BALANCE OF INFLAMMATORY CYTOKINES RELATED TO SEVERITY AND MORTALITY OF MURINE SEPSIS

We tested the hypothesis that, during sepsis, the balance of pro- and anti-inflammatory cytokines is related to severity and survival. Cecal ligation and puncture (CLP) with a large (18-gauge)-, intermediate (2 1-gauge)-, or small (26-gauge)-diameter needle, or sham laparotomy, wa s performed on outbred CD-1 mice. Concentrations of tumor necrosis fac tor alpha (TNF-alpha), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 were measured (by enzyme-linked immunosorbent assay) i n serum, peritoneal lavage fluid, and liver and lung samples at 4, 8, 24, 48, and 96 h. As the diameter of the CLP needle decreased, the mor tality rate decreased (at 48 h: large, 80%; intermediate, 40%; small, 20%; P < 0.05), the TNF-alpha and IL-6 concentrations decreased, and t he time-to-peak TNF-alpha expression increased. In contrast, IL-10 con centration increased compared with baseline (serum at 24 h: large, 2.3 -fold +/- 1.6-fold; intermediate, 2.0-fold +/- 0.5-fold; small, 19.9-f old +/- 8.3-fold; P < 0.05). Administration of IL-10 (5 mu g, intraper itoneal) prior to CLP decreased mortality (P < 0.001). Administration of polyclonal anti-IL-10 serum prior to CLP (0.5 ml intraperitoneal) h ad the opposite effect and increased mortality (P < 0.001) and TNF-alp ha, IL-6) and TNF-alpha mRNA expression compared with controls. Thus, severe sepsis is associated with a largely unopposed inflammatory resp onse, and a largely unopposed inflammatory response (with anti-IL-10) results in severe sepsis and death. Less severe sepsis is associated w ith greater anti-inflammatory mediator expression, and greater anti-in flammatory mediator expression (with IL-10) results in less severe sep sis. Thus, the balance of inflammatory mediators is related to the sev erity and mortality of murine sepsis.