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Modulation of oxazolone-induced hypersensitivity in mice by selective PDE inhibitors
I Moodley1, Y Sotsios, B Bertin
1Institut de Recherche Jouveinal 9 rue de la Loge Fresnes Cedex 94265 France.
Abstract:
The effects of PDE inhibitors on oxazolone-induced contact hypersensitivity (CS) were studied in mice. Rolipram, Ro 20-1724 and theophylline dose dependently inhibited CS but none caused >53% inhibition. ED(30) values at 24 h before challenge for rolipram, Ro 20-1724 and theophylline were 2.1, 5.4 and 30.4 mg/kg, p.o., respectively. Milrinone and SKF 94836 at 30 mg/kg caused a small, but significant inhibition of 13% and 18%, respectively, although the inhibition (8%) caused by zaprinast was not significant. Betamethasone (10 mg/kg, p.o.) caused a marked inhibition (80%) as did indomethacin (65% at 5 mg/kg, p.o.). Rolipram and Ro 20-1724 inhibited proliferation of mouse lymphoblasts with IC(50) values of 0.08 muM and 0.83 muM, respectively. In contrast, zaprinast caused only a weak inhibition (IC(50) = 119 muM) of lymphocyte proliferation, whereas SKF 94836 and theophylline failed to cause any significant inhibition at 100 muM (26% and 2%, respectively). These findings suggest that PDE IV isozymes play a principal role in mediating CS by inhibiting lymphocyte activation.
Insights
Phosphodiesterase (PDE) inhibitors, including rolipram and Ro 20-1724, demonstrated dose-dependent inhibition of contact hypersensitivity (CS) in mice. These findings suggest PDE IV isozymes are key mediators in CS by suppressing lymphocyte activation.
Area of Science:
- Immunology
- Pharmacology
Background:
- Contact hypersensitivity (CS) is an immune response mediated by T-cells.
- Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways involved in immune cell activation.
Purpose of the Study:
- To investigate the efficacy of various PDE inhibitors in modulating oxazolone-induced contact hypersensitivity in a murine model.
- To assess the impact of PDE inhibitors on lymphocyte proliferation.
Main Methods:
- Mice were treated with different PDE inhibitors (e.g., rolipram, Ro 20-1724, theophylline, milrinone, SKF 94836, zaprinast) prior to oxazolone challenge to measure CS inhibition.
- In vitro assays were performed to determine the IC(50) values of selected PDE inhibitors against mouse lymphoblast proliferation.
Main Results:
- Rolipram, Ro 20-1724, and theophylline dose-dependently inhibited CS, with ED(30) values of 2.1, 5.4, and 30.4 mg/kg, respectively.
- Rolipram and Ro 20-1724 significantly inhibited lymphocyte proliferation (IC(50) = 0.08 µM and 0.83 µM, respectively).
- Other PDE inhibitors showed varying degrees of inhibition, with betamethasone and indomethacin serving as positive controls.
Conclusions:
- PDE IV isozymes appear to play a significant role in mediating contact hypersensitivity.
- Inhibition of PDE IV may represent a therapeutic strategy for managing T-cell-mediated inflammatory conditions like CS.
