Compartmentalized transgene expression of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in mouse lung enhances allergic airways inflammation

To investigate the role of GM‐CSF in asthmatic airways inflammation, we have targeted GM‐CSF transgene to the airway cells in a mouse model of ovalbumin (OVA)‐induced allergic airways inflammation, a model in which there is marked induction of endogenous IL‐5 and IL‐4 but not GM‐CSF. Following intra...

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Bibliographic Details
Published in:Clinical and experimental immunology 1998-08, Vol.113 (2), p.157-165
Main Authors: Lei, X F, Ohkawara, Y, Stämpfli, M R, Gauldie, J, Croitoru, K, Jordana, M, Xing, Z
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
airways inflammation
Animals
Apoptosis
Asthma - immunology
Biological and medical sciences
Bronchoalveolar Lavage Fluid - cytology
Bronchoalveolar Lavage Fluid - immunology
eosinophilia
Epithelial Cells - immunology
Experimental and animal immunopathology. Animal models
Female
Gene Targeting
gene transfer
Genetic Vectors
GM‐CSF
Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis
Granulocyte-Macrophage Colony-Stimulating Factor - genetics
Granulocyte-Macrophage Colony-Stimulating Factor - immunology
Immunopathology
Interleukin-4 - analysis
Interleukin-5 - analysis
Lung - immunology
Lung - pathology
Medical sciences
Mice
Mice, Inbred BALB C
Original
Ovalbumin - immunology
Transgenes
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Summary:To investigate the role of GM‐CSF in asthmatic airways inflammation, we have targeted GM‐CSF transgene to the airway cells in a mouse model of ovalbumin (OVA)‐induced allergic airways inflammation, a model in which there is marked induction of endogenous IL‐5 and IL‐4 but not GM‐CSF. Following intranasal delivery of a replication‐deficient adenoviral gene transfer vector (Ad), transgene expression was found localized primarily to the respiratory epithelial cells. Intranasal delivery of 0.03 × 109 plaque‐forming units (PFU) of AdGM‐CSF into naive BALB/c mice resulted in prolonged and compartmentalized release of GM‐CSF transgene protein with a peak concentration of ≈ 80 pg/ml detected in bronchoalveolar lavage fluid (BALF) at day 7, but little in serum. These levels of local GM‐CSF expression per se resulted in no eosinophilia and only a minimum of tissue inflammatory responses in the lung of naive mice, similar to those induced by the control vector. However, such GM‐CSF expression in the airways of OVA‐sensitized mice resulted in a much greater and sustained accumulation of various inflammatory cell types, most noticeably eosinophils, both in BALF and airway tissues for 15–21 days post‐OVA aerosol challenge, at which times airways inflammation had largely resolved in control mice. While the levels of IL‐5 and IL‐4 in BALF and the rate of eosinophil apoptosis were found similar between different treatments, there was an increased number of proliferative leucocytes in the lung receiving GM‐CSF gene transfer. Our results thus provide direct experimental evidence that GM‐CSF can significantly contribute to the development of allergic airways inflammation through potentiating and prolonging inflammatory infiltration induced by cytokines such as IL‐5 and IL‐4.
ISSN:0009-9104
1365-2249
DOI:10.1046/j.1365-2249.1998.00652.x