A1: Late barrier dysfunction after experimental and clinical polytrauma

PI: M. Huber-Lang

After polytrauma, the cellular and molecular danger response can initiate a hidden or evident blood-organ barrier dysfunction, often leading to multiple organ failure and death. Due to limited knowledge about the underlying mechanisms, effective and targeted therapeutic approaches remain undefined. In the first funding period, we detected signs of early barrier dysfunction with appearance of glycocalyx components, tight junction proteins, and markers of organ damage after clinical and experimental polytrauma. Furthermore, we defined hemorrhagic shock as a major driver of multiple organ dysfunction, and characterized endothelial barrier and organ damage indicative of a specific temporal-spatial pattern. Early immunomodulation of activated complement on the C5a level was not beneficial in a murine polytrauma model; however, recent data on targeting C3 in primate septic or hemorrhagic shock indicated significant barrier and organ protection. Therefore, A01 hypothesizes i) that trauma/hemorrhage leads not only to early, but also to late barrier disturbances, ii) that these alterations crucially involve the central complement component C3, and iii) that targeted modulation of the posttraumatic C3 activation and approaches protecting glycocalyx integrity can prevent organ dysfunction. Studies in human polytrauma patients will shed light on the role of complement activation in development of organ failure, with a focus on acute kidney injury. In a highly standardized murine model of trauma and resuscitated hemorrhage, we will assess whether specific C3 targeting improves vital organ functions. Analyses in kidney cell lines and in mouse tissues after trauma will demonstrate which pathophysiological mechanisms downstream of C3 activation are responsible for post-traumatic renal alterations that ultimately result in organ failure. Our ultimate goal is to improve knowledge on the underlying cause of organ dysfunction and to evaluate therapeutic strategies to improve barrier integrity and outcome after severe injury.

Projektleiter

Prof. Dr. med. Markus Huber-Lang
Universitätsklinikum Ulm
Institut für Klinische und Experimentelle Trauma-Immunologie
Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 500 54800
markus.huber-lang(at)uniklinik-ulm.de

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