The pathophysiologic role of Club Cell Protein 16 in the developmentof respiratory complications - Analysis of a clinically relevantcombinatory model of chest trauma and ARDS with special regard tothe function of neutrophil granulocytes

在患有胸部/胸腔创伤的患者中，对创伤的免疫应答与呼吸系统并发症发生率增加有关，这描绘了临床高度相关的情况。因此，中性粒细胞起着重要作用。在创伤后最初，具有肺损伤的创伤患者中俱乐部细胞蛋白（CC）16的血清水平显著增加。这种增加可能是由于机械性细胞和组织损伤以及随后导致的CC 16从受损细胞释放。在创伤后的早期阶段，代偿性抗炎反应（汽车）是必要的，以抵消创伤诱导的全身炎症反应综合征（SIRS）。然而，在损伤后的早期阶段，中性粒细胞被激活，这一现象决定了中性粒细胞对延迟的次级触发物的过度炎症反应。它们的过度活化可能导致不受控制的组织损伤，也在肺中，从而可能诱导在患有肺炎的肺损伤的创伤患者中观察到的CC 16的第二峰。这种继发性CC 16增加的病理生理学相关性，从创伤患者的肺损伤和呼吸系统并发症的血清仍不清楚。因此，本研究的目的是表征a）局部释放的CC 16（肺，BAL-F）以及B）全身性CC 16（血清）水平对中性粒细胞的功能性的影响，包括评估所涉及的机制。这些数据可能为这些临床环境中的潜在治疗选项打开新的窗口。因此，在本研究中，我们打算评估在猪模型中创伤后最初（直接、早期）和延迟（创伤后数天）释放的CC 16对中性粒细胞功能（吞噬作用、凋亡、氧化爆发、迁移、成熟）、全身以及局部炎症反应、主要（多发性）创伤后器官/组织损伤的影响。CC 16对中性粒细胞的影响可能会增加该模型中临床感染（包括肺损伤）的脆弱性。此外，在体内实验中，将评估CC 16中和抗体的局部和全身应用（最初在创伤后或之后）对局部和全身炎症反应、器官功能和存活的影响。

The immune response to trauma in patients suffering from a chest/thorax trauma is linked to increased respiratory complications rates, depicting a clinically highly relevant scenario. Hereby, neutrophil granulocytes play a significant role. Initially after trauma the serum levels of Club Cell Protein (CC)16 are significantly increased in trauma patients with lung injuries. This increase may be due to the mechanical cell and tissue injury and a subsequent resulting CC16 release from damaged cells. During this initial, early post-traumatic phase, a compensatory anti-inflammatory response (CARS) is necessary to counterbalance the trauma-induced systemic inflammatory response syndrome (SIRS). However, in this early post-injury phase neutrophil granulocytes get primed, a phenomenon that determines the exaggerated inflammatory response of neutrophils to a delayed secondary trigger. Their exaggerated activation may result in uncontrolled tissue damage, also in the lungs, and thereby may induce the secondary peak of CC16 that was observed in trauma patients with lung injury suffering from pneumonia. The pathophysiologic relevance of this secondary CC16 increase in serum from trauma patients with lung injury and respiratory complications remains unclear. Therefore, the aim of the present study is to characterize the influence of a) locally released CC16 (lungs, BAL-F) as well as b) systemic CC16 (serum) levels on the functionality of neutrophil granulocytes including the evaluation of involved mechanisms. This data may open new windows for potential therapy options within these clinical settings. Therefore, in this study, we intent to evaluate the influence of the initially (directly, early) after trauma and delayed (days after trauma) released CC16 on the neutrophil functionality (phagocytosis, apoptosis, oxidative burst, migration, maturation), the systemic as well as local inflammatory reaction, organ/tissue injury after major (poly) trauma in a porcine model. The influence of CC16 on neutrophil granulocytes may increase the vulnerability for clinical infections in this model including lung injury. Additionally, in in vivo experiments, the impact of both, local and systemic application ofCC16-neutralizing antibodies, either initially after trauma or later on, on the local and systemic inflammatory reaction, organ function and survival will be evaluated.