Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III.
We evaluated the effects of antithrombin III (AT III) on the pulmonary vascular injury induced by injecting rats with lipopolysaccharide (LPS) to investigate the possible usefulness of AT III as a treatment for acute respiratory distress syndrome. The intravenous administration of AT III prevented the pulmonary accumulation of leukocytes (as evaluated by myeloperoxidase activity) and the increase in pulmonary vascular permeability to 125I-bovine serum albumin induced by LPS. The increase in pulmonary vascular permeability induced by LPS administration was unaffected by various anticoagulants but was inhibited by the leukocytopenia induced by nitrogen mustard or by the administration of a granulocyte elastase inhibitor, ONO-5046. AT III given alone, but not heparin plus AT III or Trp49-modified AT III, which lacks affinity for heparin, significantly increased the plasma concentration of 6-keto-prostaglandin F1alpha, suggesting that the interaction of AT III with heparin-like substances at the endothelial cell surface promotes the release of prostacyclin from endothelial cells in vivo. Trp49-modified AT III failed to prevent the LPS-induced accumulation of leukocytes and vascular injury. The pulmonary accumulation of leukocytes and vascular injury induced by LPS were not prevented by administering AT III to rats that were pretreated with indomethacin. The continuous intravenous infusion of prostacyclin prevented the LPS-induced pulmonary accumulation of leukocytes and vascular injury. Findings suggest that AT III depends on its ability to promote the release of prostacyclin, a potent inhibitor of leukocyte activation, from endothelial cells to prevent pulmonary vascular injury induced by LPS.
Uchiba
M
M
Department of Medicine, Kumamoto University Medical School, Japan.
Okajima
K
K
Murakami
K
K
Okabe
H
H
Takatsuki
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D011464:Epoprostenol / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009994:Osmolar Concentration; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D004731:Endotoxins; D008070:Lipopolysaccharides; D015121:6-Ketoprostaglandin F1 alpha; D000990:Antithrombin III; D006493:Heparin; D011464:Epoprostenol; D007213:Indomethacin