Hypercapnia, an elevation of the level of carbon dioxide (CO2) in blood and 
tissues, is a marker of poor prognosis in chronic obstructive pulmonary disease 
and other pulmonary disorders. We previously reported that hypercapnia inhibits 
the expression of TNF and IL-6 and phagocytosis in macrophages in vitro. In the 
present study, we determined the effects of normoxic hypercapnia (10% CO2, 21% 
O2, and 69% N2) on outcomes of Pseudomonas aeruginosa pneumonia in BALB/c mice 
and on pulmonary neutrophil function. We found that the mortality of P. 
aeruginosa pneumonia was increased in 10% CO2-exposed compared with air-exposed 
mice. Hypercapnia increased pneumonia mortality similarly in mice with acute and 
chronic respiratory acidosis, indicating an effect unrelated to the degree of 
acidosis. Exposure to 10% CO2 increased the burden of P. aeruginosa in the 
lungs, spleen, and liver, but did not alter lung injury attributable to 
pneumonia. Hypercapnia did not reduce pulmonary neutrophil recruitment during 
infection, but alveolar neutrophils from 10% CO2-exposed mice phagocytosed fewer 
bacteria and produced less H2O2 than neutrophils from air-exposed mice. 
Secretion of IL-6 and TNF in the lungs of 10% CO2-exposed mice was decreased 7 
hours, but not 15 hours, after the onset of pneumonia, indicating that 
hypercapnia inhibited the early cytokine response to infection. The increase in 
pneumonia mortality caused by elevated CO2 was reversible when hypercapnic mice 
were returned to breathing air before or immediately after infection. These 
results suggest that hypercapnia may increase the susceptibility to and/or 
worsen the outcome of lung infections in patients with severe lung disease.