| 11 th Annual Pediatric Critical Care Colloquium |
| Session/Time | Cell Physiology/Sepsis/Sat, 8:00 - 9:30 AM |
| Title | Protection From Sepsis is Mediated by, But Not Limited To, Interleukin 10 (IL-10) |
| Author | SQ, Latif, MD; AD Levine, PhD |
| Affiliation | Departments of Pediatrics and Medicine, Case Western Reserve University School of Medicine, Cleveland, OH |
| Introduction | Sepsis and the ensuin- systemic inflammatory response syndrome (SIRS) mediated by pro- inflammatory cytokines are a major cause of mortality in the PICU. The anti-inflammatory cytokine IL-10 is hi-hly protective in a murine model of acute endotoxemia induced by lipopolysaccharide (LPS), but its role in clinically relevant models of sepsis is unclear. |
| Method | Systemic inflammation was induced by cecal lioation and puncture (CLP) in C57BL/10 mice genetically engineered- for IL-10 deficiency (IL-10+-) and wild type littermates (IL-10+-). Disease progression was evaluated by clinical sions of sepsis (piloerection, tremor, tachypnea, periorbitat exudates, lethargy) and survival. Serum cytokine levels were measured by ELISA. In some experiments the necrotic cecum was removed. |
| Result | After CLP all mice.manifested clinical si-ns of sepsis in a dose dependent (i.e. puncture size) fashion. Forty hours after insult survival in IL-10-1- mice was 33% and in IL-10"' mice 58%. By 120 h survival was 0% in IL- 10+- mice and 17% in IL-10+- mice. Serum levels of TNF(X were barely detectable in IL-10" mice at all times. However, IL-6 and IL-10 serum levels increased rapidly within 5 h after CLP. By 40 h IL-6 levels remained elevated, whereas IL-10 levels declined. IL-10+- mice exhibited identical kinetics for TNFA and IL-6 for the first 20 h, but then diver-ed with dramatic sustained increases in both cytokines until death at 40 h. IL-10+- mice survived if the cecum was removed within 10 h, but not 20 h after CLP. By contrast IL-10+- mice showed 100% su,.rvival with cecal removal at both 10 and 20 h. Conclusion: IL-10 provides limited protection from mortality after CLP, a clinically relevant r,-iodel of sepsis. However, the anti-inflammatory activities of IL-10 vere still observed in the CLP model as evidenced by the increased production from 20 to 40 h of TNF(X and IL-6 in IL-10+- mice as compared to IL-10+- mice. The findin- that moribund IL-10+- mice can survive CLP by the removal of damaaed tissue at 10 h shows that systemic inflammation is 'ble in the absence of.IL-10. Lack of survival in IL-10+- mice after cecal removil at 20 h is associated Nvith draniaticilly h i -her serum concentrations of TNFct anci IL-6 and sucycyests that |
| Conclusion | IL-10 provides limited protection from mortality after CLP, a clinically relevant model of sepsis. However, the anti-inflammatory activities of IL-10 were still observed in the CLP model as evidenced bu theincreased production from 20 to 40 h of TNFa and IL-6 in IL-10 mice as compared to IL-10 mice. The finding that moriund IL-10 mice can survive CLP y the removal of damaged tissue at 10 h shows that systemic inflammations is reversible in the absence of Il-10. Lack of survival in IL-10 mice after cecal removal at 20 h is associated with dramatically higher serum concentrations of TNFa and Il-6 and suggests that IL-10 may be of greater importance later in the inflammation. |
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