Activated protein c prevents lps-induced pulmonary vascular injury
by inhibiting cytokine production.
Murakami, Kazunori, Kenji Okajima, Mitsuhiro Uchiba, Masayoshi Johno,
Tomohiro Nakagaki, Hiroaki Okabe, and Kiyoshi Takatsuki.
Departments of Medicine, Laboratory Medicine, and Dermatology,
Kumamoto University Medical School, and The Chemo-Sero-Therapeutic
Research Institute, Kumamoto, 860, JAPAN
APStracts 3:0183L, 1996.
We investigated the effect of activated protein C (APC) on pulmonary
vascular injury and the increase in TNF levels in lipopolysaccharide
(LPS)-treated rats to determine whether APC reduces LPS-induced
endothelial damage by inhibiting cytokine production. Intravenously
administered LPS (5mg/kg) induced pulmonary vascular injury, as
indicated by an increase in the lung wet/dry weight ratio. LPS
-induced pulmonary vascular injury was prevented by APC but not by
active site-blocked factor Xa (DEGR-Xa), a selective inhibitor of
thrombin generation, or inactivated APC (DIP-APC). APC, but not DEGR
-Xa or DIP-APC, significantly inhibited the LPS-induced increase in
the plasma level of TNF. APC significantly inhibited the production
of TNF by LPS-stimulated monocytes in a dose-dependent fashion in
vitro, but DIP-APC did not. APC did not inhibit the functions of
activated neutrophils in vitro. These findings suggest that APC
prevented LPS-induced pulmonary vascular injury by inhibiting TNF
production by monocytes and not via its anticoagulant activity. The
serine protease activity of APC appears to be essential for
inhibition of TNF production.
Received 11 April 1996; accepted in final form 12 September 1996.
APS Manuscript Number L114-6.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996