Volume 11 Supplement 4

Sepsis 2007

Open Access

Inhibition by telithromycin of systemic and respiratory inflammation induced by endotoxin in mice

  • Magdalena Leiva1,
  • Alfonso Ruiz-Bravo1 and
  • Maria Jimenez Valera1
Critical Care200711(Suppl 4):P28

https://doi.org/10.1186/cc6007

Published: 26 September 2007

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.

Authors’ Affiliations

(1)
Department of Microbiology, University of Granada

Copyright

© BioMed Central Ltd 2007

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