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

多处创伤性伤害是世界范围内死亡的主要原因之一，每年造成480万至500万人死亡。多发创伤最常见的后果之一是多器官衰竭（MOF），占创伤死亡总数的51-61%，由于没有具体的预防性治疗，多器官衰竭与重症监护病房（ICU）的住院时间延长和医疗保健系统成本增加有关。MOF可能是创伤性炎症和/或器官缺血的结果。创伤后的全身性炎症是由多种因素引发的，包括出血性休克引起的缺氧和组织损伤引起的损伤相关分子模式（DAMPs）的释放。肝素酶在无菌或感染性损伤后特异性释放硫酸肝素（HS）片段，导致内皮糖萼降解和血管通透性升高。促炎细胞因子MIF（巨噬细胞迁移抑制因子）与局部或全身性炎症有关，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疾病患者预后不良相关。在我们自己的初步工作中，我们确定了参与危重疾病发病机制的两个关键家族：MIF和肝素酶。我们可以证明，多发创伤患者在到达急诊室（ER）时MIF水平显著提高。在复苏后的严重出血小鼠模型中也可以发现类似的结果。使用MIF抑制剂ISO-1治疗可显著降低MIF水平，减轻器官损伤和血压下降。此外，我们可以证明，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MIF-和肝素酶系统如何在创伤患者中相互作用。我们的目标是提高我们对这些家族在多发性创伤中的动力学和临床相关性的理解，并阐明MIF抑制的保护作用的潜在信号通路。我们的初步数据表明抑制MIF具有治疗潜力，本项目将进一步证实这一点，以提供适当的治疗策略来预防和/或逆转器官损伤/衰竭，并改善多发外伤后的预后。因此，我们提出以下假设：H1：血清中肝素酶系统和mif系统成员水平升高与多发创伤患者复杂的临床病程和死亡率增加有关。H2: Heparanase、MIF、MIF-2和sCD74通过介导CD74/AMPK通路、JNK-和PI3K-Akt通路以及ERK-1/2通路参与多伤性器官损伤和功能障碍。H3: ISO-1对MIF的药理抑制减轻了创伤后免疫抑制、器官损伤/衰竭，改善了实验性多发创伤后的预后。

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.