B2: H2S-related modulation of the trauma response in nicotine-induced COPD

PIs: P. Radermacher, M. Huber-Lang

Mortality after traumatic-hemorrhagic shock is due to multi-organ failure resulting from a systemic hyper-inflammation, which is triggered by the direct physical trauma to the lung, the consecutive alveolar hypoxia and hypoxemia, as well as to the blood loss-related tissue ischemia and hypoxia. Moreover, restoration of blood flow represents an ischemia/reperfusion type of injury associated with oxidative stress and may thus further aggravate tissue damage. 

Pre-existing chronic obstructive pulmonary disease (COPD) is characterized by hypoxemia, chronic pulmonary and systemic hyper-inflammation, and both oxidative and nitrosative stress. Cigarette smoke consumption, the most important cause of COPD, aggravates the development of post-traumatic acute lung injury. While maintenance of endogenous H2S release, which is catalyzed by the 3 enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate-sulfurtransferase (3-MST), assumes particular importance for the development of COPD, equivocal data, however, were reported on the effect of H2S during acute lung injury and traumatic-hemorrhagic shock.  No data at all is available so far on the role of H2S during “acute (i.e. traumatic-hemorrhagic shock) on chronic (i.e. COPD) disease”. Therefore, this project will investigate the role of endogenous H2S release and exogenous H2S supplementation for acute lung injury and visceral organ dysfunction after traumatic-hemorrhagic shock with or without pre-existing cigarette smoke exposure-induced COPD.  Uncoupling of the mitochondrial respiratory chain resulting from oxidative and nitrosative stress and impaired barrier function are referred to as a central pathophysiological mechanism of the development of acute lung injury and visceral organ dysfunction. In various models of both acute and chronic disease H2S exerted anti-oxidative properties and improved mitochondrial function. Therefore, we will test the hypothesis whether any therapeutic effect of H2S is due to better maintenance of mitochondrial function. Since CBS and CSE are predominantly cytosolic, we will focus on the role of 3-MST, which is responsible for the majority of mitochondrial H2S production. Exogenous H2S supplementation will be investigated using the newly developed, mitochondria-targeted slow-releasing H2S donor AP39.

The specific hypotheses are:

  • H1: COPD aggravates traumatic-hemorrhagic shock-induced kidney and lung injury. 
  • H2: Genetic deletion of 3-MST further aggravates kidney and lung injury after traumatic-hemorrhagic shock.
  • H3: Mitochondria-targeted H2S supplementation after trauma maintains mitochondrial respiration and thereby improves kidney and lung function.

Video

Projektleiter

Prof. Dr. med. Dr. h.c. Peter Radermacher
Universitätsklinikum Ulm
Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung (APV)
Zentrum für Biomedizinische Forschung (ZBF)    
Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 500 60214
Fax: +49 731 500 60162
peter.radermacher(at)uni-ulm.de


Prof. Dr. med. Markus Huber-Lang
Universitätsklinikum Ulm
Zentrum für Chirurgie
Klinik für Unfallchirurgie, Hand-, Plastische und Wiederherstellungschirurgie
Zentrum für Biomedizinische Forschung (ZBF)
Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 500 54716
Fax: +49 731 500 54718
markus.huber-lang(at)uniklinik-ulm.de