Abstract
BackgroundBacterial invasion during sepsis induces disregulated systemic responses that could lead to fatal lung failure. The purpose of this study was to relate the temporal dynamics of gene expression to the pathophysiological changes in the lung during the first and second stages of E. coli sepsis in baboons.ResultsUsing human oligonucleotide microarrays, we have explored the temporal changes of gene expression in the lung of baboons challenged with sublethal doses of E. coli. Temporal expression pattern and biological significance of the differentially expressed genes were explored using clustering and pathway analysis software. Expression of selected genes was validated by real-time PCR. Cytokine levels in tissue and plasma were assayed by multiplex ELISA. Changes in lung ultrastructure were visualized by electron microscopy. We found that genes involved in primary inflammation, innate immune response, and apoptosis peaked at 2 hrs. Inflammatory and immune response genes that function in the stimulation of monocytes, natural killer and T-cells, and in the modulation of cell adhesion peaked at 8 hrs, while genes involved in wound healing and functional recovery were upregulated at 24 hrs.ConclusionThe analysis of gene expression modulation in response to sepsis provides the baseline information that is crucial for the understanding of the pathophysiology of systemic inflammation and may facilitate the development of future approaches for sepsis therapy.
Highlights
Bacterial invasion during sepsis induces disregulated systemic responses that could lead to fatal lung failure
We reasoned that microarray technology would likely provide novel insights into the pathogenesis of sepsis or acute lung injury by allowing genomic-scale analysis of the gene transcription in specific organs. This technology has been used to study the pattern of gene expression either on cells exposed in vitro to LPS [10,11,12,13] or E. coli[14], or on blood cells isolated from septic patients[15]
Using the baboon model of sepsis, here, we report for the first time a global analysis of gene expression patterns in the lung of baboons during the first 24 hrs post E. coli challenge
Summary
Bacterial invasion during sepsis induces disregulated systemic responses that could lead to fatal lung failure. The purpose of this study was to relate the temporal dynamics of gene expression to the pathophysiological changes in the lung during the first and second stages of E. coli sepsis in baboons. We reasoned that microarray technology would likely provide novel insights into the pathogenesis of sepsis or acute lung injury by allowing genomic-scale analysis of the gene transcription in specific organs In the past, this technology has been used to study the pattern of gene expression either on cells exposed in vitro to LPS [10,11,12,13] or E. coli[14], or on blood cells isolated from septic patients[15]. Our results provide information relating to the temporal changes of the gene expression during inflammation in response to E. coli infusion, which could serve as a basis for discovery of new diagnostic and prognostic indicators and biomarkers, as well as the identification and validation of new molecular targets for drug development
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