The aim of this study was to assess if one of the most common poisons of cellular respiration, i.e., carbon dioxide, is pro-inflammatory. CO2 is naturally present in the atmosphere at the level of 0.038% and involved in numerous cellular biochemical reactions. We analyzed in vitro the inflammation response induced by exposure to CO₂ for 48 hours (0 to 20%, with a constant O₂ concentration of 21%). In vivo, mice were submitted to increasing concentrations of CO₂ (0, 5, 10, 15% with a constant O₂ concentration of 21%) for one hour. The exposure to concentrations above 5% of CO₂ resulted in the increased transcription (Rnase protection assay) and secretion (Enzyme-Linked ImmunoSorbent Assay) of pro-inflammatory cytokines (Macrophage Inflammatory Protein-1 and , MIP-2, Interleukin-8, Monocyte Chemoattractant Protein-1, Interleukin-6, and RANTES - Regulated upon Activation, Normal T-cell Expressed, and Secreted) by epithelial cell lines HT-29 or A549 and primary pulmonary cells retrieved from the exposed mice. Lung inflammation was also demonstrated in vivo by mucin 5A/C enhanced production and airway hyperreactivity induction. This response was mostly mediated by the nuclear translocation of p65 Nuclear Factor kappa-B (NF-B), itself a consequence of Protein Phosphatase 2A (PP2A) activation. Short inhibiting RNAs (siRNAs) targeted toward PP2Ac reversed the effect of carbon dioxide, i.e., disrupted the NF-B activation and the pro-inflammatory cytokine secretion. In conclusion, this study strongly suggests that exposure to carbon dioxide may be more toxic than previously thought. This may be relevant for carcinogenic effects of combustion products.