The toxicity of carbon dioxide inhalation

Carbon dioxide (CO(2)) is naturally present in the atmosphere where its concentration is about 0.038%. It is also a normal constituent of the body arising from cellular respiration or taking part in several metabolic reactions. CO2 is also one of the main side-products of combustion, and in particular of cigarette smoking. Analysis of primary tobacco smoke demonstrates the presence of a high concentration at 13.5% CO(2). We designed a study to assess if CO(2), either obtained from gas canister or from cigarette combustion, is pro-inflammatory. We analyzed in vitro the inflammation response induced by exposure to CO(2) for 48 hours (0 to 20% with a constant O(2) concentration of 21%). In addition, we carried out an in vivo experiment where mice were submitted to increasing concentrations of CO(2) (0, 5, 10, 15% with a constant O(2) concentration of 21%) for one hour. The exposure to concentrations above 5% of CO(2) resulted in the dose-dependent secretion of pro-inflammatory cytokines by A549 cells and pulmonary cells retrieved from the exposed mice as demonstrated by ELISA. Lung inflammation was also demonstrated in vivo by airway hyperreactivity induction pointed out by plethysmography. This response was mediated by the nuclear translocation of p65 Nuclear Factor kappa-B (NF-kappa B), itself a consequence of Protein Phosphatase 2A (PP2A) activation. Short inhibiting RNAs (siRNAs) targeted toward catalitic subunit PP2Ac prevented the effect of CO(2), i.e. disrupted the NF-kappa B activation and the pro-inflammatory cytokine secretion. Thus, in vivo or in vitro exposure to high CO(2) concentrations leads to an inflammation response mediated by the PP2A/NF-kappa B pathway. These results strongly suggest that exposure to carbon dioxide may be more toxic than previously thought. Because of the described relationship inbetween inflammation and cancer this data may be relevant for carcinogenic effects of combustion products such as those of tobacco. Eur. J. Oncol., 14 (4), 199208, 2009