Timing of administration of anti-VLA-4 differentiates airway hyperresponsiveness in the central and peripheral airways in mice
Timing of administration of anti-VLA-4 differentiates airway hyperresponsiveness in the central and peripheral airways in mice
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DOI：
10.1164/ajrccm.162.3.9910100
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发表时间：
2000-09-01
影响因子：
24.7
通讯作者：
Gelfand, EW
中科院分区：
文献类型：
--
作者：
Kanehiro, A;Takeda, K;Gelfand, EW
气道高反应性（AHR）的发生与活化的嗜酸性粒细胞和T淋巴细胞向肺内的浸润有关。在很大程度上，嗜酸性粒细胞流入肺依赖于极晚期活化抗原-4（VLA-4）的表达。然而，嗜酸性粒细胞募集的动力学和AHR的发展还没有完全阐明。通过抗VLA-4后吸入乙酰甲胆碱（MCh）的肺阻力（RL）和动态顺应性（Cdyn）变化监测气道功能。卵白蛋白（OVA）致敏和激发BALB/c小鼠气道后，AHR增加，肺内炎性细胞数量增加。在第一次（三次）OVA气道激发前2小时向致敏小鼠施用抗VLA-4显著防止RL的变化。此外，从第一次攻击前2 h至最后一次攻击后42 h注射抗体可显著阻止RL的增加，以及支气管肺泡灌洗液（BALF）中嗜酸性粒细胞和淋巴细胞数量的增加; BALF中白细胞介素-5（IL-5）和白三烯浓度也被显著抑制。有趣的是，当在第一次攻击前2小时施用时，用抗VLA-4处理仅防止Cdyn和杯状细胞增生的变化。这些研究表明，抗VLA-4给药的时机可以选择性地影响病理过程，这些病理过程有助于过敏原激发后中央和外周气道的气道功能改变。
The development of airway hyperresponsiveness (AHR) is correlated with the infiltration into the lungs of activated eosinophils and T lymphocytes. In large part, influx of eosinophils into the lung is dependent on very late activating antigen-4 (VLA-4) expression. However, the kinetics of eosinophil recruitment and the development of AHR are not fully delineated. Airway function was monitored by changes in lung resistance (RL) and dynamic compliance (Cdyn) to methacholine (MCh) inhalation after anti-VLA-4. After ovalbumin (OVA) sensitization and airway challenge of BALB/c mice, AHR increased as did the number of lung inflammatory cells. Administration of anti-VLA-4 to sensitized mice 2 h before the first (of three) OVA airway challenges significantly prevented changes in RL. Moreover, injection of the antibody from 2 h before the first challenge to 42 h after the last challenge significantly prevented the increases in RL, as well as eosinophil and lymphocyte numbers in the bronchoalveolar lavage fluid (BALF); interleukin-5 (IL-5) and leukotriene concentrations in BALF were also significantly inhibited. Interestingly, treatment with anti-VLA-4 only prevented changes in Cdyn and goblet cell hyperplasia when administered 2 h before the first challenge. These studies demonstrate that the timing of anti-VLA-4 administration can selectively affect pathologic processes that contribute to altered airway function in the central and peripheral airways after allergen challenge.