Asosingh Kewal, Swaidani Shadi, Aronica Mark, Erzurum Serpil C
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
J Immunol. 2007 May 15;178(10):6482-94. doi: 10.4049/jimmunol.178.10.6482.
Increased numbers of submucosal vessels are a consistent pathologic component of asthmatic airway remodeling. However, the relationship between new vessel formation and asthmatic inflammatory response is unknown. We hypothesized that angiogenesis is a primary event during the initiation of airway inflammation and is linked to the recruitment of bone marrow-derived endothelial progenitor cells (EPC). To test this hypothesis, circulating EPC and EPC-derived endothelial cell colony formation of individuals with asthma or allergic rhinitis and health controls was evaluated. Circulating EPC were increased in asthma, highly proliferative, and exhibited enhanced incorporation into endothelial cell tubes as compared with controls. In an acute allergen challenge murine asthma model, EPC mobilization occurred within hours of challenge and mobilized EPC were selectively recruited into the challenged lungs of sensitized animals, but not into other organs. EPC recruitment was Th1 and Th2 dependent and was temporally associated with an increased microvessel density that was noted within 48 h of allergen challenge, indicating an early switch to an angiogenic lung environment. A chronic allergen challenge model provided evidence that EPC recruitment to the lung persisted and was associated with increasing microvessel density over time. Thus, a Th1- and Th2-dependent angiogenic switch with EPC mobilization, recruitment, and increased lung vessel formation occurs early but becomes a sustained and cumulative component of the allergen-induced asthmatic response.
黏膜下血管数量增加是哮喘气道重塑持续存在的病理组成部分。然而，新生血管形成与哮喘炎症反应之间的关系尚不清楚。我们推测血管生成是气道炎症起始过程中的一个主要事件，并且与骨髓来源的内皮祖细胞（EPC）的募集有关。为了验证这一假设，我们评估了哮喘或过敏性鼻炎患者以及健康对照者的循环EPC和EPC衍生的内皮细胞集落形成情况。与对照组相比，哮喘患者的循环EPC数量增加、增殖能力强，并且在形成内皮细胞管方面表现出更强的能力。在急性变应原激发小鼠哮喘模型中，变应原激发数小时内即发生EPC动员，动员的EPC被选择性募集到致敏动物受激发的肺中，但未进入其他器官。EPC募集依赖于Th1和Th2，并且在时间上与变应原激发48小时内微血管密度增加相关，这表明早期转变为促血管生成的肺环境。慢性变应原激发模型提供的证据表明，EPC向肺的募集持续存在，并随着时间的推移与微血管密度增加相关。因此，依赖于Th1和Th2的血管生成转换，伴有EPC动员、募集以及肺血管形成增加，在早期即发生，但成为变应原诱导的哮喘反应持续且累积的组成部分。
