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The role of tumor necrosis factor in the development of multiple organ failure in a murine model
D Burdon1, T Tiedje, K Pfeffer
1Research Center Borstel, Medical Clinic, Technical University of Munich, Germany. dhburdon@aol.com
Objective:
To elucidate the role of tumor necrosis factor (TNF) in the development of multiple organ dysfunction syndrome (MODS) after zymosan-induced peritonitis in mice.
Design:
Prospective controlled laboratory study on zymosan-induced generalized inflammation in mice. Over < or =28 days, a single intraperitoneal administration of zymosan induced a three-phase illness in C57BL mice, rendering them very ill with MODS-like symptoms from day 7 onward. Additionally, the same experiment was performed on C57BL/6 TNF-Rc-p55 knockout mice to elucidate the role of TNF and its receptor p55.
Setting:
Animal research laboratory.
Subjects:
Inbred C57BL mice and C57BL p55-/- mice received a single sterile intraperitoneal injection of zymosan suspended in paraffin oil (0.75 mg/g of body weight).
Measurements And Main Results:
The animals were monitored for survival, condition, and body weight for < or =28 days. At 3, 7, 14, and 28 days after zymosan administration, bronchoalveolar lavage was performed and lungs and livers were extracted for isolation of RNA and histopathologic evaluation. Reverse-transcriptase-polymerase chain reaction was performed to quantify TNF-alpha messenger RNA (mRNA) in the respective organs. Both animal strains went through initial shock with a high mortality rate during the first 3 days. The C57BL mice developed MODS with typical symptoms and histopathologic results correlating with excessive TNF-alpha mRNA expression from day 7 onward. In contrast, no disease, histopathologic changes, nor TNF-alpha mRNA expression in liver or lung was found within the TNF-Rc-p55-/- mice.
Conclusion:
Organ-derived TNF-alpha plays a crucial role in the development of MODS in this murine model.
Insights
Tumor necrosis factor-alpha (TNF-alpha) is critical for developing multiple organ dysfunction syndrome (MODS) in a mouse model of peritonitis. Blocking TNF-alpha signaling prevented MODS development and associated organ damage.
Area of Science:
- Immunology and Inflammation Research
- Pathophysiology of Organ Dysfunction
- Animal Models of Disease
Background:
- Multiple organ dysfunction syndrome (MODS) is a severe complication following inflammatory conditions like peritonitis.
- Tumor necrosis factor-alpha (TNF-alpha) is a key pro-inflammatory cytokine implicated in various disease processes.
Purpose of the Study:
- To investigate the specific role of TNF-alpha in the pathogenesis of MODS induced by zymosan peritonitis in a murine model.
- To determine the involvement of the TNF-alpha p55 receptor in mediating MODS development.
Main Methods:
- A prospective, controlled laboratory study using C57BL mice and C57BL/6 TNF-receptor p55 knockout mice.
- Zymosan-induced peritonitis was administered intraperitoneally to establish a model of generalized inflammation and MODS.
- Mice were monitored for survival, clinical signs, and body weight over 28 days; organ tissues (lungs, liver) were analyzed for histopathology and TNF-alpha mRNA expression.
Main Results:
- Zymosan administration induced a three-phase illness, leading to MODS-like symptoms and high mortality in wild-type C57BL mice from day 7 onwards.
- Significant increases in TNF-alpha mRNA expression were observed in the lungs and livers of C57BL mice correlating with MODS development.
- TNF-receptor p55 knockout mice exhibited no significant disease, histopathologic changes, or elevated TNF-alpha mRNA, indicating a protective effect.
Conclusions:
- Organ-derived TNF-alpha plays a critical and indispensable role in the development of MODS in this zymosan-induced peritonitis mouse model.
- Targeting the TNF-alpha pathway, specifically via the p55 receptor, could be a potential therapeutic strategy for preventing MODS.
