Sphingosine 1-phosphate (S1P) mediated adaptations to hypoxemic conditions in red blood cells (RBC) in acute and chronic respiratory diseases

1-磷酸鞘氨醇 (S1P) 介导急性和慢性呼吸道疾病中红细胞 (RBC) 对低氧血症的适应

• 批准号: 504972615
• 负责人: Professor Dr. Markus Gräler, Ph.D.
• 金额: --
• 依托单位: Klinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504972615?language=en
• 关键词: Sphingosine; phosphate; S1P; mediated; adaptations

Respiratory diseases contribute to more than 12% of documented deaths in Germany. The coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is also responsible for some very heavy pulmonary damage. The COVID-19 pandemic has made clear how vulnerable the health system is when faced with a large number of patients requiring intensive care who depend on artificial ventilation at the same time. Possibilities to avoid the need for artificial ventilation are therefore desirable not only for the patients concerned, but also for the health system as a whole. The lipid signaling molecule sphingosine 1-phosphate (S1P) is formed and stored in red blood cells (RBC) and is involved in the adaptation to hypoxic conditions. We were able to show that S1P also accumulated in RBC of severe COVID-19 patients, and that it may be involved in a metabolic shift towards enhanced glycolysis and 2,3-bisphosphoglycerate synthesis. This leads to the hypothesis that intracellular S1P in RBC could contribute to an adaptive response to hypoxic conditions in respiratory diseases, which has not yet been investigated. To test this hypothesis, in a first step, the biochemical mechanisms of S1P-modulated oxygen supply by RBC will be examined in order to then search for medically usable possibilities of preconditioning of RBC to promote oxygen release. In this context, the influence of blood antigens on the adaptation capabilities of RBC will also be investigated, as several studies have shown a preference of patients with blood group A to a serious course of COVID-19 disease. Finally, biochemical findings will also be verified in COVID-19 patients and patients with acute and chronic respiratory diseases. The findings of this project could ideally lead to new preventive and therapeutic possibilities for the treatment of serious respiratory diseases.

呼吸系统疾病占德国有记录死亡人数的12%以上。由严重急性呼吸道综合征冠状病毒-2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）也是造成一些非常严重的肺损伤的原因。COVID-19大流行清楚地表明，当面对大量需要重症监护的患者同时依赖人工通气时，卫生系统是多么脆弱。因此，避免人工通气的可能性不仅对于相关患者是期望的，而且对于整个卫生系统也是期望的。脂质信号分子鞘氨醇1-磷酸（S1 P）形成并储存在红细胞（RBC）中，并参与对缺氧条件的适应。我们能够证明，S1 P也在严重COVID-19患者的RBC中积累，并且它可能参与了向增强糖酵解和2，3-二磷酸甘油酸合成的代谢转变。这导致了这样的假设，即RBC中的细胞内S1 P可能有助于呼吸系统疾病对缺氧条件的适应性反应，这尚未被研究。为了检验这一假设，在第一步中，将检查由RBC进行的S1 P调节的氧供应的生化机制，以便然后搜索RBC预处理以促进氧释放的医学上可用的可能性。在这种情况下，还将研究血液抗原对RBC适应能力的影响，因为几项研究表明，A型血患者对严重的COVID-19疾病的偏好。最后，还将在COVID-19患者和患有急性和慢性呼吸道疾病的患者中验证生化结果。该项目的研究结果可能会为治疗严重呼吸道疾病带来新的预防和治疗可能性。