Dysfunction of intestinal mucosal immunity after clinical and experimental polytrauma

肠血屏障（GBB）由粘液、肠上皮和一系列液相蛋白（抗菌肽、补体系统）和先天免疫细胞（白细胞）组成。然而，在多发伤中，GBB代表远程损伤的主要目标。我们的初步研究结果GBB作为一个主要的驱动程序的多器官功能障碍综合征（MODS）在全身炎症提供了理论基础，以进一步研究创伤后GBB失败的免疫病理生理学。因此，我们提出i）多发性创伤导致先天性肠粘膜免疫功能障碍，ii）主要由胰腺和补体衍生的蛋白酶驱动，iii）在阻断后导致血栓炎症和（多）器官性能改善。在从高度标准化的猪和小鼠多发性创伤模型中获得的粘液和肠组织、淋巴结和血液样本中，我们将定义抗菌剂、补体和胰腺蛋白酶驱动的反应的变化。此外，肠和血液中细胞先天免疫应答的时空表征将包括中性粒细胞、单核细胞/巨噬细胞和树突细胞的检测和免疫表型分析。此外，我们将遵循微生物及其相关分子模式（MAMP）的拟议易位轴，包括早期微生物组转移。将评价通过阻断蛋白水解活性（通过氨甲环酸或TriFU作为液相抑制剂）的第一种治疗方法。最后，在一项前瞻性描述性研究中，我们的目标是将联盟内的发现转化为多发性创伤后的临床环境，并最终提供一种粘膜免疫调节方法来改善患者的预后。

The gut-blood-barrier (GBB) is composed of mucus, intestinal epithelium and an arsenal of fluid-phase proteins (antimicrobial peptides, complement system) and innate immune cells (leukocytes). However, in polytrauma the GBB represents a main target of remote injury. Our preliminary findings of the GBB as a major driver of multiple-organ dysfunction syndrome (MODS) during systemic inflammation provide the rationale to further investigate the underlying immuno-pathophysiology of posttraumatic GBB failure. Thus, we propose that i) polytrauma leads to dysfunctional innate intestinal mucosal immunity, ii) mainly driven by pancreatic- and complement-derived proteases, which iii) upon blockade result in improved thrombo-inflammation and (multiple) organ performance. In mucus and intestinal tissue, lymph nodes and blood samples obtained from highly standardized pig and murine polytrauma models, we will define changes of the antimicrobial, complement- and pancreatic proteases-driven response. Furthermore, spatial-temporal characterization of the cellular innate immune response in the intestine and blood will include detection and immune-phenotyping of neutrophils, monocytes/macrophages, and dendritic cells. In addition, we will follow the proposed translocation axis of microbes and their associated molecular patterns (MAMPs) including early microbiome shifts. First therapeutic approaches by blockade of proteolytic activity (by tranexamic acid or TriFU as fluid phase inhibitor) will be evaluated. Finally, in a prospective descriptive study we aim to translate the findings within the consortium into the clinical setting after polytrauma and to ultimately offer a mucosal-immunomodulatory approach to improve the patient outcome.