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Genomic Characterization of the Inflammatory Response Initiated by Surgery
Keith D. Coon, Landon J. Inge, Kristen Swetel, Jamie DeChon, Michael A. Smith, *Ross M. Bremner
St. Joseph's Hospital and Medical Center, Phoenix, AZ
BACKGROUND:
There are potential deleterious sequelae of the physiologic response to surgically induced stress. Some of the upregulated inflammatory cytokines have been shown to act as tumor growth factors and/or angiogenic and metastatic promotors. Modulation of these negative effects has the potential to improve outcomes from surgery, and possibly improve long-term survival after tumor resection. The profound effect of surgery on gene expression has yet to be fully elucidated. We assayed gene expression changes in an animal model of thoracotomy versus sham operation and then evaluated the ability of a cyclo-oxygenase inhibitor, celecoxib, to mediate these changes.
METHODS:
48 adult male BALC/c mice were randomized into three experimental groups: Group 1 (n = 16, sham operation with anesthesia only), Group 2 (n = 16, thoracotomy incision without opening the pleura), and Group 3 (n = 16, thoracotomy incision with perioperative COX-2 inhibition using celecoxib). Anesthesia protocols were consistent for all groups using ketamine and xylazene. Six hours after surgery, animals were sacrificed and blood was collected via cardiac puncture and processed for isolation of total RNA using the Mouse RiboPure™-Blood RNA Isolation Kit (Ambion, Austin, TX). Pooled RNA samples from each group were labeled and hybridized (in quadruplicate) to 4x44K Whole Mouse Genome Oligo Microarrays (Agilent, Foster City, CA). Gene expression profiles were analyzed to determine the genetic/biochemical effects of both surgery and celecoxib treatment.
RESULTS:
Surgery initiates a discernable cascade of gene expression changes that can be characterized and quantified by analysis via microarray. Significant gene expression changes were obtained at the p < 0.05 level by statistical analysis of quadruplicate arrays via ANOVA followed by the Benjamini and Hochberg multiple testing correction. Gene expression changes occurred in genes characterizing a variety of biochemical pathways including those that mediate the inflammatory response and angiogenesis (figure). Many of these gene expression changes induced by surgery were mitigated by perioperative treatment with celecoxib. 
CONCLUSIONS:
Surgery has a profound effect on the upregulation of many genes, many of which are related to the inflammatory response. Perioperative treatment with a COX-2 inhibitor abated many of these changes. The gene expression profile approach enables the further evaluation of genes and pathways that are deleterious to patient both in terms of perioperative recovery and tumor progression.
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