Role of neutrophil extracellular traps (NETs) in impaired Fracture in type 2 diabetics

糖尿病是世界范围内患病率和发病率最高的代谢紊乱。这种疾病与许多并发症有关，尽管这些并发症复杂且成本高，但往往会对健康造成严重损害。不仅是糖尿病患者，糖尿病前期患者也表现出骨骼结构的改变。因此，糖尿病前期/糖尿病患者比新陈代谢健康的患者更容易发生骨折。因此，假设糖尿病前期患者和以前未被发现的糖尿病患者的比率(估计德国未报告病例的数量约为。450万美元)在创伤外科手术中尤其高。在骨折的情况下，骨块的固定、周围软组织的处理以及患者随后的活动都是巨大的挑战。愈合过程往往是漫长的，并且有丰富的并发症，其中，受影响的肢体截肢并不是个例。在德国，治疗这些并发症占糖尿病相关直接费用的很大比例。为了改善糖尿病前期/糖尿病患者的骨折治疗，我们的目标是在这个项目期间建立一种筛查，使前期/糖尿病患者能够在早期阶段被发现，以便以有针对性的方式进行治疗。并发症的风险已经可以通过优化的血糖控制(药物治疗)来降低。然而，为了在未来开发有针对性的疗法，需要对潜在的机制有一个基本的了解。骨折后，中性粒细胞是最先到达骨折血肿的细胞。在小鼠模型中，研究表明糖尿病刺激中性粒细胞形成Net(中性粒细胞胞外陷阱)。在网织染病过程中，中性粒细胞与瓜氨酸组蛋白和抗菌肽一起从细胞中释放DNA，以结合病原体并使其无害。我们怀疑糖尿病患者过度形成Net会损害周围组织，从而延迟或阻止伤口和骨折的愈合。PADI4(肽基精氨酸脱亚胺酶4)在这一过程中起着特殊的作用。我们预计糖尿病患者中性粒细胞中的PADI4水平会增加，从而使细胞对NETsis刺激敏感。骨折后，糖尿病患者会经历更多的氧化和亚硝化压力。我们怀疑这是蚊虫增多症的关键触发因素。此外，我们的初步工作表明，PADI4的基因变异影响中性粒细胞对NETsis刺激的反应强度。这反过来决定了糖尿病前期/糖尿病患者对组织和植入物相关感染等并发症的易感性。这项提议的目的是证明这些假设和假设，并确定可能的潜在机制。在这个项目中获得的知识将在未来用于开发新的治疗方法，以支持糖尿病前期/骨折患者的伤口和骨折愈合。

Diabetes mellitus is the metabolic disorder with the highest prevalence and incidence worldwide. The disease is associated with numerous complications, which, despite complex and cost-intensive treatment, often cause serious damage to health. Not only diabetics but already prediabetics show an altered bone structure. As a result, pre-/diabetics suffer more often from fractures than those with healthy metabolism. It is therefore assumed that the rate of prediabetics and previously unrecognized diabetics (estimated number of unreported cases in Germany approx. 4.5 million) is particularly high in trauma surgery. In the case of a fracture, the fixation of the bone pieces, the handling of the surrounding soft tissue and the following mobilization of the patient represent great challenges. The healing process is often prolonged and rich in complications, among which the amputation of the affected limbs is not an isolated case. Treating these complications accounts for a large proportion of the direct diabetes-associated costs in Germany.In order to improve the treatment of fractures in pre-/diabetics, we aim to establish a screening during this project that enables pre-/diabetics to be identified at an early stage so that they can be treated in a targeted manner. The risk of complications can already be reduced through optimized blood sugar control (medication). However, in order to develop targeted therapies in the future, a fundamental understanding of the underlying mechanisms is required. After a fracture, neutrophils are the first cells arriving in the fracture hematoma. In a mouse model it was shown that diabetes stimulates neutrophils to form NETs (neutrophil extracellular traps). In the process of NETosis, neutrophils release their DNA from the cell with citrullinated histones and antimicrobial peptides in order to bind pathogens and render them harmless. We suspect that an excessive formation of NETs in diabetics damages the surrounding tissue and thus delays or prevents wound and fracture healing. The enzyme PADI4 (peptidyl arginine deiminase 4) plays a special role in this process. We expect increased levels of PADI4 in neutrophils from diabetics, sensitizing the cells for NETosis stimuli. After a fracture, diabetics experience increased oxidative and nitrosative stress. We suspect that this is a critical trigger for the NETosis. In addition, our preliminary work suggests that the genetic variants of PADI4 influence how strongly the neutrophils respond to the NETosis stimuli. This in turn determines the susceptibility of pre-/diabetics to complications such as tissue and implant-associated infections. Aim of this proposal is to prove these assumptions and hypotheses and to identify possible underlying mechanisms. The knowledge gained within this project will be used in the future to develop new therapeutic approaches to support wound and fracture healing in pre-/diabetics.