Bcl-2 induced protection in severe sepsis

University Of Washington, Seattle WA

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Abstract

Sepsis and/or sepsis syndrome constitutes a major cause of death in critically ill patients and mortality remains high despite advances in clinical care. Sepsis is the best single predictor for development of the Adult Respiratory Distress Syndrome (ARDS). The high mortality in sepsis coupled with the disappointing results from recent clinical trials demonstrates a continuing need for new methods of treating this disease. Recent publications have shown that over-expression of the anti-apoptotic molecule Bcl-2 in T-lymphocytes, B-lymphocytes and in gut epithelial cells results in increased survival in mouse sepsis resulting from cecal ligation and puncture (CLP). We show in preliminary experiments that over-expression of Bcl-2 in myeloid cells also provides protection in sepsis resulting from CLP and that this protection can be adoptively transferred through transplanting Bcl-2 myeloid cells into mice deficient in mature lymphocytes (Rag-/-). These data suggest that lymphocytes are not necessary for Bcl-2 over-expression to provide protection from CLP. The first hypothesis of this project states that over-expression of Bcl-2 induces the expression of a gene(s) whose product(s) is protective in severe sepsis. Additional preliminary results show that T-lymphocytes from normal mice when adoptively transferred to the peritoneum can provide protection from CLP when previously stimulated with antibodies to either CD3 or CD90. Thus our second hypothesis states that stimulation of T-lymphocytes with antibodies to either CD3 or CD90 results in expression of cyto-protective gene(s) and their product(s) provides protection from severe sepsis. We will investigate these hypotheses through the following specific aims. 1) To identify candidate gene(s) whose product(s) may be protective in severe sepsis by comparing gene expression between controls and Bcl-2 over-expressing myeloid cells, T-lymphocytes and B-lymphocytes using gene expression arrays. 2) To identify candidate gene(s) whose product(s) may be protective in severe sepsis by comparing gene expression between unstimulated T-lymphocytes and lymphocytes stimulated by monoclonal antibodies that recognize CD3 or CD90. 3) To examine the efficacy in sepsis of candidate protective genes as determined by either microarray analysis or by the proteomics approach in specific aims 1 and 2.