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From the Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
LPS (lipopolysaccharide) is one of the major factors that induce
acute lung injury. Recently, it was reported that LPS induced
disseminated endothelial apoptosis, preceding nonendothelial
tissue damage. Caspases play important roles in apoptosis,
including tumor necrosis factor-
-induced apoptosis, in
several systems. We therefore investigated whether the injection of a
caspase inhibitor prevents LPS-induced apoptosis and acute lung injury
in mice. LPS (30 mg/kg) was administered intravenously to Institute for
Cancer Research mice. Electron microscopic findings demonstrated
characteristic features of apoptosis in endothelial cells and alveolar
epithelial cells. The caspase-3 activity and the number of terminal
dUTP nick-end labeling-positive cells in lung tissues were
significantly increased after LPS administration.
Benzyloxycarbonil-Val-Ala-Asp fluoromethylketone
(Z-VAD.fmk), which is a broad-spectrum caspase
inhibitor, was injected before and after the administration of
LPS. The injection of Z-VAD.fmk suppressed the caspase-3 activity in
lung tissues, and significantly decreased the number of
terminal dUTP nick-end labeling-positive cells. Furthermore,
the survival rate of mice was prolonged significantly by the
injection of Z-VAD.fmk. These results indicate that apoptosis may play
an important role in acute lung injury, and thus that
inhibition of caspase activity may constitute a new therapeutic
approach for treatment of this disease.
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