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Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or
M K Eskandari1, G Bolgos, C Miller
1Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Abstract:
Cytokines have been studied intensively to delineate their role in the altered pathophysiology observed in septic shock. We studied the role of TNF in the lethality of two well characterized models of septic shock by inhibiting TNF's activity with a specific antibody. In the first model, sepsis was induced by cecal ligation and puncture (CLP), and in the second model sepsis was induced by either an i.p. or i.v. injection of LPS. After CLP, plasma endotoxin was detectable within 4 h and reached a peak at 8 h (136 +/- 109 ng/ml). TNF bioactivity peaked at 12 h (528 +/- 267 pg/ml) at a significantly higher level than sham-operated control mice (64 +/- 31 pg/ml). After i.p. LPS, TNF peaked much more quickly (90 min) compared with CLP and at a significantly higher level (107,900 +/- 25,000 pg/ml). Another cytokine studied in septic shock, IL-6, peaked at 12 h after CLP at 1011 +/- 431 pg/ml, and at 90 min after lethal LPS at 16,300 +/- 3,700 pg/ml. Mice were treated with an anti-TNF antibody that has been shown previously to inhibit in vivo TNF activity. Antibody treatment of mice subjected to CLP significantly reduced TNF bioactivity but did not reduce mortality or pulmonary neutrophilic infiltration. In the i.v. LPS model, anti-TNF antibody treatment concomitant with LPS injection reduced plasma TNF activity from 80,000 +/- 20,000 pg/ml to undetectable levels. However, anti-TNF treatment immediately before either i.v. or i.p. LPS did not reduce mortality. Additionally, when the antibody was administered 4 h before the lethal i.v. LPS, there was no reduction in lethality. These data show that in two separate models of septic shock blockade of TNF biologic activity will not prevent lethality.
Insights
Blocking tumor necrosis factor (TNF) activity in septic shock models did not prevent mortality. These findings suggest TNF blockade alone is insufficient to treat lethal sepsis.
Area of Science:
- Immunology
- Pathophysiology
- Critical Care Medicine
Background:
- Septic shock involves complex cytokine dysregulation.
- Tumor necrosis factor (TNF) is a key cytokine implicated in septic shock pathophysiology.
- Understanding TNF's role is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of TNF in septic shock lethality.
- To evaluate the efficacy of anti-TNF antibody treatment in reducing mortality in two distinct septic shock models.
Main Methods:
- Two established murine models of septic shock were used: cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection (intraperitoneal or intravenous).
- Mice were treated with a neutralizing anti-TNF antibody.
- Plasma cytokine levels (TNF, IL-6) and mortality rates were measured.
- Pulmonary neutrophilic infiltration was assessed in the CLP model.
Main Results:
- In the CLP model, anti-TNF treatment reduced TNF bioactivity but did not affect mortality or lung inflammation.
- In LPS-induced shock, anti-TNF treatment significantly reduced plasma TNF levels.
- However, anti-TNF administration before or after LPS challenge did not reduce mortality in either LPS model.
Conclusions:
- Blockade of TNF biologic activity is ineffective in preventing lethality in these two models of septic shock.
- TNF may not be a sole determinant of mortality in septic shock.
- Further research is needed to identify alternative therapeutic targets.