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Activated protein C attenuates endotoxin-induced pulmonary vascular injury
by inhibiting activated leukocytes in rats
K Murakami, K Okajima, M Uchiba, M Johno, T Nakagaki, H Okabe and K Takatsuki
Department of Medicine, Kumamoto University Medical School, Japan.
We investigated the effect of activated protein C (APC) on
lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats to
investigate the possible usefulness of APC as a treatment for adult
respiratory distress syndrome. Intravenously administered LPS (5 mg/kg)
significantly increased pulmonary vascular permeability. APC prevented the
LPS-induced increase in pulmonary vascular permeability observed at 6
hours. Heparin plus antithrombin III (ATIII) and active site-blocked factor
Xa (DEGR-Xa), a selective inhibitor of thrombin generation, inhibited
LPS-induced coagulopathy but did not prevent LPS-induced pulmonary vascular
injury. LPS-induced pulmonary vascular injury was significantly attenuated
in rats with nitrogen mustard-induced leukocytopenia and in rats treated
with ONO-5046, a potent granulocyte elastase inhibitor. Administration of
LPS also increased pulmonary accumulation of leukocytes, as evaluated by
measurement of myeloperoxidase activity in the lungs. APC significantly
reduced LPS- induced increases in pulmonary accumulation of leukocytes at 1
hour. Neither ATIII plus heparin nor DEGR-Xa inhibited leukocyte
accumulation. Active site-blocked APC (DIP-APC) prevented neither the
LPS-induced pulmonary accumulation of leukocytes nor the LPS-induced
increase in pulmonary vascular permeability. These results suggest that the
mechanism of APC inhibition of LPS-induced pulmonary vascular injury was
independent of its anticoagulant activity and was related to its ability to
inhibit accumulation of leukocytes. In addition, these findings suggest
that the serine protease activity of APC may be essential to its inhibitory
effect on LPS-induced pulmonary accumulation of leukocytes and subsequent
pulmonary vascular injury.
Volume 87,
Issue 2,
pp. 642-647,
01/15/1996
Copyright © 1996 by The American Society of Hematology
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