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Antitumor necrosis factor therapy in rat chronic granulomatous colitis: critical dose-timing effects on outcome
S Videla1, A García-Lafuente, M Antolín
1Digestive System Research Unit, Department of Pathology, Barcelona, Spain.
Abstract:
Inhibition of tumor necrosis fact (TNFalpha) is of potential benefit in the treatment of chronic inflammatory conditions. However, TNFalpha plays an important role in host defenses against infection, and blocking TNFalpha production may also have adverse effects. We tested the efficacy and safety of anti-TNFalpha therapy in experimental colitis induced by trinitrobenzenesulfonic acid. We cultured colonic wall specimens for bacterial growth and measured native TNFalpha protein synthesis in colonic tissue at days 0, 1, 4, 10 and 18 after induction of colitis. Anti-TNFalpha therapy (monoclonal g1 immunoglobulin, 15 mg/kg i.p., every third day) was started on either day 4 or day 10 after induction of colitis. On day 18, we measured the release of inflammatory mediators and scored colonic lesions. In acute lesions, several species of the common flora were grown, including Streptococcus, Staphylococcus, Bacteroides, clostridia and enterobacteria. In chronic lesions, only enterobacteria, clostridia and lactobacilli were isolated. TNFalpha production by inflamed colonic tissue was increased in both acute and chronic lesions. Anti-TNFalpha therapy induced a significant decrease in the release of inflammatory mediators and histopathological remission when treatment started on day 10. However, anti-TNFalpha therapy increased eicosanoid release and lesion scores when treatment started on day 4. In conclusion, acute colonic lesions showed polymicrobial infection. Anti-TNFalpha therapy induced remission of chronic intestinal inflammation, but early treatment did not prove effective.
Insights
Anti-tumor necrosis factor alpha (TNFalpha) therapy can treat chronic inflammation, but early intervention in experimental colitis worsened outcomes. Later treatment effectively reduced inflammation and promoted remission.
Area of Science:
- Gastroenterology
- Immunology
- Microbiology
Background:
- Tumor necrosis factor alpha (TNFalpha) inhibition shows promise for chronic inflammatory diseases.
- However, TNFalpha is crucial for host defense, and its blockade may cause adverse effects.
- Experimental colitis models are used to evaluate anti-TNFalpha therapy efficacy and safety.
Purpose of the Study:
- To assess the efficacy and safety of anti-TNFalpha therapy in a trinitrobenzenesulfonic acid-induced experimental colitis model.
- To investigate the role of microbial infections in acute and chronic colonic lesions.
- To determine the optimal timing for initiating anti-TNFalpha therapy to achieve remission.
Main Methods:
- Experimental colitis was induced using trinitrobenzenesulfonic acid.
- Colonic specimens were cultured for bacterial identification.
- TNFalpha protein synthesis was measured, and anti-TNFalpha therapy was administered at different time points (day 4 or day 10).
- Inflammatory mediators and lesion scores were evaluated on day 18.
Main Results:
- Acute and chronic colonic lesions exhibited polymicrobial infections, with distinct bacterial profiles.
- TNFalpha production was elevated in both acute and chronic inflamed tissues.
- Anti-TNFalpha therapy initiated on day 10 led to reduced inflammatory mediators and histopathological remission.
- Early treatment (day 4) exacerbated eicosanoid release and lesion severity.
Conclusions:
- Anti-TNFalpha therapy can induce remission in chronic intestinal inflammation.
- The timing of anti-TNFalpha therapy is critical; early intervention in acute colitis may be detrimental.
- Polymicrobial infections are present in acute colonic lesions, highlighting the complexity of the inflammatory process.