Adenosine-dependent airway inflammation and hyperresponsiveness in partially adenosine deaminase-deficient mice
Adenosine-dependent airway inflammation and hyperresponsiveness in partially adenosine deaminase-deficient mice
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DOI：
10.4049/jimmunol.167.8.4676
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发表时间：
2001-10-15
影响因子：
4.4
通讯作者：
Blackburn, MR
中科院分区：
文献类型：
--
作者：
Chunn, JL;Young, HWJ;Blackburn, MR
腺苷是一种信号核苷，在哮喘患者的肺中升高。我们设计了一种小鼠模型，由于代谢腺苷的腺苷脱氨酶(ADA)的部分表达，导致腺苷水平升高。ADA酶活性水平降低的小鼠是由于ADA基因在其他ADA缺陷小鼠的胃肠道中异位表达而产生的。这些小鼠发展为进行性肺部炎症和损伤，并在4-5个月龄时死于呼吸窘迫。与这种表型相关的是肺腺苷水平的进行性增加。6周龄时的呼吸道生理学检查显示出气道高反应性的改变。在使用ADA酶疗法降低腺苷水平后，这种情况被逆转，也通过使用腺苷受体拮抗剂茶碱，这表明核苷及其受体都参与了呼吸道生理变化。所有四种腺苷受体在对照组和部分ADA缺陷小鼠的肺中都有表达。然而，在部分ADA缺乏的肺中，A(1)、A(2B)和A(3)腺苷受体的转录水平显著升高。小鼠肺泡巨噬细胞明显增多，单核细胞趋化蛋白-3在小鼠支气管上皮细胞中表达升高，这可能在调节肺部炎症和气道高反应性方面有重要意义。总而言之，这些发现表明，腺苷的升高可以直接影响肺部炎症和生理。
Adenosine is a signaling nucleoside that is elevated in the lungs of asthmatics. We have engineered a mouse model that has elevated levels of adenosine as a result of the partial expression of the enzyme that metabolizes adenosine, adenosine deaminase (ADA). Mice with lowered levels of ADA enzymatic activity were generated by the ectopic expression of an ADA minigene in the gastrointestinal tract of otherwise ADA-deficient mice. These mice developed progressive lung inflammation and damage and died at 4-5 mo of age from respiratory distress. Associated with this phenotype was a progressive increase in lung adenosine levels. Examination of airway physiology at 6 wk of age revealed alterations in airway hyperresponsiveness. This was reversed following the lowering of adenosine levels using ADA enzyme therapy and also through the use of the adenosine receptor antagonist theophylline, implicating both the nucleoside and its receptors in airway physiological alterations. All four adenosine receptors were expressed in the lungs of both control and partially ADA-deficient mice. However, transcript levels for the A(1), A(2B), and A(3) adenosine receptors were significantly elevated in partially ADA-deficient lungs. There was a significant increase in alveolar macrophages, and monocyte chemoattractant protein-3 was found to be elevated in the bronchial epithelium of these mice, which may have important implications in the regulation of pulmonary inflammation and airway hyperresponsiveness. Collectively, these findings suggest that elevations in adenosine can directly impact lung inflammation and physiology.