Project Details
Projekt
Dysfunction of intestinal mucosal immunity after polytrauma - impact of remote pancreatic injury
Applicant
Professor Dr. Markus Huber-Lang
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 465409392
The gut-blood-barrier (GBB), vital for sustenance and immune defense can be disturbed following direct or remote tissue trauma. So far, we identified trauma-induced GBB disruption as a major driver of multiple-organ dysfunction syndrome (MODS) and demonstrated that polytrauma (PT) leads to the activation of complement- and pancreatic-derived proteases, contributing to impaired mucosal immunity. In our porcine PT model, blockade of both complement and Toll-like receptor activation improved hemodynamics and organ function. Preliminary findings indicate that PT also induces remote acute pancreatic injury (API). However, the role of API in intestinal dysfunction and its potential interplay with GBB failure remain unclear. Therefore, in the second funding period, we hypothesize that dysfunction of mucosal immunity after PT is driven by trauma-induced API. Within the consortium’s PT patient cohort (n=250), we will characterize the incidence and severity of (remote) API by biochemical analyses, imaging, and established scoring. In a clinically relevant pig PT model (in collaboration with RWTH Aachen), we aim to spatiotemporally define API and GBB disruption and track the translocation of pathogen-associated molecular patterns (PAMPs), including toxins, along the gut-lymph node-spleen-blood-organ axis post-trauma. Furthermore, using a human organoid-on-the chip model, we will explore cellular and molecular mechanisms of the pancreas-GBB-crosstalk in various trauma microenvironments. Finally, we will assess novel approaches, including innate immunity modulators and sealing compounds to restore the GBB and pancreatic integrity. Ultimately, our goal is to offer immunomodulatory strategies to improve patient outcomes.
DFG Programme
Research Units
