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Tissue Anti-inflammatory Responses are Associated With Severity of Infection in Sepsis FREE TO VIEW

Alix Ashare, MD; Linda S. Powers, MS; Noah S. Butler, MHS; Kevin C. Doerschug, MD; Gary W. Hunninghake, MD
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University of Iowa, Iowa City, IA


Chest. 2003;124(4_MeetingAbstracts):120S-b-121S. doi:10.1378/chest.124.4_MeetingAbstracts.120S-b
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PURPOSE:  Sepsis represents a systemic inflammatory response to infection. Some animal studies indicated that largely unopposed pro-inflammatory responses resulted in death, while greater anti-inflammatory responses resulted in less severe sepsis. Other studies show that increased anti-inflammatory cytokines may be more predictive of mortality. Using a murine model of polymicrobial sepsis, we evaluated tissue levels of pro- and anti-inflammatory cytokines in relation to local severity of infection at time points of organ injury and mortality.

METHODS:  Sepsis was induced in thirty-six C57BL/6 mice by cecal ligation and puncture (CLP). Mice were sacrificed at 6, 16, 24, and 48 hours. Livers tissue was analyzed for levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNFα), and soluble TNF receptor 1 (sTNFR1) by ELISA. Bacterial DNA concentrations in liver tissues were measured using quantitative real-time PCR with primers specific for the bacterial 16s ribosomal RNA gene.

RESULTS:  CLP resulted in 29% mortality at 24 hours, and 60% mortality at 48 hours. After CLP, there was an increase in liver pro-inflammatory cytokines IL-1β and TNFα that peaked at 6 hours. In contrast, levels of anti-inflammatory factors sTNFR1 and IL-1ra peaked at 24 hours. The ratio of IL-1ra to IL-1β suggested a pro-inflammatory response at 6 hours, but an anti-inflammatory predominance at 24 hours. Bacterial concentrations in liver peaked at 24 hours, concomitant with the transition to an anti-inflammatory response. The degree of anti-inflammatory responses correlated with the bacterial concentrations.CONCLUSIONS: The initial local pro-inflammatory response to sepsis is followed by a predominantly anti-inflammatory response. This transition is associated with an increase in bacterial concentration, organ injury, and mortality.

CLINICAL IMPLICATIONS:  The transition to an anti-inflammatory state is associated with a period of immunosuppression during which there is increased severity of infection, increased end-organ damage, and increased mortality. Future studies involving therapies aimed at altering the inflammatory response in sepsis should carefully evaluate the severity of infection during the progression of sepsis.

DISCLOSURE:  A. Ashare, None.

Tuesday, October 28, 2003

2:30 PM - 4:00 PM




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