Apolipoprotein A-I Attenuates Ovalbumin-Induced Neutrophilic Airway Inflammation via a Granulocyte Colony-Stimulating Factor-Dependent Mechanism
Apolipoprotein A-I Attenuates Ovalbumin-Induced Neutrophilic Airway Inflammation via a Granulocyte Colony-Stimulating Factor-Dependent Mechanism
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DOI：
10.1165/rcmb.2011-0322oc
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发表时间：
2012-08-01
影响因子：
6.4
通讯作者：
Levine, Stewart J.
中科院分区：
文献类型：
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作者：
Dai, Cuilian;Yao, Xianglan;Levine, Stewart J.
载脂蛋白A-I(apoA-I)是高密度脂蛋白的重要组成部分，可介导细胞内胆固醇的反向转运，减轻血管炎症。我们研究了内源性apoA-I是否调节卵清蛋白(OVA)诱导的小鼠呼吸道炎症。我们发现，与生理盐水攻击的野生型(WT)小鼠相比，OVA攻击的小鼠肺中apoA-I的表达显著减少。接下来，为了探讨内源性apoA-I在OVA诱导的气道炎发病机制中的作用，WT和apoA-I-/-小鼠通过腹腔注射OVA和氢氧化铝致敏，然后经鼻腔多次激发OVA 4周。与WT小鼠相比，OVA攻击的apoA-I-/-小鼠表现出气道中性粒细胞增加的表型，这可以通过注射5A apoA-I模拟肽来挽救。多种途径促进OVA攻击的apoA-I-/-小鼠的中性粒细胞炎症，包括(1)促炎症细胞因子(IL-17A和TNF-α)，(2)CXC趋化因子(CXCL5)，(3)血管黏附分子(即血管细胞黏附分子-1)和(4)粒细胞集落刺激因子(G-CSF)的表达上调。由于OVA激发的apoA-I-/-小鼠支气管肺泡灌洗液(BALF)中G-CSF浓度显著升高，我们推测G-CSF表达增强可能是介导中性粒细胞炎症增加的主要途径。鼻腔注射中和抗G-CSF抗体证实了这一点，与接受对照抗体的小鼠相比，OVA攻击的apoA-I-/-小鼠的BALF中性粒细胞显著减少了72%。我们得出结论，内源性apoA-I主要通过G-CSF依赖的机制负性调节OVA诱导的中性粒细胞气道炎症。此外，这些发现表明载脂蛋白A-I可能在调节哮喘中性粒细胞气道炎症的严重程度中发挥重要作用。
Apolipoprotein A-I (apoA-I) is a key component of high-density lipoproteins that mediates reverse cholesterol transport from cells and reduces vascular inflammation. We investigated whether endogenous apoA-I modulates ovalbumin (OVA)-induced airway inflammation in mice. We found that apoA-I expression was significantly reduced in the lungs of OVA-challenged, compared with saline-challenged, wild-type (WT) mice. Next, to investigate the role of endogenous apoA-I in the pathogenesis of OVA-induced airway inflammation, WT and apoA-I-/- mice were sensitized by intraperitoneal injections of OVA and aluminum hydroxide, followed by multiple nasal OVA challenges for 4 weeks. OVA-challenged apoA-I-/- mice exhibited a phenotype of increased airway neutrophils compared with WT mice, which could be rescued by an administration of a 5A apoA-I mimetic peptide. Multiple pathways promoted neutrophilic inflammation in OVA-challenged apoA-I-/- mice, including the up-regulated expression of (1) proinflammatory cytokines (IL-17A and TNF-alpha), (2) CXC chemokines (CXCL5), (3) vascular adhesion molecules (i.e., vascular cell adhesion molecule-1), and (4) granulocyte colony-stimulating factors (G-CSF). Because concentrations of G-CSF in bronchoalveolar lavage fluid (BALF) were markedly increased in OVA-challenged apoA-I-/- mice, we hypothesized that enhanced G-CSF expression may represent the predominant pathway mediating increased neutrophilic inflammation. This was confirmed by the intranasal administration of a neutralizing anti-G-CSF antibody, which significantly reduced BALF neutrophilia by 72% in OVA-challenged apoA-I-/- mice, compared with mice that received a control antibody. We conclude that endogenous apoA-I negatively regulates OVA-induced neutrophilic airway inflammation, primarily via a G-CSF-dependent mechanism. Furthermore, these findings suggest that apoA-I may play an important role in modulating the severity of neutrophilic airway inflammation in asthma.