Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Chest. 2011 Oct;140(4):1048-1054. doi: 10.1378/chest.11-0158.
New treatments are needed for patients with severe asthma. We hypothesized that a clinically relevant experimental model of house dust mite (HDM)-induced murine asthma could be used to discover new pathways that regulate disease severity. In HDM-challenged mice, genome-wide expression profiling of the asthmatic lung transcriptome identified apolipoprotein E (apoE) as a steroid-unresponsive gene with persistently upregulated expression despite dexamethasone treatment. ApoE and low-density lipoprotein receptor (LDLR) knockout mice were used to demonstrate that apoE, which is produced by lung macrophages, functions in a paracrine fashion by binding to LDLRs expressed on ciliated airway epithelial cells, to negatively modulate airway hyperreactivity, mucin gene expression, and goblet cell hyperplasia. Furthermore, administration of an apoE mimetic peptide, which corresponded to the LDLR-binding domain of apoE, prevented the induction of airway inflammation, airway hyperreactivity, and goblet cell hyperplasia in HDM-challenged apoE knockout mice. This suggests that therapeutic strategies that activate the apoE-LDLR pathway, such as apoE mimetic peptides, may represent a novel treatment approach for patients with asthma. Similarly, we showed that administration of a 5A apolipoprotein A-I mimetic peptide attenuated the induction of HDM-mediated asthma in mice. These preclinical data suggest that apoE and apoA-I mimetic peptides might be developed into alternative treatments for patients with severe asthma. Future clinical trials will be required to determine whether inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides are effective for the treatment of severe asthma, including patients with phenotypes that lack effective therapeutic options.
需要为严重哮喘患者开发新的治疗方法。我们假设，尘螨（HDM）诱导的实验性小鼠哮喘模型可用于发现调节疾病严重程度的新途径。在 HDM 挑战的小鼠中，哮喘肺转录组的全基因组表达谱分析确定载脂蛋白 E（apoE）为类固醇无反应基因，尽管用地塞米松治疗但其表达仍持续上调。apoE 和低密度脂蛋白受体（LDLR）敲除小鼠用于证明由肺巨噬细胞产生的 apoE 通过与纤毛气道上皮细胞表达的 LDLR 结合，以旁分泌方式发挥作用，从而负调节气道高反应性、粘蛋白基因表达和杯状细胞增生。此外，给予与 apoE 的 LDLR 结合域相对应的 apoE 模拟肽可防止 HDM 挑战的 apoE 敲除小鼠中气道炎症、气道高反应性和杯状细胞增生的诱导。这表明激活 apoE-LDLR 途径的治疗策略，如 apoE 模拟肽，可能代表哮喘患者的一种新的治疗方法。同样，我们表明，给予 5A 载脂蛋白 A-I 模拟肽可减轻 HDM 介导的哮喘在小鼠中的诱导。这些临床前数据表明，apoE 和 apoA-I 模拟肽可能被开发为严重哮喘患者的替代治疗方法。需要进行未来的临床试验来确定吸入的载脂蛋白 E 或载脂蛋白 A-I 模拟肽是否对严重哮喘，包括缺乏有效治疗选择的表型患者有效。
