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 (21-gauge)-, or small (26-gauge)-diameter needle, or sham laparotomy, was performed on outbred CD-1 mice. Concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 were measured (by enzyme-linked immunosorbent assay) in 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 mortality rate decreased (at 48 h: large, 80%; intermediate, 40%; small, 20%; P < 0.05), the TNF-alpha and IL-6 concentrations decreased, and the time-to-peak TNF-alpha expression increased. In contrast, IL-10 concentration increased compared with baseline (serum at 24 h: large, 2.3-fold +/- 1.6-fold; intermediate, 2.0-fold +/- 0.5-fold; small, 49.9-fold +/- 8.3-fold; P < 0.05). Administration of IL-10 (5 microg, intraperitoneal) prior to CLP decreased mortality (P < 0.001). Administration of polyclonal anti-IL-10 serum prior to CLP (0.5 ml intraperitoneal) had the opposite effect and increased mortality (P < 0.001) and TNF-alpha, IL-6, and TNF-alpha mRNA expression compared with controls. Thus, severe sepsis is associated with a largely unopposed inflammatory response, and a largely unopposed inflammatory response (with anti-IL-10) results in severe sepsis and death. Less severe sepsis is associated with greater anti-inflammatory mediator expression, and greater anti-inflammatory mediator expression (with IL-10) results in less severe sepsis. Thus, the balance of inflammatory mediators is related to the severity and mortality of murine sepsis.
Department of Medicine, The University of Michigan, Ann Arbor 48109, USA.
K R
KR
Walley
N W
NW
Lukacs
T J
TJ
Standiford
R M
RM
Strieter
S L
SL
Kunkel
D000818:Animals; D001202:Ascitic Fluid / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis* / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis*; D008099:Liver / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D010533:Peritoneal Lavage; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000235:genetics
D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10