Dysfunction of intestinal mucosal immunity after clinical and experimental polytrauma

肠-血屏障（GBB）由黏液、肠上皮、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，在多发外伤中，GBB是远程损伤的主要目标。我们初步发现GBB是全身性炎症期间多器官功能障碍综合征（MODS）的主要驱动因素，为进一步研究创伤后GBB衰竭的潜在免疫病理生理学提供了理论依据。因此，我们提出i)多重创伤导致先天性肠黏膜免疫功能失调，ii)主要由胰腺和补体来源的蛋白酶驱动，iii)阻断后导致血栓炎症和（多）器官功能改善。在高度标准化的猪和鼠多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、补体和胰腺蛋白酶驱动反应的变化。此外，肠道和血液中细胞先天免疫反应的时空表征将包括中性粒细胞、单核/巨噬细胞和树突状细胞的检测和免疫表型。此外，我们将遵循提出的微生物易位轴及其相关分子模式（MAMPs），包括早期微生物组的变化。第一种通过阻断蛋白水解活性（氨甲环酸或三氟脲作为流体相抑制剂）的治疗方法将被评估。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研究结果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.