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from alveolar macrophages
is blunted by glycine
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Glycine blunts lipopolysaccharide (LPS)-induced
increases in intracellular calcium concentration
([Ca2+]i)
and tumor necrosis factor-
(TNF-) production by
Kupffer cells through a glycine-gated chloride channel. Alveolar
macrophages, which have a similar origin as Kupffer cells, play a
significant role in the pathogenesis of several lung diseases including
asthma, endotoxemia, and acute inflammation due to inhaled bacterial
particles and dusts. Therefore, studies were designed here to test the
hypothesis that alveolar macrophages could be inactivated by glycine
via a glycine-gated chloride channel. The ability of glycine to prevent endotoxin [lipopolysaccharide (LPS)]-induced increases in
[Ca2+]i
and subsequent production of superoxide and TNF- in alveolar macrophages was examined. LPS caused a transient increase in
intracellular calcium to nearly 200 nM, with
EC50 values slightly greater than 25 ng/ml. Glycine, in a dose-dependent manner, blunted the increase in
[Ca2+]i,
with an IC50 less than 100 µM.
Like the glycine-gated chloride channel in the central nervous system,
the effects of glycine on
[Ca2+]i
were both strychnine sensitive and chloride dependent. Glycine also
caused a dose-dependent influx of radiolabeled chloride with EC50 values near 10 µM, a
phenomenon which was also inhibited by strychnine (1 µM). LPS-induced
superoxide production was also blunted in a dose-dependent manner by
glycine and was reduced ~50% with 10 µM glycine. Moreover, TNF-
production was also inhibited by glycine and also required nearly 10 µM glycine for half-inhibition. These data provide strong
pharmacological evidence that alveolar macrophages contain
glycine-gated chloride channels and that their activation is protective
against the LPS-induced increase in
[Ca2+]i
and subsequent production of toxic radicals and cytokines.
glycine-gated chloride channel; intracellular calcium; tumor
necrosis factor-
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