Bacterial infection with sepsis is associated with a high mortality rate (29%)(19). Identifying the mediators produced during sepsis which result in harmful effects or recovery, as well as the patterns of gene expression which control their production, would improve the development and administration of medicines designed to modulate this inflammatory response. However the septic response involves the activation of several different pro-inflammatory plasma proteolytic cascades as well as the cellular production of pro-inflammatory molecular mediators (e.g. cytokines, adhesion molecules, growth factors, oxidants, nitric oxide etc). In addition to the release of pro-inflammatory mediators, this response is associated with the production of anti-inflammatory molecules which provide endogenous control over the response. Attempts to fully characterize this response in individual patients have been unsuccessful due in part to its complexity and redundant nature as well as to the disparate roles it plays both in host defense as well as tissue injury. Such a characterization may be essential however for the application of new therapies designed to modulate inflammation during sepsis in the future. Oligonucleotide microarray analysis is a rapidly growing technology which identifies individual or groups of genes which are up or down regulated in a sample of cells. Expression profiling data can be used to identify, on a genome-wide basis, the specific genes that are responsive to particular regulatory mechanism during the development of disease. A rat genome U34A array, which analyzes about 7,000 full length sequences and approximately 1,000 EST clusters (GeneChip, Affymetrix, Inc., Santa Clara, CA) to measure rat gene expression has been produced. The primary purpose of the studies underway in this project is to apply oligonucleotide microarray to determine genes which may be important in the development of sepsis and septic shock during infection. Rat genome U34A arrays are being used to identify genes from circulating mononuclear cells (lymphocytes and monocytes), which are either up or down regulated in dose ordered fashion during graded bacterial infection either acutely, subacutely or at recovery (i.e. 6, 24 or 168 h after the onset of infection respectively) in a well characterized rat model of sepsis. These genes or their gene products will then serve as targets for potential treatments or prognostic testing in later sepsis studies. Experiments thus far completed have shown that there is a subpopulatioon of genes represented on the microarrays under study that do show significant dose ordered expression levels. However, up or down regulation with infection which is apparent quickly at 6 h does not demonstrate dose ordering until 24 h. Furthermore, the majority of genes showing this pattern, rather than being upregulated are down regulated. The relevance of these generalized expression patterns are now being analyzed in functionally related groups of genes as well for individual genes producing products strongly associated with either the harmful or beneficial effects of the inflammatory response.
| Eichacker, Peter Q; Parent, Chantal; Kalil, Andre et al. (2002) Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 166:1197-205 |
