Septic shock is a leading cause of death in intensive care units nationwide. My research is focused on deciphering the molecular events associated with the onset and progression of this disease, particularly as it relates to the synthesis inflammatory mediators from cells of the blood.
The interaction of bacterial endotoxin and cells of the immune system initiates an inflammatory response that is rapid and robust. Left unchecked, this response can progress to a state of widespread inflammation, organ failure and ultimately death, in a disease referred to as septic shock. Mediators of this immune response have been recently identified and have supported efforts to further understand the molecular events that precipitate the onset of this disease. We have focused our efforts at identification of mechanisms that control the synthesis of inflammatory proteins that are found in the blood of patients with septic shock. In particular, we are studying the mechanisms that control the synthesis of interleukin 1-beta (IL-1beta), a low molecular weight inflammatory protein that is rapidly synthesized by cells of the immune system in response to endotoxin and whose expression is tightly regulated at the level of gene transcription as well as by post-transcriptional and post-translational mechanisms. In contrast to blood cells from healthy individuals, we have found that blood cells from septic shock patients do not synthesize IL-1beta in response to endotoxin and appear to be in an immune adapted, refractory state. We are studying this immune adapted state using models that include endotoxin adapted human tissue culture cell lines, in vitro adapted human peripheral blood leukocytes and blood leukocytes from patients with septic shock. Immune adaptation in these models involves changes in endotoxin receptor signaling, as well as changes in transcription of the IL-1beta gene.