Role of acid sphingomyelinase in bronchial asthma

酸性鞘磷脂酶（ASM）是催化鞘脂代谢重要反应的酶之一。它的缺乏导致神经退行性尼曼-匹克病，这是一种溶酶体积累性疾病，患者表现出神经功能障碍以及肺部感染或间歇性阻塞性呼吸困难。既往研究证实了ASM对急性肺损伤肺水肿形成的影响。此外，临床试验揭示了asm抑制剂作为囊性纤维化患者治疗靶点的潜在作用。由于ASM在支气管哮喘中的作用完全未知，我们在本研究中讨论了这一主题。我们实验室的初步研究表明，在过敏原诱导的哮喘小鼠模型中，asm缺乏具有明显下调th2细胞因子的保护作用。在此建议的背景下，我们想在急性和慢性支气管哮喘模型中详细研究asm缺陷小鼠。因此，它必须被定义，如果asm依赖的调节免疫细胞是显著参与哮喘表型的发展。此外，ASM的免疫学相关性应该在骨髓嵌合体中得到证实。在进一步的实验中，我们明确地想要确定免疫细胞类型，其中asm依赖影响哮喘疾病的活动。ASM-KO和野生型动物的T淋巴细胞和抗原提呈细胞的体外分化应该有助于鉴定asm依赖的细胞表型和这些细胞的细胞因子产生。为了明确T细胞是全球asm调节的参与者，我们将ASM-KO动物的CD4+ T淋巴细胞转移到RAG1-KO小鼠中。如果T细胞似乎只是一种二级调节细胞类型，我们将重点关注抗原提呈细胞的asm调节。我们计划构建rag1 - asm双敲除小鼠，这有助于我们研究不依赖淋巴细胞的哮喘炎症。本研究的第三个目的是在吸入阿米替林或氟西汀等asm抑制剂的基础上，开发支气管哮喘的新治疗策略。我们将区分两个概念：预防治疗，在致敏之前开始asm抑制，以及治疗概念，在过敏原激发之后开始asm抑制。如果其中一种策略有效，我们就可以证明一种新的、潜在的支气管哮喘治疗方法。综上所述，本研究应明确界定ASM在哮喘中的免疫学作用，并为吸入ASM抑制剂的新治疗策略提供第一个证据。

The acid sphingomyelinase (ASM) is one of the enzymes that catalyzes important reactions of the sphingolipid metabolism. Its deficiency causes the neurodegenerative Niemann-Pick disease, a lysosomal accumulation disease, in which patients exhibit neurological deficits as well as pulmonary infections or intermittent episodes of obstructive dyspnea. Previous studies demonstrated the influence of ASM on pulmonary edema formation in acute lung injury. Additionally, clinical trials revealed the potential effect of ASM-inhibitors as therapeutic target in patients with cystic fibrosis. As the role of ASM in bronchial asthma is completely unknown we addressed the topic in this study.Preliminary studies in our lab demonstrated a protective role of ASM-deficiency in a murine model of allergen-induced asthma with a clear downregulation of TH2-cytokines. In the context of this proposal we would like to study ASM-deficient mice in detail in a model of acute and chronic bronchial asthma. Thereby, it has to be defined, if the ASM-dependent regulation of immunological cells is significantly involved in the development of an asthmatic phenotype. In addition, this immunological relevance of ASM should be demonstrated with bone marrow chimeras.During the further experiments, we clearly want to define the immunological cell types, which ASM-dependent influence asthmatic disease activity. In vitro differentiations of T lymphocytes and antigen-presenting cells of ASM-KO and wildtype animals should help to identify the ASM-dependent cellular phenotype and the cytokine production of these cells. To clearly identify T cells as global ASM-regulated player, CD4+ T lymphocytes of ASM-KO animals will be transferred into RAG1-KO mice. If T cells appear to be only a secondary regulated cell type, we will focus on the ASM-regulation of antigen-presenting cells. We plan to generate a RAG1-ASM-double-knockout-mouse, which helps us to study the asthmatic inflammation independent of lymphocytes.The third aim of this study is to develop new therapeutic strategies in bronchial asthma based upon an inhalation of ASM-inhibitors like amitriptyline or fluoxetine. We would distinguish between two concepts: The preventive therapy, beginning with an ASM-inhibition starting previous to sensitization, and the therapeutic concept, with an ASM-inhibition next to allergen-provocation. If one of these strategies will be effective, we could demonstrate a new, potentially treatment of bronchial asthma.Summing up, this study should clearly define the immunological role of ASM in asthma and should provide first evidence for new therapeutic strategies with inhalations of ASM-inhibitors.