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.

肠道刺（GBB）由粘液，肠上皮和流体相蛋白（抗菌肽，补体系统）和先天免疫细胞（白细胞）组成。但是，在多龙头中，GBB代表了远程伤害的主要目标。我们将GBB作为全身炎症期间多器官功能障碍综合征（MOD）的主要驱动力的初步发现提供了进一步研究创伤后GBB失败的潜在免疫神经生理学的基本原理。因此，我们提出i）多发性乳腺导致功能障碍的先天肠粘膜免疫，ii）主要由胰腺和补体衍生的蛋白酶驱动，这是在阻断后造成的，这会导致改善的血栓炎性和（多）器官性能。在粘液和肠道组织中，从高度标准化的猪和鼠多发性模型获得的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的反应的变化。此外，肠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的检测和免疫 - 表型，单核细胞/巨噬细胞和树突状细胞。此外，我们将遵循所提出的微生物的易位轴及其相关的分子模式（MAMP），包括早期微生物组移位。将评估通过蛋白水解活性阻断（通过Tranexamic Acid或Trifu作为液相抑制剂）进行的首次治疗方法。最后，在一项前瞻性描述性研究中，我们旨在将财团内的发现转化为多发性毛虫后的临床环境，并最终提供粘膜免疫调节方法来改善患者的结果。