Böll Svenja, Ziemann Sebastian, Ohl Kim, Klemm Patricia, Rieg Annette D, Gulbins Erich, Becker Katrin Anne, Kamler Markus, Wagner Norbert, Uhlig Stefan, Martin Christian, Tenbrock Klaus, Verjans Eva
Department of Pediatrics, Medical Faculty, RWTH Aachen University, University Hospital Aachen, Aachen, Germany.
Institute of Pharmacology and Toxicology, RWTH Aachen University, University Hospital Aachen, Aachen, Germany.
Allergy. 2020 Mar;75(3):603-615. doi: 10.1111/all.14039. Epub 2019 Oct 8.
Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of T 1-directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in T 2-regulated allergic bronchial asthma.
To determine the role of Asm under baseline conditions, wild-type (WT) and Asm mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro T 2 differentiations with cells from WT and Asm mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin-induced model of asthma in WT- and Asm mice.
At baseline, Asm mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm T cells in bronchoalveolar lavage fluid released lower levels of IL-4 and IL-5, and these results were paralleled by decreased production of typical T 2 cytokines in Asm T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and T 2 cytokines.
Asm deficiency could induce higher numbers of T 2 cells in the lung, but those cells release decreased T 2 cytokine levels. Hereby, Asm animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade.
过敏性疾病尤其是过敏性哮喘是在儿童期以及成人中普遍高发的疾病。酸性鞘磷脂酶（ASM）是鞘脂途径的关键调节因子。先前的研究确定了ASM与如囊性纤维化和急性肺损伤等T1主导型肺部疾病发病机制的关联。在此，我们确定ASM在T2调节的过敏性支气管哮喘中的作用。
为了确定基础条件下Asm的作用，使用flexiVent装置对野生型（WT）和Asm基因敲除小鼠进行通气，并使用乙酰胆碱测定支气管高反应性。对支气管肺泡灌洗液和肺组织进行流式细胞术和细胞因子测量，随后用来自WT和Asm基因敲除小鼠的细胞进行体外T2分化，并用阿米替林阻断Asm。作为原理验证，我们在WT和Asm基因敲除小鼠中进行了卵清蛋白诱导的哮喘模型。
在基础状态下，Asm基因敲除小鼠表现出更好的肺力学，但支气管高反应性未改变。支气管肺泡灌洗液中数量更多的Asm基因敲除T细胞释放出较低水平的IL-4和IL-5，并且这些结果与体外Asm基因敲除T淋巴细胞中典型T2细胞因子产生的减少相平行。用阿米替林孵育T细胞可模拟该表型。在卵清蛋白哮喘模型中，Asm基因敲除动物免受高疾病活性影响，表现出更好的肺功能以及更低水平的嗜酸性粒细胞和T2细胞因子。
Asm基因缺失可在肺中诱导产生更多数量的T2细胞，但这些细胞释放的T2细胞因子水平降低。由此，Asm基因敲除动物对支气管哮喘具有抗性，这可能提供新的治疗策略，例如使用ASM阻断剂。
