Chronic or high dose acute caffeine treatment protects mice against oleic acid-induced acute lung injury via an adenosine A₂A receptor-independent mechanism

• Published in: European journal of pharmacology 2011-03, Vol.654 (3), p.295-303
• Main Authors: Li, Jun, Li, Gongbo, Hu, Jian-Lin, Fu, Xiao-Hong, Zeng, Yi-Jun, Zhou, Yuan-Guo, Xiong, Gang, Yang, Nan, Dai, Shuang-Shuang, He, Feng-Tian
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Acute Lung Injury - prevention & control; adenosine; Animals; antagonists; Biological and medical sciences; caffeine; Caffeine - administration & dosage; Caffeine - pharmacology; Cyclic AMP - metabolism; Cytokines - genetics; Dose-Response Relationship, Drug; Drug Administration Schedule; drugs; edema; gene expression regulation; Gene Expression Regulation - drug effects; hemorrhage; interleukin-1; Lung - drug effects; Lung - immunology; Lung - metabolism; Lung - pathology; lungs; Medical sciences; messenger RNA; Mice; Neutrophil Infiltration - drug effects; Oleic Acid - pharmacology; Pharmacology. Drug treatments; pneumonia; Receptor, Adenosine A2A - metabolism; receptors; tumor necrosis factor-alpha; Water - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.12.040

The antagonism or genetic deletion of adenosine A₂A receptors has been shown to exacerbate tissue damage in acute lung injury. Caffeine, a widely consumed behavioral drug, acts as a non-selective antagonist of A₂A receptor and also has additional pharmacological effects. Thus, the protective vs. deleterious effects of caffeine in acute lung injury should be evaluated. In a murine oleic acid-induced model of acute lung injury, we found that chronic caffeine treatment by drinking water (0.1g/l or 0.25g/l for 2weeks before acute lung injury) or acute caffeine treatment at high dose (i.p. 50mg/kg, injection, 30min before acute lung injury) significantly attenuated the lung edema, hemorrhage, neutrophil recruitment as well as the inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) expressions in both of the wild type (WT) and A₂A receptor knockout (KO) mice. This profile was accompanied by increased cAMP levels and up-regulation of A2B receptor mRNAs in the lungs. In contrast, acute caffeine treatment at low dose (i.p. 5mg/kg or 15mg/kg, injection, 30min before acute lung injury) enhanced the inflammation and lung damage in WT mice with decreasing cAMP but not in A₂A receptor KO mice. These results indicate that caffeine either enhances lung damage by antagonizing A₂A receptor or exerts protection against lung damage via A₂A receptor-independent mechanisms, depending on the timing of exposure (chronic vs. acute) and dose of administration (low vs. high). These findings provide new insight of caffeine in acute lung injury and highlight the potential benefit and strategy of caffeine intake or administration for preventing acute lung injury.