Heparanase and macrophage migration inhibitory factor as diagnostic/therapeutic targets in trauma and haemorrhagic shock-associated multiple organ failure

乙酰肝素酶和巨噬细胞迁移抑制因子作为创伤和失血性休克相关多器官衰竭的诊断/治疗靶点

• 批准号: 495734019
• 负责人: Privatdozent Dr. Lukas Martin
• 金额: --
• 依托单位: Klinik für Operative Intensivmedizin und Intermediate Care
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/495734019?language=en
• 关键词: Heparanase; macrophage; migration; inhibitory; factor

Injuries with multiple traumata are one of the leading causes of death worldwide, resulting in 4.8-5 million deaths per year. One of the most common consequences in multiple traumata is the multi organ failure (MOF), which is responsible for 51-61% of all deaths in trauma and is associated with longer stays in the intensive care units (ICU) and raised costs for healthcare systems, as there is no specific, preventive treatment. MOF can be a result of a trauma-induced inflammation and/or organ ischemia. The systemic inflammation after trauma is triggered by a multitude of factors including poor oxygen supply due to haemorrhagic shock and the release of damage-associated molecular patterns (DAMPs) caused by tissue injury. Heparanase specifically releases heparan sulfate (HS) fragments after sterile or infectious insults which leads to endothelial glycocalyx degradation and elevated vascular permeability. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is associated with local or systemic inflammation and increased plasma MIF levels correlate with poor outcome in patients with sepsis, systemic inflammatory response syndrome and other critical illnesses.In our own preliminary work, we identified 2 key families that are involved in the pathogenesis of critical illness: MIF and heparanase. We could show that polytrauma patients exhibited significantly enhanced MIF levels on arrival to the emergency room (ER). Similar findings could be detected in a murine model of severe haemorrhage followed by resuscitation. Treatment with the MIF-inhibitor ISO-1 significantly reduced MIF levels and attenuated organ damage and the fall in blood pressure. In additions, we could show, that heparanase activity and HS serum levels were significantly elevated in patients with septic shock compared to healthy volunteers. The question that arises now is how the MIF- and heparanase system interact in trauma patients. Our goal is to improve our understanding of the kinetics and clinical relevance of these families in polytrauma and elucidate potential signalling pathways responsible for the protective effects of MIF inhibition. Our preliminary data suggest a therapeutic potential of inhibiting MIF, which shall be confirmed by this project to provide an adequate therapeutic strategy to prevent and/or reverse organ damage/failure and improve outcome after polytrauma. Therefore, we propose the following hypothesis:H1: Elevated serum levels of members of the Heparanase-System and MIF-System are associated with a complicated clinical course and increased mortality in patients with polytrauma. H2: Heparanase, MIF, MIF-2 and sCD74 contribute to organ injury and dysfunction caused by polytrauma by mediating CD74/AMPK pathway, the JNK- and PI3K-Akt pathways and ERK-1/2 pathway. H3: Pharmacological inhibition of MIF by ISO-1 attenuates the post-traumatic immunosuppression, organ damage/failure and improves outcome after experimental polytrauma.

多处创伤是全世界主要的死亡原因之一，每年造成480万至500万人死亡。多发性创伤最常见的后果之一是多器官衰竭(MOF)，占创伤死亡人数的51%-61%，并与更长时间在重症监护病房(ICU)的停留有关，并增加了医疗保健系统的成本，因为没有专门的预防性治疗。MOF可能是创伤引起的炎症和/或器官缺血的结果。创伤后的全身炎症是由多种因素引起的，包括失血性休克引起的氧气供应不足和组织损伤引起的损伤相关分子模式(DAMP)的释放。乙酰肝素酶在无菌或感染性损伤后特异性地释放硫酸乙酰肝素(HS)片段，导致内皮细胞糖基化降解和血管通透性增加。促炎症细胞因子MIF(巨噬细胞移动抑制因子)与局部或全身炎症有关，血浆MIF水平升高与脓毒症、全身炎症反应综合征和其他危重病患者预后不良相关。在我们自己的前期工作中，我们确定了两个参与危重病发病机制的关键家族：MIF和肝素酶。我们可以显示，多发伤患者在到达急诊室(ER)时MIF水平显著升高。在严重出血后复苏的小鼠模型中也可以检测到类似的发现。MIF抑制剂ISO-1的治疗显著降低了MIF水平，减轻了器官损伤和血压下降。此外，我们可以发现，与健康志愿者相比，感染性休克患者的肝素酶活性和HS血清水平显著升高。现在出现的问题是，在创伤患者中，MIF-和肝素酶系统是如何相互作用的。我们的目标是提高我们对这些家庭在多发性创伤中的动力学和临床相关性的理解，并阐明负责MIF抑制的保护作用的潜在信号通路。我们的初步数据显示了抑制MIF的治疗潜力，该项目将证实这一点，以提供足够的治疗策略来预防和/或逆转器官损伤/衰竭，并改善多发伤后的预后。因此，我们提出以下假设：H1：肝素酶系统和MIF系统成员的血清水平升高与复杂的临床病程和多发伤患者的死亡率增加有关。H2：肝素酶、MIF、MIF-2和sCD74通过介导CD74/AMPK通路、JNK-和PI3K-Akt通路以及ERK-1/2通路参与多发伤后的器官损伤和功能障碍。H3：ISO-1对MIF的药理抑制可减轻创伤后免疫抑制、器官损伤/衰竭，并改善实验性多发伤后的预后。