The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in Aspergillus fumigatus sensitized mice.
The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in Aspergillus fumigatus sensitized mice.
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DOI：
10.1186/1465-9921-13-100
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发表时间：
2012-11-12
影响因子：
5.8
通讯作者：
Haczku A
中科院分区：
文献类型：
--
作者：
Jiang Z;Fehrenbach ML;Ravaioli G;Kokalari B;Redai IG;Sheardown SA;Wilson S;Macphee C;Haczku A
脂蛋白相关磷脂酶 A2 (Lp-PLA2)/血小板激活因子乙酰水解酶 (PAF-AH) 与心血管疾病的发病机制有关。由于循环血小板活化因子（PAF）增加可能会诱发或增加过敏性气道反应的严重性，因此这种酶的治疗靶向受到挑战。本研究的目的是利用小鼠模型在体外和体内研究 Lp-PLA2 基因缺陷是否会增加 PAF 和 IgE 介导的炎症反应的风险。生成 Lp-PLA2-/- 小鼠并与 C57BL/6 背景回交。使用从小鼠获得的血清和支气管肺泡灌洗液 (BAL) 样品中的水解测定来测量 PAF-AH 活性。制备了烟曲霉（Af）特异性血清，用于小鼠体内和体外肥大细胞的被动过敏致敏。在用 Af 特异性血清或 DNP-IgE 致敏并分别用 Af 或 DNP 攻击的骨髓来源的肥大细胞中研究了 β-己糖胺酶释放。小鼠经气管内注射脂多糖 (LPS) 和 PAF，并在 24 小时后进行研究。小鼠被动或主动地对 Af 敏感，并在单次鼻内 Af 攻击后 48 小时进行研究。比较野生型 (WT) 和 Lp-PLA2-/- 小鼠之间的气道对乙酰甲胆碱的反应性、肺组织和 BAL 中的炎症细胞流入、免疫球蛋白 (ELISA) 和细胞因子 (Luminex) 谱。 Lp-PLA2-/- 血清中或通过用高饱和浓度的选择性 Lp-PLA2 抑制剂 SB-435495 体外处理血清样品，PAF-AH 活性降低，但并未完全消除。 PAF 吸入显着增强了 LPS 处理的 WT 和 Lp-PLA2-/- 小鼠的气道炎症，程度相似。致敏的 WT 和 Lp-PLA2-/- 骨髓来源的肥大细胞在受到过敏原或 IgE 交联刺激至同等水平后释放 β-己糖胺酶。野生型和 Lp-PLA2-/- 小鼠在 Af 攻击后通过显着的 IgE 产生、气道炎症和高反应性对被动或主动过敏致敏做出反应。这些品系之间的 BAL 细胞流入没有差异，而 Lp-PLA2-/- 小鼠中 IL-4、IL-5、IL-6 和嗜酸细胞活化趋化因子的释放减弱。 Af 致敏的 WT 和 Lp-PLA2-/- 小鼠中总 IgE 水平没有差异。我们得出的结论是，C57BL/6 小鼠的 Lp-PLA2 缺陷不会导致 PAF/LPS 治疗或被动或主动过敏和激发后气道炎症或高反应性加剧。
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. 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. 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. 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.
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DOI：
10.1159/000233441
发表时间：
1984-01-01
期刊：
INTERNATIONAL ARCHIVES OF ALLERGY AND APPLIED IMMUNOLOGY
影响因子：
--
作者：
KALLOS, P;KALLOS, L
通讯作者：
KALLOS, L
影响因子：
4.8
作者：
Haczku, A;Emami, K;Rizi, RR
通讯作者：
Rizi, RR
影响因子：
3.6
作者：
Lu, Jing;Pierce, Marissa;Caplan, Michael
通讯作者：
Caplan, Michael
影响因子：
4.4
作者：
Haczku, Angela;Cao, Yang;Crouch, Erika C.
通讯作者：
Crouch, Erika C.
影响因子：
20.1
作者：
Liu J;Chen R;Marathe GK;Febbraio M;Zou W;McIntyre TM
通讯作者：
McIntyre TM