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Departments of 1 Anesthesiology, 2 Biochemistry and Molecular Genetics, and 3 Pharmacology and 4 The Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35233-4234
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.
carbon dioxide; nitration; inflammation; superoxide; free radical; peroxynitrite
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