Chronic or high dose acute caffeine treatment protects mice against oleic acid-induced acute lung injury via an adenosine A2A receptor-independent mechanism.
The antagonism or genetic deletion of adenosine A(2A) 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 A(2A) 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 2 weeks 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 A(2A) 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 A(2A) receptor KO mice. These results indicate that caffeine either enhances lung damage by antagonizing A(2A) receptor or exerts protection against lung damage via A(2A) 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.
Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Jun
J
Li
Gongbo
G
Li
Jian-Lin
JL
Hu
Xiao-Hong
XH
Fu
Yi-Jun
YJ
Zeng
Yuan-Guo
YG
Zhou
Gang
G
Xiong
Nan
N
Yang
Shuang-Shuang
SS
Dai
Feng-Tian
FT
He
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D019301:Oleic Acid / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D014867:Water / Q000378:metabolism
D016207:Cytokines; D043705:Receptor, Adenosine A2A; D014867:Water; D019301:Oleic Acid; D002110:Caffeine; D000242:Cyclic AMP