The pathophysiologic role of Club Cell Protein 16 in the development of respiratory complications - Analysis of a clinically relevant combinatory model of chest trauma and ARDS with special regard to the function of neutrophil granulocytes

• Applicants: Professor Dr. Frank Hildebrand; Professor Dr. Ingo Marzi, since 5/2020; Professorin Dr. Borna Relja
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 383969007

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.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Sebastian Wutzler, until 4/2020