The role, interplay and phenotypic changes of platelets in inflammation mediated organ damage.

一个平衡的炎症反应可以让身体保护自己免受外部病原体的侵害，而过度的炎症反应会损害机体本身。这种不受控制的炎症反应可以在脓毒症患者中观察到，在较小程度上也可以在关节炎患者中观察到。在这里，炎症细胞的募集和不受阻碍的激活以及内皮屏障的破坏不仅会导致局部炎症并发症，如水肿形成或关节破坏，而且由于全身炎症反应过度也会导致继发性（远端）器官损伤。重要的是，任何炎症反应必须终止和解决，以防止持续的器官损伤。已发现血小板对关节炎的急性发作和急性肺损伤有影响，但对血小板的溶解潜力、血小板和巨噬细胞表型的变化、对炎症细胞募集的影响以及血小板微粒介导继发性器官功能障碍的作用知之甚少。有趣的是，已经发现血小板微颗粒直接介导局部炎症，但也发现血小板微颗粒传播到体内的偏远区域，在关节炎期间在淋巴和骨髓中检测到这些颗粒。本项目旨在阐明血小板介导的炎症和炎症过程解决的潜在机制，以及微颗粒对继发性器官损伤、炎症和解决的影响。我们将在不同的疾病模型和器官中研究血小板与巨噬细胞的相互作用和表型变化，巨噬细胞是炎症和细胞清除的主要因素。由于关节炎、结肠炎和败血症等炎症性疾病是常见的临床疾病，导致医院费用和死亡率高，因此提高对炎症、继发性器官损伤的调节机制的理解和解决这些问题对于翻译工作至关重要。

A well-balanced inflammatory reaction allows the body to defend itself against external pathogens, whereas an overshooting inflammatory response can harm the organism itself. Such uncontrolled inflammatory response can be observed in septic patients and to a lesser extent also in arthritis patients. Herein, the recruitment and unhindered activation of inflammatory cells and breaking of the endothelial barrier lead to not only local inflammatory complications, such as edema formation or joint destruction, but due to a systemic overshooting inflammatory response also to secondary (remote) organ damage. Importantly, any inflammatory response must be terminated and resolved to prevent ongoing organ damage. Platelets have been found to affect acute onset of arthritis as well as acute lung injury, but little is known about the resolution potential of platelets, changes in platelet and macrophage phenotypes, impact of such on recruitment of inflammatory cells and the role of platelet-microparticles in mediation of secondary organ dysfunction. Interestingly, platelet-microparticles have been found to directly mediate local inflammation but dissemination of platelet-microparticles to remote regions within the body has also been discovered, detecting these particles in lymph and bone marrow during arthritis. This project aims to elucidate underlying mechanisms of platelet-mediated inflammation and resolution of inflammatory processes as well as the impact of microparticles on secondary organ damage, inflammation, and resolution. Of special interest, interplay of platelets with macrophages, which are known to be main contributors to both inflammation and cell-clearance during resolution, and phenotypic changes will be examined in different disease models and organs. As inflammatory conditions such as arthritis, colitis and sepsis are common clinical morbidities resulting in high hospital expenditures and mortality rates, advancing the understanding of regulatory mechanisms of inflammation, secondary organ damage and resolution of such is of utmost importance for translational endeavors.