Hypercapnia, the elevation of CO2 in blood and tissues, commonly occurs in 
severe acute and chronic respiratory diseases, and is associated with increased 
risk of mortality. Recent studies have shown that hypercapnia adversely affects 
innate immunity, host defense, lung edema clearance and cell proliferation. 
Airway epithelial dysfunction is a feature of advanced lung disease, but the 
effect of hypercapnia on airway epithelium is unknown. Thus, in the current 
study we examined the effect of normoxic hypercapnia (20% CO2 for 24 h) vs 
normocapnia (5% CO2), on global gene expression in differentiated normal human 
airway epithelial cells. Gene expression was assessed on Affymetrix microarrays, 
and subjected to gene ontology analysis for biological process and 
cluster-network representation. We found that hypercapnia downregulated the 
expression of 183 genes and upregulated 126. Among these, major gene clusters 
linked to immune responses and nucleosome assembly were largely downregulated, 
while lipid metabolism genes were largely upregulated. The overwhelming majority 
of these genes were not previously known to be regulated by CO2. These changes 
in gene expression indicate the potential for hypercapnia to impact bronchial 
epithelial cell function in ways that may contribute to poor clinical outcomes 
in patients with severe acute or advanced chronic lung diseases.