半胱氨酰马尿酸调节半胱氨酰白三烯的前炎症性肺作用。
Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes.
机构信息
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
出版信息
J Allergy Clin Immunol. 2020 Jan;145(1):335-344. doi: 10.1016/j.jaci.2019.09.028. Epub 2019 Oct 14.
BACKGROUND
Cysteinyl leukotrienes (CysLTs) are potent prophlogistic mediators in asthmatic patients; however, inhibition of CysLT receptor 1 is not a consistently effective treatment, suggesting additional regulatory mechanisms. Other cysteinyl-containing lipid mediators (LMs) derived from docosahexaenoic acid, namely maresin conjugates in tissue regeneration (MCTRs), were recently discovered. Therefore their production and actions in the lung are of considerable interest.
OBJECTIVE
We sought to determine MCTR production, bioactions, and mechanisms in the human lung and in patients with experimental allergic airway inflammation.
METHODS
LM metabololipidomic profiling of the lung was performed by using liquid chromatography with tandem mass spectrometry. Donor-derived human precision-cut lung slices were exposed to leukotriene (LT) D, MCTRs, or both before determination of airway contraction. The actions of exogenous MCTRs on murine allergic host responses were determined in the setting of ovalbumin- and house dust mite-induced lung inflammation.
RESULTS
Lipidomic profiling showed that the most abundant cysteinyl LMs in healthy human lungs were MCTRs, whereas CysLTs were most prevalent in patients with disease. MCTRs blocked LTD-initiated airway contraction in human precision-cut lung slices. In mouse allergic lung inflammation MCTRs were present with temporally regulated production. With ovalbumin-induced inflammation, MCTR1 was most potent for promoting resolution of eosinophils, and MCTR3 potently decreased airway hyperreactivity to methacholine, bronchoalveolar lavage fluid albumin, and serum IgE levels. MCTR1 and MCTR3 inhibited lung eosinophilia after house dust mite-induced inflammation.
CONCLUSION
These results identified lung MCTRs that blocked human LTD-induced airway contraction and promoted resolution of murine allergic airway responses when added exogenously. Together, these findings uncover proresolving mechanisms for lung responses that can be disrupted in patients with disease.
背景
半胱氨酰白三烯（CysLTs）是哮喘患者中强有力的前炎症介质；然而，CysLT 受体 1 的抑制作用并不是一种始终有效的治疗方法，这表明存在其他调节机制。其他来源于二十二碳六烯酸的含半胱氨酸的脂质介质（LMs），即组织再生中的maresin 缀合物（MCTRs），最近被发现。因此，它们在肺部的产生和作用引起了相当大的兴趣。
目的
我们旨在确定 MCTR 在人肺和实验性变应性气道炎症患者中的产生、生物活性和机制。
方法
采用液相色谱-串联质谱法对肺 LM 代谢脂质组学进行分析。在测定气道收缩之前，将供体衍生的人精确切割肺切片暴露于白三烯（LT）D、MCTRs 或两者。在卵白蛋白和屋尘螨诱导的肺炎症中，确定外源性 MCTR 对小鼠变应性宿主反应的作用。
结果
脂质组学分析显示，健康人肺中最丰富的半胱氨酸 LMs 是 MCTRs，而在疾病患者中最常见的是 CysLTs。MCTRs 阻断 LTD 引发的人精确切割肺切片中的气道收缩。在小鼠变应性肺炎症中，MCTRs 存在且具有时间调节的产生。在卵白蛋白诱导的炎症中，MCTR1 对促进嗜酸性粒细胞消退最有效，MCTR3 则强烈降低气道对乙酰甲胆碱、支气管肺泡灌洗液白蛋白和血清 IgE 水平的高反应性。MCTR1 和 MCTR3 抑制屋尘螨诱导的炎症后肺嗜酸性粒细胞浸润。
结论
这些结果确定了肺 MCTRs，它们可以阻断人 LTD 引发的气道收缩，并在外源性添加时促进小鼠变应性气道反应的消退。这些发现共同揭示了肺反应的促解决机制，这些机制在疾病患者中可能会被破坏。
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