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The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir induce apoptosis and decrease barrier function in
Hagen Bode1, Luzie Lenzner, Oliver Holger Kraemer
1Department of Gastroenterology/Infectious Diseases, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany. hagen.bode@charite.de
Antiviral Therapy
|September 13, 2005
Summary
HIV protease inhibitors (PIs) cause diarrhoea by inducing apoptosis in intestinal cells, not necrosis or tight junction issues. This cell death mechanism may offer new avenues for cancer therapy.
Area of Science:
- Gastroenterology
- Pharmacology
- Cell Biology
Background:
- Diarrhoea is a common side effect of HIV protease inhibitors (PIs).
- Intestinal barrier disruption is a suspected cause of PI-induced diarrhoea.
- The specific mechanisms of epithelial damage, including tight junction integrity, apoptosis, and necrosis, were unclear.
Purpose of the Study:
- To investigate the mechanisms behind HIV protease inhibitor (PI)-induced intestinal epithelial damage.
- To determine if tight junction dysregulation, apoptosis, or necrosis are responsible for this damage.
Main Methods:
- HT-29/B6 colon cell monolayers were treated with saquinavir, nelfinavir, and ritonavir.
- Epithelial barrier function was assessed by measuring transepithelial resistance.
- Apoptosis and necrosis were quantified using nucleosome ELISA and LDH measurements, respectively.
- Tight junction components (occludin, zonula occludens-1) were analyzed via Western blot.
- Apoptosis induction in human intestinal explants was evaluated by detecting PARP cleavage.
Main Results:
- HIV PIs significantly decreased transepithelial resistance by over 44%.
- Massive apoptotic body formation was observed, with nucleosome levels increasing up to 22-fold.
- No evidence of necrosis was found, as indicated by low LDH release.
- Expression of tight junction proteins occludin and zonula occludens-1 remained unchanged.
- PARP cleavage, a marker of apoptosis, increased in human intestinal tissue treated with PIs.
Conclusions:
- HIV PI-induced intestinal barrier disruption is primarily caused by massive apoptosis, not necrosis or tight junction alterations.
- This apoptosis induction in intestinal epithelial cells may lead to leak-flux diarrhoea in vivo.
- The findings suggest potential therapeutic applications of PI-induced apoptosis in anticancer strategies.