Dual role of plasma secreted sphingomyelinase activity during sepsis and development of organ failure

血浆分泌的鞘磷脂酶SMPD 1亚型的水解活性在全身炎症反应如脓毒症和多器官衰竭患者中增强。在第一个资助期，我们扩展了我们的知识，无论是增加功能上的细胞应激反应：作为一个例子，我们发现，从脓毒症患者获得的酶特异性诱导内皮细胞中的宏域形成，内皮细胞凋亡的诱导可能被废除的低分子抑制剂。除了这些机制的方法，增加了各种微生物的菌落形成单位的数量，压倒性的细胞因子反应和更明显的多微生物腹膜炎后的SMPD 1缺陷小鼠血小板减少。感染后早期死亡率增加，但后期死亡率延迟，以及我们在不同模型中的转录组方法的结果提示，我们打算进一步表征SMPD 1介导的宏结构域形成对趋化性和白细胞/内皮相互作用的作用。为了这些目标，我们计划开发一种新的体内活性相关荧光增强方法，结合生物成像设置，监测细菌传播。我们的目的是阐明SMPD 1在器官功能障碍的感染性和非感染性模型中的作用，并确定其抑制对器官衰竭发展的有益作用的时间。我们期待SMPD 1的分泌亚型在炎症中的功能作用的新结果，避免其抑制的不良影响。

The hydrolytic activity of the plasma secreted isoform of sphingomyelinase SMPD1 is enhanced in patients with systemic inflammatory response such as sepsis and multiple organ failure. In the first funding periode, we extended our knowledge, whether the increase is functionally significant for cellular stress response: As an example, we found that the enzyme obtained from patients with sepsis specifically induced macro-domain formation in endothelial cells and that the induction of endothelial apoptosis might be abrogated by low molecular inhibitors. In addition to these mechanistic approaches, an increased number of colony forming units of a variety of micro-organisms, an overwhelming cytokin response and more pronounced thrombocyto-penia in SMPD1-deficient mice subsequent to polymicrobial peritonitis were observed. Increased mortality in the early phase after infection, but a delayed in the later one, as well as prompted by results from our transcriptomal approach in different models, we intend to further characterize the role of SMPD1-mediated macrodomain formation for chemotaxis and leukocyte/ endothelium interaction. For these aims, we plan to develop a novel in-vivo activity-linked fluorescence enhancement approach in combination with a bio-imaging setting, monitoring bacterial dissemination. We aim to elucidate the role of SMPD1 in infectious and non-infectious models of organ dysfunction and to define the time for beneficial effects of its inhibition with repsect to the development of organ failure. We expect novel results for the functional role of the secreted isoform of SMPD1 in inflammation avoiding adverse effects of its inhibition.