Department of Anatomy & Embryology and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, The Netherlands.
Division of Pulmonary Disease and Critical Care, Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA.
BMC Pulm Med. 2017 Nov 28;17(1):158. doi: 10.1186/s12890-017-0490-7.
(Over-)expression of arginase may limit local availability of arginine for nitric oxide synthesis. We investigated the significance of arginase1 (ARG1) for the development of airway hyperresponsiveness (AHR) and lung inflammation in female mice with ovalbumin (OVA)-induced allergic asthma.
Arg1 was ablated in the lung by crossing Arg1 and Tie2Cre mice. OVA sensitization and challenge were conducted, and AHR to methacholine was determined using the Flexivent system. Changes in gene expression, chemokine and cytokine secretion, plasma IgE, and lung histology were quantified using RT-qPCR, ELISA, and immunohistochemistry, respectively.
Arg1 ablation had no influence on the development of OVA-induced AHR, but attenuated OVA-induced increases in expression of Arg2 and Nos2, Slc7a1, Slc7a2, and Slc7a7 (arginine transporters), Il4, Il5 and Il13 (T2-type cytokines), Ccl2 and Ccl11 (chemokines), Ifng (T1-type cytokine), Clca3 and Muc5ac (goblet cell markers), and OVA-specific IgE. Pulmonary IL-10 protein content increased, but IL-4, IL-5, IL-13, TNFα and IFNγ content, and lung histopathology, were not affected. Arg1 elimination also decreased number and tightness of correlations between adaptive changes in lung function and inflammatory parameters in OVA/OVA-treated female mice. OVA/OVA-treated female mice mounted a higher OVA-IgE response than males, but the correlation between lung function and inflammation was lower. Arg1-deficient OVA/OVA-treated females differed from males in a more pronounced decline of arginine-metabolizing and -transporting genes, higher plasma arginine levels, a smaller OVA-specific IgE response, and no improvement of peripheral lung function.
Complete ablation of Arg1 in the lung affects mRNA abundance of arginine-transporting and -metabolizing genes, and pro-inflammatory genes, but not methacholine responsiveness or accumulation of inflammatory cells.
精氨酸酶的过度表达可能会限制局部一氧化氮合成所需的精氨酸。我们研究了肺中精氨酸酶 1（ARG1）在卵清蛋白（OVA）诱导的变应性哮喘雌性小鼠气道高反应性（AHR）和肺炎症发展中的意义。
通过交叉 Arg1 和 Tie2Cre 小鼠来使肺中的 Arg1 缺失。进行 OVA 致敏和激发，使用 Flexivent 系统测定乙酰甲胆碱引起的 AHR。使用 RT-qPCR、ELISA 和免疫组织化学分别定量基因表达、趋化因子和细胞因子分泌、血浆 IgE 和肺组织学变化。
Arg1 缺失对 OVA 诱导的 AHR 的发展没有影响，但减弱了 OVA 诱导的 Arg2 和 Nos2、Slc7a1、Slc7a2 和 Slc7a7（精氨酸转运蛋白）、Il4、Il5 和 Il13（T2 型细胞因子）、Ccl2 和 Ccl11（趋化因子）、Ifng（T1 型细胞因子）、Clca3 和 Muc5ac（杯状细胞标志物）和 OVA 特异性 IgE 的表达增加。肺中 IL-10 蛋白含量增加，但 IL-4、IL-5、IL-13、TNFα 和 IFNγ 含量以及肺组织病理学没有受到影响。Arg1 消除还降低了 OVA/OVA 处理的雌性小鼠中肺功能与炎症参数适应性变化之间的相关性的数量和紧密性。OVA/OVA 处理的雌性小鼠比雄性小鼠产生更高的 OVA-IgE 反应，但肺功能与炎症之间的相关性较低。Arg1 缺失的 OVA/OVA 处理的雌性小鼠与雄性小鼠的差异在于，精氨酸代谢和转运基因的下降更为明显，血浆精氨酸水平更高，OVA 特异性 IgE 反应更小，外周肺功能没有改善。
肺中 Arg1 的完全缺失会影响精氨酸转运和代谢基因以及促炎基因的 mRNA 丰度，但不影响乙酰甲胆碱反应性或炎症细胞的积累。
