Measuring in vivo responses to endogenous and exogenous oxidative stress using a novel haem oxygenase 1 reporter mouse.
Measuring in vivo responses to endogenous and exogenous oxidative stress using a novel haem oxygenase 1 reporter mouse.
复制标题
DOI：
10.1113/jp274915
复制
发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Wolf CR
中科院分区：
文献类型：
--
作者：
McMahon M;Ding S;Acosta-Jimenez LP;Frangova TG;Henderson CJ;Wolf CR
血红素加氧酶1（Hmox 1）是一种细胞保护酶，具有抗炎和抗氧化特性，可响应多种有害环境刺激和疾病状态而诱导。直到现在，还没有能够在体内监测其表达的工具。在一个新的Hmox 1报告基因模型中，我们提供了Hmox 1在整个小鼠体内表达的高保真单细胞分辨率蓝图。我们首次表明，Hmox 1是组成性表达的屏障组织之间的内部和外部环境的界面，它是高度诱导全身炎症过程中的肌肉细胞。这些数据表明新的生物学见解Hmox 1的作用，并铺平了道路，使用该模型来研究环境压力在疾病病理学中的作用。Hmox 1蛋白作为体内应激反应的生物标志物具有很大的希望，因为它在应激或受损细胞中高度诱导。然而，Hmox 1的表达模式迄今为止仅在与人类相关性有限的简单模式生物中可用。我们现在报告了一种新的Hmox 1报告细胞系，它可以在小鼠中获得这些信息，这是研究人类疾病和毒理学的首选模型系统。使用最先进的策略，我们表达了来自小鼠Hmox 1基因座的多个互补报告分子，包括萤火虫荧光素酶，以允许Hmox 1表达的长期非侵入性成像，以及β-半乳糖苷酶用于死后表达模式的高分辨率映射。我们通过确认报告基因表达的保真度及其对氧化和炎症刺激的反应性来验证该模型。除了提供Hmox 1在小鼠中表达的蓝图，提供新的生物学见解外，这项工作还为该模型的广泛应用铺平了道路，以建立由内源性过程诱导的细胞应激以及暴露于药物和环境因子引起的细胞应激。它还将使研究氧化应激在疾病发病机制及其预防中的作用成为可能。血红素加氧酶1（Hmox 1）是一种细胞保护酶，具有抗炎和抗氧化特性，可响应多种有害环境刺激和疾病状态而诱导。直到现在，还没有能够在体内监测其表达的工具。在一个新的Hmox 1报告基因模型中，我们提供了Hmox 1在整个小鼠体内表达的高保真单细胞分辨率蓝图。我们首次表明，Hmox 1是组成性表达的屏障组织之间的内部和外部环境的界面，它是高度诱导全身炎症过程中的肌肉细胞。这些数据表明新的生物学见解Hmox 1的作用，并铺平了道路，使用该模型来研究环境压力在疾病病理学中的作用。
Haem oxygenase 1 (Hmox1) is a cytoprotective enzyme with anti‐inflammatory and anti‐oxidant properties that is induced in response to multiple noxious environmental stimuli and disease states. Tools to enable its expression to be monitored in vivo have been unavailable until now. In a new Hmox1 reporter model we provide high‐fidelity, single‐cell resolution blueprints for Hmox1 expression throughout the body of mice. We show for the first time that Hmox1 is constitutively expressed at barrier tissues at the interface between the internal and external environments, and that it is highly induced in muscle cells during systemic inflammation. These data suggest novel biological insights into the role of Hmox1 and pave the way for the use of the model to study the role of environmental stress in disease pathology. Hmox1 protein holds great promise as a biomarker of in vivo stress responses as it is highly induced in stressed or damaged cells. However, Hmox1 expression patterns have thus far only been available in simple model organisms with limited relevance to humans. We now report a new Hmox1 reporter line that makes it possible to obtain this information in mice, a premiere model system for studying human disease and toxicology. Using a state‐of‐the‐art strategy, we expressed multiple complementary reporter molecules from the murine Hmox1 locus, including firefly luciferase, to allow long‐term, non‐invasive imaging of Hmox1 expression, and β‐galactosidase for high‐resolution mapping of expression patterns post‐mortem. We validated the model by confirming the fidelity of reporter expression, and its responsiveness to oxidative and inflammatory stimuli. In addition to providing blueprints for Hmox1 expression in mice that provide novel biological insights, this work paves the way for the broad application of this model to establish cellular stresses induced by endogenous processes and those resulting from exposure to drugs and environmental agents. It will also enable studies on the role of oxidative stress in the pathogenesis of disease and its prevention. Haem oxygenase 1 (Hmox1) is a cytoprotective enzyme with anti‐inflammatory and anti‐oxidant properties that is induced in response to multiple noxious environmental stimuli and disease states. Tools to enable its expression to be monitored in vivo have been unavailable until now. In a new Hmox1 reporter model we provide high‐fidelity, single‐cell resolution blueprints for Hmox1 expression throughout the body of mice. We show for the first time that Hmox1 is constitutively expressed at barrier tissues at the interface between the internal and external environments, and that it is highly induced in muscle cells during systemic inflammation. These data suggest novel biological insights into the role of Hmox1 and pave the way for the use of the model to study the role of environmental stress in disease pathology.