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Am J Physiol Lung Cell Mol Physiol (December 3, 2004). doi:10.1152/ajplung.00231.2004
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Submitted on June 22, 2004
Accepted on November 30, 2004

The anti-inflammatory response is associated with mortality and severity of infection in sepsis

Alix Ashare1*, Linda S. Powers1, Noah S. Butler1, Kevin C. Doerschug1, Martha M. Monick1, and Gary W. Hunninghake2

1 Department of Internal Medicine, Division of Pulmonary and Critical and Occupational Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA
2 Department of Internal Medicine, Division of Pulmonary and Critical and Occupational Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA; Internal Medicine, Veterans' Administration Medical Center, Iowa City, Iowa, USA

* To whom correspondence should be addressed. E-mail: alix-ashare{at}uiowa.edu.

Using a murine model of sepsis, we found that the balance of tissue pro- to anti-inflammatory cytokines directly correlated with severity of infection and mortality. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Liver tissue was analyzed for levels of interleukin (IL)-1{beta}, IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNF{alpha}), and soluble TNF receptor 1 (sTNFR1) by ELISA. Bacterial DNA was measured using quantitative real-time PCR. After CLP, early predominance of pro-inflammatory cytokines (6 hours) transitioned to anti-inflammatory predominance at 24 hours. The elevated anti-inflammatory cytokines were mirrored by increased tissue bacterial levels. The degree of anti-inflammatory response compared to pro-inflammatory response correlated with the bacterial concentration. To modulate the timing of the anti-inflammatory response, mice were treated with IL-1ra prior to CLP. This resulted in decreased pro-inflammatory cytokines, earlier bacterial load and increased mortality. These studies show that the initial tissue pro-inflammatory response to sepsis is followed by an anti-inflammatory response. The anti-inflammatory phase is associated with increased bacterial load and mortality. These data suggest that it is the timing and magnitude of the anti-inflammatory response that predicts severity of infection in a murine model of sepsis.




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