Yanira Riffo-Vasquez1, Francis Man2, Clive P Page2. 1. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, UK. Electronic address: yanira.vasquez@kcl.ac.uk. 2. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, UK.
Abstract
RATIONAL: 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. OBJECTIVES: 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). CONCLUSION: Doxofylline inhibits LPS-induced inflammation in the lungs of mice.
RATIONAL: 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. OBJECTIVES: We have investigated the actions of doxofylline against the effects of Escherichia coliLPS 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). CONCLUSION:Doxofylline inhibits LPS-induced inflammation in the lungs of mice.
Authors: Dingxin Pan; Richard T Amison; Yanira Riffo-Vasquez; Domenico Spina; Simon J Cleary; Michael J Wakelam; Clive P Page; Simon C Pitchford; Heidi C E Welch Journal: Blood Date: 2014-12-23 Impact factor: 22.113