (IL-5) release from bronchoalveolar lavage fluid (BALf) CD34(+) cells were evaluated by using cell-culture techniques. Allergen exposure induces increase in CD135(+) primitive myeloid progenitors within the BM CD34(+) cell population, without significant changes in total number of CD34(+) cells or newly produced CD34(+) cells. CD34(+)/IL-5Ralpha(+) cells in the first stage of cell differentiation were found only in BM, arguing that early commitment of CD34(+) cells into the eosinophil lineage is restricted to the BM compartment. Allergen exposure induces a shift in differentiation of BM, blood, and BALf eosinophillineage-committed CD34(+) cells toward mature eosinophils and recruitment of these cells via blood into airway. We further demonstrate in vitro that ability to multiply persists in BALf CD34(+) cells but not CD34(-) cells, likely via autocrine IL-5 release and IL-5-induced up-regulation of IL-5Ralpha.
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| 4. |
- Sergejeva, Svetlana, 1972, et al.
(författare)
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Intranasal fluticasone propionate inhibits allergen induced bone marrow eosinophilia in mice.
- 2002
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Ingår i: Pulmonary pharmacology & therapeutics. - : Elsevier BV. - 1094-5539. ; 15:2, s. 129-34
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Tidskriftsartikel (refereegranskat)abstract
- Local corticosteroids are currently the most efficient safe anti-allergic treatment, which attenuate eosinophilic tissue inflammation through several mechanisms. We evaluated the effect of local airways corticosteroid on repeated allergen exposure-induced bone marrow activation and airway eosinophilia using the number of eosinophils in bone marrow, bronchoalveolar lavage fluid (BALf) and airways tissue as study end-points. Male BALB/c mice were sensitized by intraperitoneal injections of aluminum-precipitated ovalbumin (OVA) on two different days (5 days apart). Eight days after the second sensitization, the animals were challenged intranasally with OVA or phosphate-buffered saline (PBS) on 5 consecutive days. Concomitantly with challenges mice were treated with fluticasone propionate or respective vehicle. OVA exposures induced a significant increase in eosinophil numbers in bone marrow, BALf and airways tissue (P<0.005). Treatment with fluticasone propionate significantly reduced the increase of absolute number of mature bone marrow eosinophils (P=0.014) and showed a tendency towards decrease in the immature bone marrow eosinophil number (P=0.057) compared to controls. However, fluticasone propionate had no significant effect on BALf and airways tissue eosinophils (P=0.28 and 0.07, respectively). In this murine allergy model intranasal corticosteroid reduced number of bone marrow mature eosinophils, but did not significantly affect airways cell populations.
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| 5. |
- Sergejeva, Svetlana, 1972
(författare)
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Mechanisms of allergic airway inflammation. Role of bone marrow
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergic airway (AW) inflammation is characterized by accumulation of inflammatory cells within the AW. It is likely that the accumulation of cells within AW is a combination of increased production, migration and prolonged survival of the cells. Inflammatory cells develop from CD34+hematopoietic progenitor cells. Importantly, allergic subjects have increased numbers of CD34+progenitors in bone marrow (BM) and AW. The aims of this thesis were to determine the mechanisms underlining the allergeninduced accumulation of eosinophils and neutrophils in the AW. With reference to allergen-induced AW eosinophilia, the contribution of eosinophilopoiesis in different compartments was studied. In addition, the contribution of the pro-inflammatory cytokine IL-17 in accumulation of eosinophils and neutrophils within the AW was evaluated. The effect of local corticosteroids and systemic blockage of IL-17 cytokine, respectively, were determined. For that purpose, mice models of allergen exposure-induced allergic inflammation and nasal biopsies from allergic rhinitis patients were used. Repeated allergen exposure of sensitized mice resulted in an increase in the number of primitive myeloid progenitors within the BM CD34+cell population. The earliest eosinophil-committed CD34+cells were restricted to the BM compartment. After the allergen exposure, a substantial part of CD34+progenitor cells was de novo produced. In the BM, allergen exposure increased the number of CD34+eosinophilic cells and CD34-mature eosinophils. In blood and AW, allergen exposure induced an increase in the number of CD34+eosinophilic cells, CD34- mature eosinophils and also in newly produced CD34+cells. Furthermore, allergen exposure induced a shift in differentiation of BM, blood and BALf eosinophil-committed CD34+cells towards more mature eosinophils. Importantly, AW CD34+cells from allergen-exposed mice expressed stem cell antigen (Sca-1), produced eosinophil colonies and in response to stimulation with IL-5 expressed IL-5 receptor a chain (IL-5Ra). Moreover, AW CD34+eosinophilic cells themselves released high amounts of IL-5 after unspecific stimulation. In the mouse model of repeated allergen exposure, administration of an intranasal corticosteroid, fluticasone propionate (FP), significantly reduced the allergen-induced elevation of BM eosinophil number, without substantial effect on the number of AW eosinophils. In subjects with allergic rhinitis, the exposure to allergen increased the number of nasal mucosal CD34+hematopoietic cells concomitantly with up-regulation of CXCR4 expression within the CD34+cell population. Furthermore, also the number of CD34+eosinophils in nasal mucosa was increased following exposure to allergen. A local corticosteroid, FP, provided protection against this pollen-induced increase in tissue CD34+cells. The systemic pre-treatment with an anti-IL-17 antibody in allergen-exposed mice reduced the number of AW neutrophils, but not eosinophils, without any significant changes in BM granulocyte counts. In addition, the expression of matrix metalloproteinase-9 (MMP-9) by AW neutrophils but not eosinophils was downregulated by the pre-treatment with anti-IL-17 antibody. In conclusion, this thesis demonstrates the exclusive role of BM in the first-line commitment of hematopoietic progenitors into the eosinophilic lineage. Importantly, allergen exposure induces not only a shift in the differentiation of eosinophil-committed progenitors towards mature cells, but also increases in the number of primitive myeloid progenitors in BM. In response to allergen exposure, CD34+progenitor cells are mobilized into the airways with one mechanism being CXCR4-mediated cell recruitment. The AW CD34+cells maintain a phenotype of a true hematopoietic progenitor cells and retain the ability to multiply likely via autocrine IL-5 release and IL-5-induced up-regulation of IL-5Ra. Local corticosteroids inhibit the allergen-induced BM and AW eosinophilopoiesis as well as allergen-induced CXCR4-mediated recruitment of CD34+cells into AW. Endogenous IL-17 increases the number of MMP-9+ neutrophils in allergic AW inflammation, without substantial effect on the number of eosinophils.
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| 6. |
- Sitkauskiene, Brigita, et al.
(författare)
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Regulation of Bone Marrow and Airway CD34+ Eosinophils by Interleukin-5
- 2004
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Ingår i: Am J Respir Cell Mol Biol. ; 30:3
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the effect of a neutralizing anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) on bone marrow and airway CD34(+) and immature eosinophils. A focus was to determine the effect of the timing of treatment. Balb/c mice were ovalbumin-sensitized and subsequently exposed to ovalbumin for 5-10 d via airway route. Animals were treated intraperitoneally with TRFK-5 or its isotype control (50 microg) once at different time points. Newly produced eosinophils were labeled using 5-bromo-2'-deoxyuridine (BrdU). BrdU(+) and CD34(+) eosinophil numbers were examined by immunocytochemistry. TRFK-5 reduced bone marrow immature eosinophils within 3 d. This effect was closely related to a reduction of BrdU(+) and CD34(+) bone marrow eosinophils, and reduced numbers of blood eosinophils. However, bronchoalveolar lavage (BAL) eosinophilia was not attenuated to the same degree. The effect of TRFK-5 was most prominent in the extended allergen-exposure protocol, where the treatment was given in the middle of the exposure, with strongly reduced bone marrow CD34(+) and immature bone marrow eosinophils, blood eosinophils as well as BAL BrdU(+) eosinophils, and BAL CD34(+) eosinophils. These data argue that anti-IL-5 downregulates eosinophilopoiesis within 3 d by action in the bone marrow, by inhibition of the early stages of eosinophil maturation from CD34(+) cells.
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