Role of the PlexinB1 / Semaphorin4D axis for the control of inflammation during lung injury

PlexinB1/Semaphorin4D 轴在肺损伤期间控制炎症中的作用

• 批准号: 324452025
• 负责人: Professor Dr. Peter Rosenberger
• 金额: --
• 依托单位: Klinik für Anaesthesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/324452025?language=en
• 关键词: Role; PlexinB1; Semaphorin4D; axis; control

The presence of dysregulated inflammation, inappropriate accumulation of leukocytes an altered permeability of the alveolar barrier remain the central pathophysiologic changes of lung injury and the adult respiratory distress syndrome. In this process the migration of granulocytes and the orchestration of the inflammatory response are still incompletely understood. The search for novel therapies for conditions associated with inflammation has indicated that neuronal guidance proteins (NGP) might have significant influence on conditions caused by acute inflammation. NGPs and their target receptors were originally described in the context of axonal development but recent years have shown that they also might influence mechanisms of acute inflammation. In previous work we were able to show that the guidance protein Semaphorin7A and its receptor play an important role during hypoxic and pulmonary inflammation. We have now extended this work and describe a role for Semaphorin4D (Sema4D) and PlexinB1 (PLXNB1) during inflammation causing lung injury. In preliminary experiments we were able to demonstrate that Sema4D and PlexinB1 are significantly regulated during inflammation in vitro. These changes in expression translate into altered formation of platelet neutrophil complexes and also changed severity of pulmonary inflammation in a model of LPS induced lung injury. These results propose an important role for the Sema4D-PlexinB1 axis during the development of pulmonary inflammation and lung injury. Therefore we plan here to further investigate the interaction of Sema4D and PlexinB1 with known mechanisms of leukocyte recruitment. Furthermore we aim to describe the functional implications of the Sema4D-PlexinB1 axis for the development and maintenance of lung injury and in a last step we aim to elucidate potential novel therapeutic options derived from these findings.

炎症失调、白细胞过度聚集和肺泡屏障通透性改变是肺损伤和成人呼吸窘迫综合征的主要病理生理变化。在这个过程中，粒细胞的迁移和炎症反应的协调仍然没有完全理解。对与炎症相关的病症的新疗法的研究表明，神经元引导蛋白（NGP）可能对由急性炎症引起的病症具有显著影响。NGP及其靶受体最初是在轴突发育的背景下描述的，但近年来表明它们也可能影响急性炎症的机制。在以前的工作中，我们能够表明，导向蛋白Semaphorin 7A及其受体在缺氧和肺部炎症中发挥重要作用。我们现在已经扩展了这项工作，并描述了Semaphorin 4D（Sema 4D）和丛蛋白B1（PLXNB 1）在炎症引起肺损伤期间的作用。在初步实验中，我们能够证明Sema 4D和丛蛋白B1在体外炎症过程中受到显着调节。这些表达变化转化为血小板中性粒细胞复合物形成的改变，也改变了LPS诱导的肺损伤模型中肺部炎症的严重程度。这些结果表明Sema 4D-PlexinB 1轴在肺部炎症和肺损伤的发展过程中起重要作用。因此，我们计划在这里进一步研究Sema 4D和丛蛋白B1与已知的白细胞募集机制的相互作用。此外，我们的目标是描述的Sema 4D-PlexinB 1轴的肺损伤的发展和维护的功能意义，并在最后一步，我们的目标是阐明潜在的新的治疗方案，从这些发现。