Doxofylline, a novofylline inhibits lung inflammation induced by lipopolysacharide in the mouse.
BACKGROUND
Doxofylline is a xanthine drug that has been used as a treatment for respiratory diseases for more than 30 years. In addition to doxofylline being a bronchodilator, some studies have indicated that doxofylline also has anti-inflammatory properties, although little is known about the effect of this drug on lung inflammation.


OBJECTIVE
We have investigated the actions of doxofylline against the effects of Escherichia coli LPS in the lungs of BALB/c mice.


METHODS
Animals have been treated with doxofylline (0.1, 0.3 and 1 mg/kg i.p.) 24, -and 1 h before, and 6 h after intra-nasal instillation of LPS (10 μg/mouse). Readouts were performed 24 h later.


RESULTS
Doxofylline at 1 and 0.3, but not at 0.1 mg/kg, significantly inhibit neutrophil recruitment to the lung induced by LPS (LPS: 208.4 ± 14.5 versus doxofylline: 1 mg/kg: 106.2 ± 4.8; 0.3 mg/kg: 105.3 ± 10.7 × 10(4) cells/ml). Doxofylline significantly inhibited IL-6 and TNF-α release into BAL fluid in comparison to LPS-treated animals (LPS: 1255.6 ± 143.9 versus doxofylline 1 mg/kg: 527.7 ± 182.9; 0.3 mg/kg: 823.2 ± 102.3 pg/ml). Intra-vital microscopy of the tracheal tissue demonstrated that doxofylline significantly reduced LPS-mediated leukocyte adhesion to the vessel wall (LPS: 5.9 ± 2.4 versus doxofylline 0.3 mg/kg: 1.78 ± 0.87 cells/100 μm/15 s). Similarly, intra-vital microscopy of cremaster muscle demonstrated that doxofylline significantly reduced LPS-mediated leukocyte transmigration across the blood vessel wall (LPS: 9.3 ± 3.5 versus doxofylline0.3 mg/kg: 3.1 ± 1.87 cells/100 μm(2)). Doxofylline (0.1-10 μM) also reduced fMLP-induced leukocyte migration in vitro, achieving a maximum effect at 10 μM (fMLP: 37.8 ± 0.5 versus doxofylline 10 μM: 15.1 ± 1.2 cells × 10(4)/ml).


CONCLUSIONS
Doxofylline inhibits LPS-induced inflammation in the lungs of mice.
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, UK. Electronic address: yanira.vasquez@kcl.ac.uk.
Yanira
Y
Riffo-Vasquez
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, UK.
Francis
F
Man
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, UK.
Clive P
CP
Page
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000188:drug therapy* / Q000503:physiopathology; D013806:Theophylline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D008070:Lipopolysaccharides; D013806:Theophylline; C029797:doxofylline
Doxofylline; Inflammation; LPS; Lung; Mice; Neutrophils