Bcl-2 induced protection in severe sepsis

脓毒症和/或脓毒症综合征是危重病人死亡的主要原因，尽管临床护理取得了进步，但死亡率仍然很高。脓毒症是成人呼吸窘迫综合征（ARDS）发展的最佳单一预测因子。败血症的高死亡率加上最近的临床试验令人失望的结果表明，继续需要新的方法来治疗这种疾病。最近的研究表明，抗凋亡分子Bcl-2在t淋巴细胞、b淋巴细胞和肠上皮细胞中的过度表达可提高盲肠结扎和穿刺（CLP）引起的小鼠脓毒症的存活率。我们在初步实验中表明，髓细胞中Bcl-2的过度表达也对CLP引起的脓毒症提供保护，并且这种保护可以通过将Bcl-2髓细胞移植到缺乏成熟淋巴细胞的小鼠（Rag-/-）中来过继转移。

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.