Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats.
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.
Murakami
K
K
Department of Medicine, Kumamoto University Medical School, Japan.
Okajima
K
K
Uchiba
M
M
Johno
M
M
Nakagaki
T
T
Okabe
H
H
Takatsuki
K
K
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D000990:Antithrombin III / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control*; D004731:Endotoxins / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015951:Factor Xa / Q000494:pharmacology; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006493:Heparin / Q000494:pharmacology; D019272:Leukocyte Elastase; D007970:Leukopenia / Q000139:chemically induced / Q000150:complications; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000032:analysis; D011486:Protein C / Q000627:therapeutic use*; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D000925:Anticoagulants; D004731:Endotoxins; D004791:Enzyme Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D011486:Protein C; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; D000990:Antithrombin III; D005340:Fibrinogen; D006493:Heparin; C069195:sivelestat; D009195:Peroxidase; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D013917:Thrombin; D015951:Factor Xa; D005998:Glycine