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

炎症失调、白细胞不适当积聚和肺泡屏障通透性改变的存在仍然是肺损伤和成人呼吸窘迫综合征的中心病理生理变化。在这个过程中，粒细胞的迁移和炎症反应的协调仍然不完全清楚。对炎症相关疾病的新疗法的研究表明，神经元引导蛋白（NGP）可能对急性炎症引起的疾病有重大影响。ngp及其靶受体最初是在轴突发育的背景下被描述的，但近年来已经表明它们也可能影响急性炎症的机制。在之前的工作中，我们能够证明指导蛋白Semaphorin7A及其受体在缺氧和肺部炎症中发挥重要作用。我们现在扩展了这项工作，并描述了信号蛋白4d （Sema4D）和PlexinB1 （PLXNB1）在炎症引起的肺损伤中的作用。在初步实验中，我们能够证明Sema4D和PlexinB1在体外炎症过程中受到显著调节。在LPS诱导的肺损伤模型中，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，也改变了肺部炎症的严重程度。这些结果表明Sema4D-PlexinB1轴在肺部炎症和肺损伤的发展过程中起重要作用。因此，我们计划在此进一步研究Sema4D和PlexinB1与已知白细胞募集机制的相互作用。此外，我们的目标是描述Sema4D-PlexinB1轴在肺损伤发展和维持中的功能意义，最后一步，我们的目标是阐明从这些发现中衍生出的潜在的新治疗选择。

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.