Dual role of plasma secreted sphingomyelinase activity during sepsis and development of organ failure

• Applicant: Professor Dr. Ralf Claus, Ph.D.
• Subject Area: Anatomy and Physiology
• Term: from 2007 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 39174683

The hydrolytic activity of the plasma secreted isoform of sphingomyelinase SMPD1 is enhanced in patients with systemic inflammatory response such as sepsis and multiple organ failure. In the first funding periode, we extended our knowledge, whether the increase is functionally significant for cellular stress response: As an example, we found that the enzyme obtained from patients with sepsis specifically induced macro-domain formation in endothelial cells and that the induction of endothelial apoptosis might be abrogated by low molecular inhibitors. In addition to these mechanistic approaches, an increased number of colony forming units of a variety of micro-organisms, an overwhelming cytokin response and more pronounced thrombocyto-penia in SMPD1-deficient mice subsequent to polymicrobial peritonitis were observed. Increased mortality in the early phase after infection, but a delayed in the later one, as well as prompted by results from our transcriptomal approach in different models, we intend to further characterize the role of SMPD1-mediated macrodomain formation for chemotaxis and leukocyte/ endothelium interaction. For these aims, we plan to develop a novel in-vivo activity-linked fluorescence enhancement approach in combination with a bio-imaging setting, monitoring bacterial dissemination. We aim to elucidate the role of SMPD1 in infectious and non-infectious models of organ dysfunction and to define the time for beneficial effects of its inhibition with repsect to the development of organ failure. We expect novel results for the functional role of the secreted isoform of SMPD1 in inflammation avoiding adverse effects of its inhibition.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1267: Sphingolipids - Signals and Disease