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Reduction of Sephadex-induced lung inflammation and bronchial hyperreactivity by rapamycin
J N Francischi1, D M Conroy, S Cloutier
1Department of Pharmacology, Faculty of Medicine of Sherbrooke, Quebec, Canada.
Abstract:
Rapamycin is a macrolide antibiotic whose potent immunosuppressor activity was recently described in vivo and in vitro. The aim of the present work was to determine if rapamycin could affect an established inflammatory response. Conscious pathogen-free Dunkin-Hartley guinea pigs (300-400 g) were injected intravenously with Sephadex beads (G50, superfine, 10 to 40 microns, 24 mg/kg) to induce lung inflammation and bronchial hyperreactivity. Bronchoalveolar lavage (BAL) fluid was collected 2, 12 and 24 h after Sephadex administration and the cells were counted. Bronchial tissue was used to construct dose-response (contraction, g) curves to histamine and acetylcholine 24 h after the Sephadex injection, using a cascade system. Results are presented as area under the log dose-response curves. Test animals were injected with rapamycin (5 mg/kg) or its vehicle by the intramuscular route either 2 or 12 h after Sephadex injection and BAL fluid collected 24 h after Sephadex administration. Rapamycin administration 2 h after Sephadex reduced eosinophil and lymphocyte numbers in BAL by 52 and 55%, respectively, but not ex vivo bronchial hyperreactivity induced by Sephadex injection. However, rapamycin administration 12 h after Sephadex reduced BAL eosinophil and lymphocyte numbers (55 and 62%, respectively) and bronchial hyperreactivity. The increase in neutrophil numbers in BAL induced by Sephadex injection was not modified by rapamycin. Since lymphocyte numbers in BAL were significantly increased in Sephadex-treated animals at 12 h but not at 2 h after Sephadex injection, the present results suggest that the inhibition of bronchial hyperreactivity by rapamycin may be dependent on the presence of lymphocytes elicited into the airways by Sephadex injection.
Insights
Rapamycin reduced airway inflammation and hyperreactivity when administered 12 hours after Sephadex-induced lung inflammation in guinea pigs. This effect appears linked to rapamycin
Area of Science:
- Immunology
- Pharmacology
- Respiratory Medicine
Background:
- Rapamycin is a macrolide antibiotic with known immunosuppressive properties.
- Inflammatory responses and bronchial hyperreactivity are key features of respiratory diseases.
- The effect of rapamycin on established inflammatory conditions requires further investigation.
Purpose of the Study:
- To investigate the impact of rapamycin on established lung inflammation and bronchial hyperreactivity.
- To determine the optimal timing for rapamycin intervention in an inflammatory model.
- To explore the cellular mechanisms underlying rapamycin's effects on airway inflammation.
Main Methods:
- Sephadex beads were used to induce lung inflammation and bronchial hyperreactivity in guinea pigs.
- Bronchoalveolar lavage (BAL) was performed to analyze cellular infiltration.
- Rapamycin was administered at different time points (2h and 12h post-Sephadex) to assess its efficacy.
- Ex vivo bronchial reactivity to histamine and acetylcholine was measured.
Main Results:
- Rapamycin administration 2 hours post-Sephadex reduced eosinophils and lymphocytes in BAL fluid but did not affect bronchial hyperreactivity.
- Rapamycin administration 12 hours post-Sephadex significantly reduced BAL eosinophils and lymphocytes and also attenuated bronchial hyperreactivity.
- Neutrophil counts in BAL fluid were not altered by rapamycin treatment.
- Lymphocyte infiltration correlated with the observed inhibition of bronchial hyperreactivity.
Conclusions:
- Rapamycin can effectively reduce established lung inflammation and bronchial hyperreactivity in a guinea pig model.
- The therapeutic efficacy of rapamycin in this model is time-dependent, with later administration being more effective.
- The data suggest that rapamycin's ability to inhibit bronchial hyperreactivity may be mediated by its effects on lymphocytes.