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

John D. Lang, Phillip Chumley, Jason P. Eiserich, Alvaro Estevez, Thad Bamberg, Ahmad Adhami, John Crow, Bruce A. Freeman

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Ventilator strategies allowing for increases in carbon dioxide (CO2) tensions (hypercapnia) are being emphasized to ameliorate the consequences of inflammatory-mediated lung injury. Inflammatory responses lead to the generation of reactive species including superoxide (O2/-), nitric oxide (·NO), and their product peroxynitrite (ONOO-). The reaction of CO2 and ONOO- can yield the nitrosoperoxocarbonate adduct ONOOCO2/-, a more potent nitrating species than ONOO-. Based on these premises, monolayers of fetal rat alveolar epithelial cells were utilized to investigate whether hypercapnia would modify pathways of ·NO production and reactivity that impact pulmonary metabolism and function. Stimulated cells exposed to 15% CO2 (hypercapnia) revealed a significant increase in ·NO production and nitric oxide synthase (NOS) activity. Cell 3-nitrotyrosine content as measured by both HPLC and immunofluorescence staining also increased when exposed to these same conditions. Hypercapnia significantly enhanced cell injury as evidenced by impairment of monolayer barrier function and increased induction of apoptosis. These results were attenuated by the NOS inhibitor N-monomethyl-L-arginine. Our studies reveal that hypercapnia modifies ·NO-dependent pathways to amplify cell injury. These results affirm the underlying role of ·NO in tissue inflammatory reactions and reveal the impact of hypercapnia on inflammatory reactions and its potential detrimental influences.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number5 23-5
StatePublished - 2000
Externally publishedYes


  • Carbon dioxide
  • Free radical
  • Inflammation
  • Nitration
  • Peroxynitrite
  • Superoxide

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology
  • Physiology (medical)


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