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Suppression of pulmonary granulomatous inflammation by immunomodulating agents
M Hashimoto1, K Kobayashi, N Yamagata
1First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Abstract:
We demonstrated previously that macrophages and macrophage-derived cytokines including lymphocyte-activating factors (LAFs) play a critical role in lung granuloma formation in mice and that granulomas sizes correlated with LAF activity in the lesions. In the present study, we examined the effects of D-penicillamine (D-Pc), 2-acetylthiomethyl-3-(4-methyl-benzoyl)propionic acid (KE-298) and dexamethasone (Dex) on dextran bead-induced lung granulomas in mice. KE-298 is a newly synthesized compound containing sulfur (S) similar to D-Pc. Large granulomas developed, which reached peak intensity within 3 days and declined in size thereafter. Aqueous lung extracts of the mice contained high levels of LAF that were correlated with granuloma sizes. The lesions and local LAF activity were inhibited by administration of these agents. The most potent inhibitor was Dex. The suppressive effect of KE-298 was similar to that of D-Pc. These results suggest that suppression of granulomas may be attributed to inhibition of LAF activity/synthesis by these agents.
Insights
This study shows that D-penicillamine, KE-298, and dexamethasone reduce lung granuloma size in mice by inhibiting lymphocyte-activating factors (LAFs). These findings suggest LAF inhibition as a therapeutic strategy for granulomatous diseases.
Area of Science:
- Immunology
- Pharmacology
Background:
- Macrophages and lymphocyte-activating factors (LAFs) are crucial for lung granuloma formation.
- Granuloma size in mice correlates with local LAF activity.
Purpose of the Study:
- To investigate the effects of D-penicillamine (D-Pc), KE-298, and dexamethasone (Dex) on dextran bead-induced lung granulomas in mice.
- To assess the impact of these agents on LAF activity within lung granulomas.
Main Methods:
- Induction of lung granulomas in mice using dextran beads.
- Administration of D-Pc, KE-298, and Dex to treated groups.
- Measurement of granuloma size and LAF levels in lung extracts.
Main Results:
- D-Pc, KE-298, and Dex significantly inhibited lung granuloma formation and size.
- LAF levels in lung extracts were positively correlated with granuloma size.
- Dexamethasone was the most potent inhibitor, while KE-298 showed effects similar to D-Pc.
Conclusions:
- Suppression of lung granulomas by D-Pc, KE-298, and Dex is likely mediated by the inhibition of LAF activity or synthesis.
- These findings suggest potential therapeutic targets for managing granulomatous conditions.