Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences
Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences
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DOI：
10.1016/j.taap.2008.03.004
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发表时间：
2008-08-01
影响因子：
3.8
通讯作者：
Last, Jerold A.
中科院分区：
文献类型：
--
作者：
Kenyon, Nicholas J.;Bratt, Jennifer M.;Last, Jerold A.
无论是在人类患者的临床研究中，还是在经过充分研究的卵清蛋白诱导的气道炎症小鼠模型中，肺部精氨酸酶基因表达都与哮喘有关。精氨酸酶被认为通过将精氨酸（产生瓜氨酸和NO的一氧化氮合酶的底物）转移到产生鸟氨酸和尿素的替代代谢途径中来调节肺中的NO水平。本研究测量了精氨酸酶I和精氨酸酶11浓度，这些精氨酸酶I和精氨酸酶11浓度来自暴露于卵蛋白气溶胶的致敏Balb/c小鼠的离体微解剖气道制剂。我们发现精氨酸酶11在正常小鼠的气道中有组成性表达，而精氨酸酶1在正常小鼠的气道中检测不到，而在卵清蛋白小鼠的气道中其表达增加。精氨酸酶I的表达与肺部炎症的存在密切相关，通过肺灌洗的细胞计数进行量化，表明暴露于卵清蛋白的小鼠肺部的大部分或全部精氨酸酶I存在于炎症细胞中，而不是存在于气道上皮中。在孤立气道中精氨酸酶I的表达增加与肺顺应性降低之间也存在显著的相关性。另一方面，虽然我们发现与正常气道相比，暴露于卵清蛋白的小鼠气道中精氨酸酶11的表达也显著增加，但相对增加的幅度远小于精氨酸酶1，这表明炎症细胞对暴露于卵清蛋白的小鼠气道中精氨酸酶11含量的贡献较小。离体气道精氨酸酶含量与卵清蛋白暴露小鼠呼气中no浓度无明显相关性。然而，暴露于卵清蛋白的小鼠呼出的NO浓度与肺灌洗的淋巴细胞含量之间存在相关性。暴露于卵清蛋白2周的Balb/c小鼠离体气道中发现的精氨酸浓度约为正常小鼠离体微解剖气道中发现的浓度的一半。用精氨酸酶抑制剂对小鼠进行全身处理可显著增加一氧化氮的产生量，这是通过测定卵清蛋白小鼠肺灌洗上清液中亚硝酸盐+硝酸盐（NOx）的含量来测定的。我们的结果与假设一致，即肺对卵清蛋白挑战的反应包括大气道中的适应性反应，通过将精氨酸分流到代谢途径中以增加NO的合成，调节气道上皮和上皮下细胞内精氨酸的浓度。(C) 2008爱思唯尔公司版权所有。
Arginase gene expression in the lung has been linked to asthma both in clinical studies of human patients and in the well-studied mouse model of ovalbumin-induced airway inflammation. Arginase is thought to regulate NO levels in the lung by its ability to divert arginine, the substrate for nitric oxide synthases that produce citrulline and NO, into an alternative metabolic pathway producing ornithine and urea. In the present study arginase I and arginase 11 concentrations were measured in isolated microdissected airway preparations from sensitized Balb/c mice exposed to ovalbumin aerosol. We found that arginase 11 was constitutively expressed in the airways of normal mice, whereas arginase I was undetectable in normal airways, while its expression was increased in airways of mice exposed to ovalbumin. The expression of arginase I strongly Correlated with the presence of lung inflammation, as quantified by differential cell counts in lung lavage, suggesting that most, or all, of the arginase I in lungs of mice exposed to ovalbumin is present in the inflammatory cells rather than in the airway epithelium. There was also a significant correlation between increased expression of arginase I in the isolated airways and decreased lung compliance. On the other hand, while we found arginase 11 expression to also be significantly increased in airways from mice exposed to ovalbumin as compared with normal airways, the relative increase was much less than that observed for arginase 1, suggesting that there was a smaller contribution of inflammatory cells to the arginase 11 content of the airways in mice exposed to ovalbumin. There was no apparent correlation between the content of arginase in isolated airways and exhaled NO concentration in the expired air from mice exposed to ovalbumin. However, there was a correlation between exhaled NO concentration from mice exposed to ovalbumin and the lymphocyte content of the lung lavage.The concentration of arginine found in isolated airways from Balb/c mice exposed for 2 weeks to ovalbumin was about half of the value found in isolated microdissected airways from normal mice. Treatment of mice systemically with an arginase inhibitor significantly increased the amount of NO produced, as measured as the amount of nitrite+nitrate (NOx) in lung lavage supernatant prepared from mice exposed to ovalbumin. Our results are consistent with the hypothesis that the response of the lung to ovalbumin challenge includes an adaptive response in the large airways regulating the concentration of arginine within cells of the airway epithelium and subepithelial layer, by shunting of arginine into the metabolic pathway for increased synthesis of NO. (C) 2008 Elsevier Inc. All rights reserved.