Sepsis is amongst the world’s biggest public health problems with an estimated 18 million cases per year and a mortality rate of up to 50%. Despite advances in medical treatment incidencts in Australia have doubled between 1997 and 20051. Failure of more than 30 clinical trials to treat sepsis shows that there is an urgent need for new therapy options2. Macrophages play a key role in immune activation during sepsis as producers of a wide range of mediator molecules3. Blood serum of septic patients has the ability to induce apoptosis in embryonic fibroblast cell lines4 and transcriptional and translational activation of the BH3 only protein Bim5 in lymphocytes of healthy patients. However the molecular mechanisms of Bim induction during sepsis leading to a prolonged phase of immunosuppression are currently unknown. We could show that supernatants of LPS activated murine macrophages lead to transcriptional and translational induction of Bim triggering apoptosis of primary lymphocytes and MEFs in vitro. In order to purify the apoptosis- inducing factor we established a biochemical purification protocol and a cell-based assay system. A list of candidate proteins in the active fraction was obtained by Mass Spectrometry analysis. Further, a library of >5000 FDA approved drugs was screened in a cell based assay and potential hits will be evaluated and characterized for their ability to block Bim induction on transcriptional and translational level in vitro and if applicable in vivo. Findings in our lab deciphering the molecular pathways involved in Bim mediated apoptosis of immune cells during sepsis might lead to desperately needed therapy options.
1 Peake S et al. 2007 Critical Care Med , 11 (Suppl 2):P7.
2 Hotchkiss and Nicholson 2006 Nat Rev Immunol. Nov; 6(11): 813-22
3 Avni D et al 2010 Mol Immunology 47,1396-1403
4 Vaki et al 2011 J Leukoc Biol March 2011 89:325-326
5 Schwulst et al 2008 Shock, Vol. 30, No. 2, pp. 127-134