09/2009 Prof. Dr. Konrad Reinhart/ PD Dr. Ralf A. Claus
Ceramide formation in host response to bacterial and fungal
infection and development of organ failure
Abstract:
In addition to the function in membrane stabilization,
sphingolipids and its metabolites were increasingly approved as
key players in mechanisms of cellular stress response such as
recognizing and elimination of microbial pathogens. The limiting
step in sphingomyelin metabolism is the hydrolytic activity of
sphingomyelinases, of which the secreted isoform has been shown
to be increased in sepsis, chronic inflammation and organ
failure. Own results and data from other groups emphasize its
activity essential during the early phase of host response in
gram negative infection as shown by overwhelming secretion of
cytokines, increased mortality as well as reduced phagocytosis
in loss-of-function studies. However, there is also
increasing evidence, that ceramide formation is involved in the
development of organ failure during severe infection.
In this project, we will characterize the putative dual function
of secreted sphingomyelinase to define the consequence for
ceramide formation and orchestration of host response. For this
purpose, the kinetic and dynamic of sphingomyelin hydrolysis in
clearly defined models of inflammation and organ failure will be
analyzed, i.e. polymicrobial cavity infection
(peritonitis/sepsis), infection with gram negative rsp.
gram-positive bacteria/with fungi and non-infectious conditions
such as endotoxic shock and zymosan-induced multiple organ
failure. Furthermore, it will be tested, whether (and from which
time point) a pharmacological inhibition of ceramide generation
may have a benefit with respect to organ function and survival.
Comparative transcriptomics will be performed by Illumina-technology.
Finally, we aim at the elucidation of differences of adherence,
chemotaxis and diapedesis of activated leukocytes in living mice
by intravital microscopy.
References: Doehner W, Bunck AC, Rauchhaus M, von Haehling S,
Brunkhorst FM, Cicoira M, Tschope C, Ponikowski P, Claus RA,
Anker SD (2007) Secretory sphingomyelinase is upregulated in
chronic heart failure: a second messenger system of immune
activation relates to body composition, muscular functional
capacity, and peripheral blood flow. Eur Heart J. 28:821-8.
Claus RA, Bunck AC, Bockmeyer CL, Brunkhorst FM, Lösche W,
Kinscherf R, Deigner HP (2005) Role of increased
sphingomyelinase activity in apoptosis and organ failure of
patients with severe sepsis. FASEB J. 19:1719-21.
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