Background
Lower respiratory tract infections are the cause of septic shock in 25% of patients. Telithromycin (TEL), the first ketolide antibiotic, is used for treatment of respiratory infections. TEL is a semisynthetic derivative of the macrolide erythromycin. Beyond their antimicrobial activity, macrolides display immunomodulatory effects, including the inhibition of inflammatory reactions. In the present study, we demonstrate the anti-inflammatory effects of TEL on a septic shock model and a respiratory inflammation model in mice.
Materials and methods
TEL was a gift from Aventis Pharma (Neuville-sur-Saonc, France). Lipopolysaccharide (LPS) from Escherichia coli O26:B6 was purchased from Sigma Chemical Co. (St Louis, MO, USA). BALB/c female mice (10–12 weeks old) were maintained in the facilities of the University of Granada. To induce septic shock, mice were injected intraperitoneally with a dose of 50 mg LPS/kg body weight. To induce respiratory inflammation, mice were exposed for 20 minutes to aerosolized LPS (500 μg/ml saline) in a chamber connected to an air nebulizer (Miko, CA-MI s.n.c., Italy). To investigate the effects of TEL, mice received a single dose of 20 mg ketolide/kg body weight by intraperitoneal injection, 1 hour prior to the administration of LPS. Heparinized blood samples were centrifuged, and plasma was stored at -20°C until cytokine determination. To obtain bronchoalveolar lavage (BAL) fluids, the lungs were lavaged with 1 ml phosphate-buffered saline through an intratracheal catheter. Enzyme immunoassays kits were use to determine TNFα (Pierce Endogen, Rockford, IL, USA) and macrophage inflammatory peptide 2 (MIP-2) (R&D Systems, Minneapolis, MN, USA). The differences in cytokine levels were analyzed using Student's t test. P < 0.05 was considered significant.
Results
When mice were intraperitoneally challenged with a lethal dose of LPS, TEL protected 50% of animals and significantly reduced the plasma levels of TNFα at 2 hours after LPS administration. In the respiratory inflammation model, the treatment with TEL significantly reduced the BAL levels of TNFα and MIP-2 at 4 hours post endotoxin (Table 1).
Table 1.
Effect of telithromycin on cytokine levels in bronchoalveolar lavage and plasma in a mouse respiratory inflammation model
| Treatment | TNFα in BAL (pg/ml) | MIP-2 in BAL (pg/ml) | MIP-2 in plasma (pg/ml) |
|---|---|---|---|
| None | 11 ± 6 | 41 ± 3 | 1 ± 4 |
| TEL | 9 ± 4 | 28 ± 2 | 0 ± 0 |
| LPS | 2846 ± 369 | 1637 ± 254 | 40 ± 10 |
| TEL + LPS | 1279 ± 285a | 1020 ± 240b | 24 ± 5c |
aP < 0.005, significantly different from mice treated with LPS alone.
bP < 0.001, significantly different from mice treated with LPS alone.
cP < 0.05, significantly different from mice treated with LPS alone.
Conclusion
TEL exerts anti-inflammatory activity in vivo that may contribute to its pharmacological effectiveness in the treatment of respiratory infections and their possible progression to septic shock.