Wagner Elizabeth M, Jenkins John, Schmieder Anne, Eldridge Lindsey, Zhang Qiong, Moldobaeva Aigul, Zhang Huiying, Allen John S, Yang Xiaoxia, Mitzner Wayne, Keupp Jochen, Caruthers Shelton D, Wickline Samuel A, Lanza Gregory M
Department of Medicine, Johns Hopkins University, Baltimore, MD, USA,
Angiogenesis. 2015 Jan;18(1):1-11. doi: 10.1007/s10456-014-9441-6. Epub 2014 Aug 23.
Expanded and aberrant bronchial vascularity, a prominent feature of the chronic asthmatic airway, might explain persistent airway wall edema and sustained leukocyte recruitment. Since it is well established that there are causal relationships between exposure to house dust mite (HDM) and the development of asthma, determining the effects of HDM in rats, mammals with a bronchial vasculature similar to humans, provides an opportunity to study the effects of bronchial angiogenesis on airway function directly. We studied rats exposed bi-weekly to HDM (Der p 1; 50 μg/challenge by intranasal aspiration, 1, 2, 3 weeks) and measured the time course of appearance of increased blood vessels within the airway wall. Results demonstrated that within 3 weeks of HDM exposure, the number of vessels counted within airway walls of bronchial airways (0.5-3 mm perimeter) increased significantly. These vascular changes were accompanied by increased airway responsiveness to methacholine. A shorter exposure regimen (2 weeks of bi-weekly exposure) was insufficient to cause a significant increase in functional vessels or reactivity. Yet, 19F/1H MR imaging at 3T following αvβ3-targeted perfluorocarbon nanoparticle infusion revealed a significant increase in 19F signal in rat airways after 2 weeks of bi-weekly HDM, suggesting earlier activation of the process of neovascularization. Although many antigen-induced mouse models exist, mice lack a bronchial vasculature and consequently lack the requisite human parallels to study bronchial edema. Overall, our results provide an important new model to study the impact of bronchial angiogenesis on chronic inflammation and airways hyperreactivity.
支气管血管增多和异常是慢性哮喘气道的一个显著特征，这可能解释了气道壁持续水肿和白细胞持续募集的原因。由于暴露于屋尘螨（HDM）与哮喘的发生之间存在因果关系已得到充分证实，因此在大鼠（一种支气管血管系统与人类相似的哺乳动物）中确定HDM的作用，为直接研究支气管血管生成对气道功能的影响提供了一个机会。我们研究了每两周暴露于HDM（Der p 1；通过鼻内吸入每次激发50μg，共1、2、3周）的大鼠，并测量了气道壁内血管增多出现的时间进程。结果表明，在HDM暴露3周内，支气管气道（周长0.5 - 3mm）气道壁内计数的血管数量显著增加。这些血管变化伴随着气道对乙酰甲胆碱反应性的增加。较短的暴露方案（每两周暴露2周）不足以导致功能性血管或反应性显著增加。然而，在每两周进行HDM暴露2周后，在3T下注射靶向αvβ3的全氟碳纳米颗粒后进行的19F/1H磁共振成像显示，大鼠气道中的19F信号显著增加，表明血管生成过程更早被激活。尽管存在许多抗原诱导的小鼠模型，但小鼠缺乏支气管血管系统，因此缺乏研究支气管水肿所需的与人类相似的模型。总体而言，我们的结果提供了一个重要的新模型，用于研究支气管血管生成对慢性炎症和气道高反应性的影响。
