Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway

Ventilator strategies allowing for increases in carbon dioxide (CO2) tensio ns (hypercapnia) are being emphasized to ameliorate the consequences of inf lammatory-mediated lung injury. Inflammatory responses lead to the generati on of reactive species including superoxide (O-2(-)), nitric oxide (. NO), and their product peroxynitrite (ONOO-). The reaction of CO2 and ONOO- can yield the nitrosoperoxocarbonate adduct ONOOCO2-, a more potent nitrating s pecies than ONOO-. Based on these premises, monolayers of fetal rat alveola r epithelial cells were utilized to investigate whether hypercapnia would m odify pathways of . NO production and reactivity that impact pulmonary meta bolism and function. Stimulated cells exposed to 15% CO2 (hypercapnia) reve aled a significant increase in . NO production and nitric oxide synthase (N OS) activity. Cell 3-nitrotyrosine content as measured by both HPLC and imm unofluorescence staining also increased when exposed to these same conditio ns. Hypercapnia significantly enhanced cell injury as evidenced by impairme nt of monolayer barrier function and increased induction of apoptosis. Thes e results were attenuated by the NOS inhibitor N-monomethyl-L-arginine. Our studies reveal that hypercapnia modifies . NO-dependent pathways to amplif y cell injury. These results affirm the underlying role of . NO in tissue i nflammatory reactions and reveal the impact of hypercapnia on inflammatory reactions and its potential detrimental influences.