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.
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.
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.
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.
A. Ashare, None.