B7 N: Effects of impaired glucocorticoid receptor function in hemorrhagic shock-induced lung injury with pre-existing cigarette smoke- induced chronic obstructive pulmonary disease

PI: S. Vettorazzi, M. Wepler

Hemorrhagic shock (HS) leads to hypoxia-induced systemic inflammation, which can cause acute lung injury (ALI). ALI, a frequent complication of trauma, is aggravated by lung co-morbidities like chronic obstructive pulmonary disease (COPD). COPD is characterized by oxidative and nitrosative stress, as well as both pulmonary and systemic hyper-inflammation, and the most common cause for COPD is cigarette smoke (CS) exposure. Anti-inflammatory acting glucocorticoids (GCs) mediate their effects through the glucocorticoid receptor (GR) and are used to treat patients with COPD, whereas their clinical use in ALI remains controversial. The applicants’ previous work shows that non-resuscitated mice lacking one mode of GR action, the GR dimerization (GRdim), are highly susceptible to systemic inflammation and ALI, showing that the GR dimerization is of importance to repress inflammation. Also, in previous experiments the applicants observed that the lack of GR dimerization aggravates LPS-induced endotoxic shock and impairment of lung function in mechanically ventilated and resuscitated mice, indicating that the GR dimer is a crucial mediator of hemodynamic stability and lung function during LPS-induced endotoxic shock. Moreover, the GR in macrophages (MØ) acts in synergy with pro-inflammatory signaling to up-regulate the alternative MØ marker sphingosine kinase 1 (SphK1), which is decisive for resolution of inflammation in ALI. The relevance of this GC paradigm shift will be tested during HS and CS-induced lung injury in GRdim mice and mice lacking the GR in MØ (GRLysMCre). Furthermore, the impact of the synergistic (through pro- and anti-inflammatory signaling) regulated MØ marker SphK1, shown to be crucial for ALI, will be investigated in SphK1LysMCre mice during HS, with a pre-existing COPD, and GC treatment. The results will answer the question if selective GR dimer activation and the GR in MØ might be a promising clinical tool to improve outcome in patients after trauma.

Projektleiter

Dr. rer. nat. Sabine Vettorazzi
Universität Ulm
Institut für Molekulare Endokrinologie der Tiere
Zentrum für Biomedizinische Forschung
Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 50 32631
E-mail: sabine.vettorazzi(at)uni-ulm.de


Dr. med. Martin Wepler
Universitätsklinikum Ulm
Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 500 60254
E-mail: martin.wepler(at)uni-ulm.de