MULTIPLE SYSTEM ORGAN FAILURE MAY BE INFLUENCED BY MACROPHAGE HYPOACTIVATION AS WELL AS HYPERACTIVATION - IMPORTANCE OF THE DOUBLE CHALLENGE

Objective: To find out if an infective challenge caused by a burn foll owed by caecal ligation and puncture in mice caused more abnormalities of the immune response than burn alone or caecal ligation and punctur e alone. Design: Laboratory study. Setting: University hospital, USA. Material: 80 male 7-8 week old A/J mice. Interventions: Burn followed 10 days later by caecal ligation and puncture (n = 18), caecal ligatio n and puncture alone (n = 24), burn alone (n = 20), and controls (n = 18). The mice had their spleens removed on day 11 (n = 28; 6, 8, 8, an d 6 in the respective groups), day 12 (n = 26; 6, 8, 6, and 6), and da y 13 (n = 26; 6, 8, 6, and 6), and splenocytes and adherent cells were harvested for measurement of prostaglandin E(2) (PGE(2)), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), and tumour necr osis factor alpha (TNF-alpha). Main outcome measures: Alterations in t he production of the cytokines. Results: After the double challenge (b urn followed by caecal ligation and puncture) there were significant r eductions in production of TNF-alpha and IL-6 compared with caecal lig ation and puncture alone (p < 0.05), burn alone (p < 0.05), and contro ls (p < 0.05). These findings indicate that activation of macrophages was reduced after infection; production of TNF-alpha, IL-1, and IL-6 b y splenocytes stimulated by lipopolysaccharide was reduced. Conclusion s: The differences do not seem big enough to indicate that mortality w ould be increased after caecal ligation and puncture alone. Only when there has been a previous injury (which resulted in hyperactivation of macrophages followed by a more pronounced hypoactivation) would morta lity increase. In view of clinical trials with antiendotoxin and antiT NF antibodies that failed to improve survival in infected patients, we suggest that the mechanisms of the cellular immune response need furt her clarification.