Hypercapnia, the elevation of CO2 in blood and tissue, commonly develops in 
patients with advanced lung disease and severe pulmonary infections, and it is 
associated with high mortality. We previously reported that hypercapnia alters 
expression of host defense genes, inhibits phagocytosis, and increases the 
mortality of Pseudomonas pneumonia in mice. However, the effect of hypercapnia 
on autophagy, a conserved process by which cells sequester and degrade proteins 
and damaged organelles that also plays a key role in antimicrobial host defense 
and pathogen clearance, has not previously been examined. In the present study 
we show that hypercapnia inhibits autophagy induced by starvation, rapamycin, 
LPS, heat-killed bacteria, and live bacteria in the human macrophage. Inhibition 
of autophagy by elevated CO2 was not attributable to acidosis. Hypercapnia also 
reduced macrophage killing of Pseudomonas aeruginosa. Moreover, elevated CO2 
induced the expression of Bcl-2 and Bcl-xL, antiapoptotic factors that 
negatively regulate autophagy by blocking Beclin 1, an essential component of 
the autophagy initiation complex. Furthermore, small interfering RNA targeting 
Bcl-2 and Bcl-xL and the small molecule Z36, which blocks Bcl-2 and Bcl-xL 
binding to Beclin 1, prevented hypercapnic inhibition of autophagy and bacterial 
killing. These results suggest that targeting the Bcl-2/Bcl-xL-Beclin 1 
interaction may hold promise for ameliorating hypercapnia-induced 
immunosuppression and improving resistance to infection in patients with 
advanced lung disease and hypercapnia.