Dysfunction of intestinal mucosal immunity after clinical and experimental polytrauma

临床和实验性多发伤后肠粘膜免疫功能障碍

• 批准号: 495641357
• 负责人: Professor Dr. Markus Huber-Lang
• 金额: --
• 依托单位: Institut für Klinische und Experimentelle Trauma-Immunologie (ITI)
• 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/495641357?language=en
• 关键词: Dysfunction; intestinal; mucosal; immunity; after

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.

肠血屏障(GBB)由粘液、肠上皮和大量的液相蛋白(抗菌肽、补体系统)和天然免疫细胞(白细胞)组成。然而，在多发伤中，基底节是远程损伤的主要靶点。我们的初步发现是全身炎症时多器官功能障碍综合征(MODS)的主要驱动力，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基础。因此，我们认为：1)多发伤导致固有肠道黏膜免疫功能紊乱，2)主要由胰腺和补体衍生的蛋白酶驱动，3)阻断后可改善血栓炎症和(多)器官功能。在高度标准化的猪和小鼠多发伤模型中获得的粘液和肠道组织、淋巴结和血液样本中，我们将定义抗菌素、补体和胰蛋白酶驱动的反应的变化。此外，肠道和血液中细胞固有免疫反应的时空特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，我们将跟踪提出的微生物易位轴及其相关分子模式(MAMP)，包括微生物组早期移位。首先，将评估通过阻断蛋白分解活性(通过氨甲环酸或曲氟沙星作为液体相抑制剂)的治疗方法。最后，在一项前瞻性描述性研究中，我们的目标是将联合体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。