The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in aspergillus fumigatus sensitized mice

Respiratory Research

Angela Haczku³  Colin Macphee¹  Stephen Wilson⁵  Steven A Sheardown⁴  Imre G Redai²  Blerina Kokalari²  Giulia Ravaioli²  Melane L Fehrenbach²  Zhilong Jiang² 

[1] Department of Vascular Biology and Thrombosis, GlaxoSmithKline, King of Prussia, PA, USA;Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA;Pulmonary, Allergy and Critical Care Division, Translational Research Laboratories, 125 South 31st Street, Philadelphia, PA, 19104-3403, USA;Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge, UK;GSK Laboratory Animal Sciences, GlaxoSmithKline, Stevenage, UK

关键词: Degranulation;    Mast cells;    IgE;    Airway inflammation;    Knock-out mice;    PAF-AH;    Lp-PLA₂;   

Others  :  796610
DOI  :  10.1186/1465-9921-13-100

 received in 2012-08-01, accepted in 2012-11-06,  发布年份 2012

【 摘 要 】

Background

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂)/platelet-activating factor acetylhydrolase (PAF-AH) has been implicated in the pathogenesis of cardiovascular disease. A therapeutic targeting of this enzyme was challenged by the concern that increased circulating platelet activating factor (PAF) may predispose to or increase the severity of the allergic airway response. The aim of this study was to investigate whether Lp-PLA₂ gene deficiency increases the risk of PAF and IgE-mediated inflammatory responses in vitro and in vivo using mouse models.

Methods

Lp-PLA₂-/- mice were generated and back crossed to the C57BL/6 background. PAF-AH activity was measured using a hydrolysis assay in serum and bronchoalveolar lavage (BAL) samples obtained from mice. Aspergillus fumigatus (Af)-specific serum was prepared for passive allergic sensitization of mice in vivo and mast cells in vitro. β- hexosaminidase release was studied in bone marrow derived mast cells sensitized with Af-specific serum or DNP-IgE and challenged with Af or DNP, respectively. Mice were treated with lipopolysaccharide (LPS) and PAF intratracheally and studied 24 hours later. Mice were sensitized either passively or actively against Af and were studied 48 hours after a single intranasal Af challenge. Airway responsiveness to methacholine, inflammatory cell influx in the lung tissue and BAL, immunoglobulin (ELISA) and cytokine (Luminex) profiles were compared between the wild type (WT) and Lp-PLA₂-/- mice.

Results

PAF-AH activity was reduced but not completely abolished in Lp-PLA₂-/- serum or by in vitro treatment of serum samples with a high saturating concentration of the selective Lp-PLA₂ inhibitor, SB-435495. PAF inhalation significantly enhanced airway inflammation of LPS treated WT and Lp-PLA₂-/- mice to a similar extent. Sensitized WT and Lp-PLA₂-/- bone-marrow derived mast cells released β-hexosaminidase following stimulation by allergen or IgE crosslinking to equivalent levels. Wild type and Lp-PLA₂-/- mice responded to passive or active allergic sensitization by significant IgE production, airway inflammation and hyperresponsiveness after Af challenge. BAL cell influx was not different between these strains while IL-4, IL-5, IL-6 and eotaxin release was attenuated in Lp-PLA₂-/- mice. There were no differences in the amount of total IgE levels in the Af sensitized WT and Lp-PLA₂-/- mice.

Conclusions

We conclude that Lp-PLA₂ deficiency in C57BL/6 mice did not result in a heightened airway inflammation or hyperresponsiveness after PAF/LPS treatment or passive or active allergic sensitization and challenge.

【 授权许可】

   
2012 Jiang et al.; licensee BioMed Central Ltd.

【 图 表 】

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