Department of Anatomy & Embryology and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200MD, Maastricht, The Netherlands.
Department of Medicine, College of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont, VT, Burlington, USA.
Respir Res. 2018 May 23;19(1):98. doi: 10.1186/s12931-018-0809-9.
Asthma is a chronic respiratory condition, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. The hypothesis that the substantially increased expression of arginase 1 in activated macrophages limits the availability of L-arginine for nitric oxide synthesis, and thus increases AHR in lungs of mice with experimentally induced allergic asthma was recently refuted by several studies. In the present study, we tested the hypothesis that, instead, a low circulating concentration of arginine aggravates AHR in the same murine asthma model. Female FVB F/A2 transgenic mice, which overexpress rat arginase 1 in their enterocytes, exhibit a ~ 50% decrease of their plasma L-arginine concentration.
Adult female F/A2 mice and their wild-type littermates (F/A2 ) were sensitized and challenged with ovalbumin (OVA/OVA). Lung function was assessed with the flexiVent™ system. Adaptive changes in the expression of arginine-metabolizing or -transporting enzymes, chemokines and cytokines, and lung histology were quantified with qPCR, ELISA, and immunohistochemistry, respectively.
Reduction of circulating L-arginine concentration significantly increased AHR in OVA/OVA-treated mice and, to a lesser extent, even in PBS/OVA-treated mice. The pulmonary inflammatory response in OVA/OVA-treated F/A2 and F/A2 mice was comparable. OVA/OVA-treated F/A2 mice differed from similarly treated female mice, in which arginase 1 expression in lung macrophages was eliminated, by a complete absence of an adaptive increase in the expression of arginine-metabolizing or -transporting enzymes.
A reduction of the circulating L-arginine concentration rather than the macrophage-mediated increase of arginine catabolism worsens AHR.
哮喘是一种慢性呼吸道疾病，其特征为气道高反应性（AHR）和炎症。最近的几项研究反驳了这样一种假设，即活化的巨噬细胞中精氨酸酶 1 的表达显著增加，限制了 L-精氨酸用于一氧化氮合成的可用性，从而增加了实验性诱导的变应性哮喘小鼠肺部的 AHR。在本研究中，我们检验了这样一种假设，即相反，循环中低浓度的精氨酸会加重同一小鼠哮喘模型中的 AHR。在其肠细胞中过度表达大鼠精氨酸酶 1 的 FVB F/A2 转基因雌性小鼠，其血浆 L-精氨酸浓度降低约 50%。
成年雌性 F/A2 小鼠及其野生型同窝仔（F/A2）用卵清蛋白（OVA/OVA）致敏和激发。使用 flexiVentTM 系统评估肺功能。通过 qPCR、ELISA 和免疫组织化学分别定量检测精氨酸代谢或转运酶、趋化因子和细胞因子的适应性表达以及肺组织学变化。
循环 L-精氨酸浓度的降低显著增加了 OVA/OVA 处理的小鼠的 AHR，在较小程度上甚至增加了 PBS/OVA 处理的小鼠的 AHR。OVA/OVA 处理的 F/A2 和 F/A2 小鼠的肺部炎症反应相似。与同样用 OVA 处理的、肺巨噬细胞中精氨酸酶 1 表达被消除的雌性小鼠不同，OVA/OVA 处理的 F/A2 小鼠完全没有适应性增加精氨酸代谢或转运酶的表达。
循环 L-精氨酸浓度的降低而非巨噬细胞介导的精氨酸分解代谢增加会加重 AHR。
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