Doxofylline, a novofylline inhibits lung inflammation induced by lipopolysacharide in the mouse

RationalDoxofylline 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.ObjectivesWe have investigated the actions of doxofylline against the effects of Escherichia coli LPS in the lungs of BALB/c mice.MethodsAnimals 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.ResultsDoxofylline 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 × 104 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 μm2). 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 × 104/ml).ConclusionDoxofylline inhibits LPS-induced inflammation in the lungs of mice.