Sepsis is defined as the systemic inflammatory response from infection and is a major cause of morbidity and mortality with an annual death rate of over 175,000 people in the United States alone. The host response to sepsis is an intricate interplay of numerous inflammatory and anti-inflammatory processes including the coagulation cascade, complement system, kinin system, and many others. Immunologic defenses are activated in sepsis as well; and there is recruitment and activation of granulocytes, lymphocytes, and monocytes. Recent studies demonstrate that sepsis causes a marked decrease in circulating lymphocytes which is accompanied by extensive apoptosis of lymphocytes in tissues throughout the body. Although it is speculated that sepsis-induced apoptosis of lymphocytes may be beneficial in sepsis by down-regulating the inflammatory response, it is also possible that loss of lymphocytes is excessive and impairs the ability of the host to eradicate the infection. Recently, the anti- apoptotic protein BCL-2 has been shown to prevent cell death from a remarkable number of diverse stimuli including hypoxia, ionizing radiation, oxidant injury and excitotoxins.
The aims of this investigation are to pursue their initial observations demonstrating that transgenic mice which selectively overexpress BCL-2 in T lymphocytes have complete protection against lymphocyte apoptosis and improved survival in sepsis. These findings indicate that strategies which prevent lymphocyte death in sepsis may improve survival. Transgenic mouse constructs in which BCL-2 is selectively overexpressed in T, B, or both T and B lymphocytes will be employed in sepsis. Lymphocyte transfer experiments in Rag-1 mice, which are totally deficient in mature T and B cells, will be examined also. Rag-1 mice will be transfused with T or B lymphocytes that overexpress BCL-2 and effects on apoptosis and survival recorded. Mechanisms of BCL-2's protective effect will be investigated as well. Finally, autopsy sample from patient who died of sepsis or other causes will be examined to correlate BCL-2's expression with lymphocyte apoptosis and gain insight into possible mechanisms of apoptosis such as caspase activation and cytochrome c release.
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