Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway
Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway
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DOI：
10.4049/jimmunol.169.9.5315
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发表时间：
2002-11-01
影响因子：
4.4
通讯作者：
Stevens, ME
中科院分区：
文献类型：
--
作者：
Schmidlin, F;Amadesi, S;Stevens, ME
胰蛋白酶和肥大细胞类胰蛋白酶可以通过切割蛋白酶激活受体2（PAR 2）向呼吸道的上皮细胞、肌细胞和神经纤维发出信号。由于类胰蛋白酶抑制剂正在开发用于治疗哮喘，因此需要精确了解PAR 2对气道炎症的作用。我们通过比较缺乏或过度表达PAR 2的卵蛋白致敏和激发小鼠，研究了PAR 2在气道过敏性炎症中的作用。在野生型小鼠中，在气道上皮细胞和肌细胞中检测到免疫反应性PAR 2，并且鼻内施用PAR 2激动剂刺激巨噬细胞浸润到支气管肺泡灌洗液中。免疫野生型小鼠的OVA激发刺激白细胞浸润到支气管肺泡灌洗液中，并诱导气道对吸入乙酰甲胆碱的高反应性。与野生型动物相比，嗜酸性粒细胞浸润在缺乏PAR 2的小鼠中被抑制了73%，在过表达PAR 2的小鼠中增加了88%。类似地，与野生型动物相比，对吸入乙酰甲胆碱（40 μ g/ml）的气道高反应性在缺乏PAR 2的小鼠中降低了38%，在过表达PAR 2的小鼠中增加了52%。与野生型动物相比，PAR 2缺失也使OVA致敏的IgE水平降低了4倍。因此，PAR 2有助于免疫的发展和气道的过敏性炎症。我们的研究结果支持类胰蛋白酶抑制剂和PAR 2拮抗剂可能是炎症性气道疾病的有效治疗方法的建议。
Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 mug/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease.