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Multiple system organ failure may be influenced by macrophage hypoactivation as well as hyperactivation--importance
R G Holzheimer1, R Molloy, M V Mendez
1Department of Surgery, Brigham and Womens Hospital, Harvard University Medical School, Boston, MA, USA.
Objective:
To find out if an infective challenge caused by a burn followed by caecal ligation and puncture in mice caused more abnormalities of the immune response than burn alone or caecal ligation and puncture 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 ligation 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, and 6 in the respective groups), day 12 (n = 26; 6, 8, 6, and 6), and day 13 (n = 26; 6, 8, 6, and 6), and splenocytes and adherent cells were harvested for measurement of prostaglandin E2 (PGE2), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), and tumour necrosis factor alpha (TNF-alpha).
Main Outcome Measures:
Alterations in the production of the cytokines.
Results:
After the double challenge (burn followed by caecal ligation and puncture) there were significant reductions in production of TNF-alpha and IL-6 compared with caecal ligation and puncture alone (p < 0.05), burn alone (p < 0.05), and controls (p < 0.05). These findings indicate that activation of macrophages was reduced after infection; production of TNF-alpha, IL-1, and IL-6 by splenocytes stimulated by lipopolysaccharide was reduced.
Conclusions:
The differences do not seem big enough to indicate that mortality would 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 mortality increase. In view of clinical trials with antiendotoxin and antiTNF antibodies that failed to improve survival in infected patients, we suggest that the mechanisms of the cellular immune response need further clarification.
Insights
A combined burn and infection challenge in mice significantly reduced immune response cytokines like tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). This suggests a complex immune suppression following severe injury, requiring further investigation into cellular mechanisms.
Area of Science:
- Immunology
- Sepsis Research
- Burn Injury Research
Background:
- Severe injuries like burns can predispose individuals to secondary infections.
- Understanding the immune response to combined insults is crucial for improving patient outcomes.
- Previous studies have shown altered cytokine profiles in sepsis and burn models.
Purpose of the Study:
- To investigate the impact of a sequential burn and caecal ligation and puncture (CLP) challenge on the murine immune response.
- To compare the immune abnormalities induced by combined injury versus single insults (burn or CLP alone).
- To analyze alterations in cytokine production, including TNF-alpha, IL-1, IL-2, and IL-6.
Main Methods:
- A murine model involving burn injury followed by CLP was utilized.
- Groups included combined burn-CLP, CLP alone, burn alone, and controls.
- Splenocytes were harvested at specific time points post-injury for cytokine analysis.
Main Results:
- The combined burn-CLP group exhibited significantly reduced production of TNF-alpha and IL-6 compared to single-insult groups and controls.
- These findings suggest a suppressed macrophage activation and reduced splenocyte cytokine production following the double challenge.
- Specific reductions were observed in TNF-alpha, IL-1, and IL-6 production when splenocytes were stimulated.
Conclusions:
- The immune response alterations following combined burn and CLP do not appear to significantly increase mortality on their own.
- A prior injury leading to macrophage hyperactivation followed by hypoactivation may be necessary to increase mortality.
- Further research into the cellular immune response mechanisms is needed, especially in light of failed clinical trials with antiendotoxin and anti-TNF therapies.
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