Hypoargininemia exacerbates airway hyperresponsiveness in a mouse model of asthma

Respiratory Research

Roy H. E. Cloots¹  S. Eleonore Köhler¹  Els Terwindt¹  Wouter H. Lamers¹  Matthew E. Poynter² 

[1] Department of Anatomy & Embryology and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University;Department of Medicine, College of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont;

关键词: Arginine availability;    Lung function;    Transgenes;    Pulmonary inflammation;   

DOI  :  10.1186/s12931-018-0809-9

来源: DOAJ

【 摘 要 】

Abstract Background 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 tg/tg transgenic mice, which overexpress rat arginase 1 in their enterocytes, exhibit a ~ 50% decrease of their plasma L-arginine concentration. Methods Adult female F/A2 tg/tg mice and their wild-type littermates (F/A2 wt/wt ) 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. Results 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 tg/tg and F/A2 wt/wt mice was comparable. OVA/OVA-treated F/A2 tg/tg 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. Conclusion A reduction of the circulating L-arginine concentration rather than the macrophage-mediated increase of arginine catabolism worsens AHR.

【 授权许可】

Unknown