Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma
Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma
复制标题
DOI：
10.1152/ajplung.00208.2006
复制
发表时间：
2007-05-01
影响因子：
4.9
通讯作者：
Cook-Mills, Joan M.
中科院分区：
文献类型：
--
作者：
Abdala-Valencia, Hiam;Earwood, Julie;Cook-Mills, Joan M.
肺嗜酸性粒细胞增多是哮喘最一致的标志之一。实验性哮喘患者嗜酸性粒细胞向肺的浸润依赖于内皮细胞上的粘附分子血管细胞粘附分子-1 （VCAM-1）。VCAM-1的连接激活内皮细胞NADPH氧化酶，这是体外VCAM-1依赖性白细胞迁移所必需的。为了研究内皮源性NADPH氧化酶是否在体内调节嗜酸性粒细胞的募集，对NADPH氧化酶缺乏的小鼠（CYBB小鼠）进行照射，并接受野生型造血细胞培养嵌合CYBB小鼠。在卵清蛋白（OVA）的刺激下，嵌合CYBB小鼠与内皮细胞结合的嗜酸性粒细胞数量增加，肺组织和支气管肺泡灌洗液中的嗜酸性粒细胞减少。这种情况的发生与VCAM-1表达、细胞因子/趋化因子水平（IL-5、IL-10、IL-13、IFN γ或eotaxin）、T细胞、中性粒细胞或单核细胞数量或ova小鼠灌洗液或肺组织的变化无关。重要的是，ova挑战嵌合CYBB小鼠气道高反应性（AHR）降低。通过气管内给药嗜酸性粒细胞绕过内皮细胞，恢复ova致嵌合CYBB小鼠的AHR。这些数据表明，VCAM-1诱导内皮细胞NADPH氧化酶对过敏性炎症期间嗜酸性粒细胞的募集是必要的。此外，这些研究为哮喘治疗中靶向vcam -1依赖性信号通路提供了基础。
Pulmonary eosinophilia is one of the most consistent hallmarks of asthma. Infiltration of eosinophils into the lung in experimental asthma is dependent on the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Ligation of VCAM-1 activates endothelial cell NADPH oxidase, which is required for VCAM-1-dependent leukocyte migration in vitro. To examine whether endothelial-derived NADPH oxidase modulates eosinophil recruitment in vivo, mice deficient in NADPH oxidase ( CYBB mice) were irradiated and received wild-type hematopoietic cells to generate chimeric CYBB mice. In response to ovalbumin ( OVA) challenge, the chimeric CYBB mice had increased numbers of eosinophils bound to the endothelium as well as reduced eosinophilia in the lung tissue and bronchoalveolar lavage. This occurred independent of changes in VCAM-1 expression, cytokine/chemokine levels (IL-5, IL-10, IL-13, IFN gamma, or eotaxin), or numbers of T cells, neutrophils, or mononuclear cells in the lavage fluids or lung tissue of OVA-challenged mice. Importantly, the OVA-challenged chimeric CYBB mice had reduced airway hyperresponsiveness (AHR). The AHR in OVA-challenged chimeric CYBB mice was restored by bypassing the endothelium with intratracheal administration of eosinophils. These data suggest that VCAM-1 induction of NADPH oxidase in the endothelium is necessary for the eosinophil recruitment during allergic inflammation. Moreover, these studies provide a basis for targeting VCAM-1-dependent signaling pathways in asthma therapies.