title: Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation.
abstract: Tissue factor pathway inhibitor (TFPI) is an important physiologic inhibitor of the extrinsic pathway of the coagulation system. We investigated whether recombinant TFPI (rTFPI) could reduce pulmonary vascular injury by inhibiting leukocyte activation in rats given lipopolysaccharide (LPS). Pre- or posttreatment of animals with rTFPI significantly inhibited LPS-induced pulmonary vascular injury, as well as coagulation abnormalities. rTFPI significantly inhibited increases in lung tissue levels of tumor necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase. Expression of TNF-alpha messenger RNA in the lung after LPS administration was significantly reduced by rTFPI administration. However, neither DX-9065a, a selective inhibitor of Factor Xa, nor recombinant Factor VIIa treated with dansyl-glutamylglycylarginyl-chloromethyl ketone, a selective inhibitor of Factor VIIa, had any effects on LPS-induced pulmonary vascular injury despite their potent anticoagulant effects. rTFPI significantly inhibited TNF-alpha production by LPS-stimulated monocytes in vitro. rTFPI also significantly inhibited several formyl-Met-Leu-Phe-induced neutrophil functions, as well as increases in the expression of CD11b and CD18 on the neutrophil cell surface in vitro. Additionally, rTFPI inhibited increases in levels of intracellular calcium, a second messenger of neutrophil activation, in formyl-Met-Leu-Phe-stimulated neutrophils in vitro. These results strongly suggested that rTFPI reduces pulmonary vascular injury by inhibiting leukocyte activation, as well as coagulation abnormalities in rats given LPS.
authors.affiliation: Department of Laboratory Medicine and Second Department of Surgery, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: P
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: K
authors.initials: K
authors.lastname: Okajima
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: M
authors.initials: M
authors.lastname: Uchiba
authors.forename: H
authors.initials: H
authors.lastname: Okabe
authors.forename: K
authors.initials: K
authors.lastname: Okabe
authors.forename: Y
authors.initials: Y
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D003619:Dansyl Compounds / Q000494:pharmacology; D015942:Factor VIIa / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005343:Fibrinolytic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides; D008074:Lipoproteins / Q000097:blood / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011654:Pulmonary Edema / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D003619:Dansyl Compounds; D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D008070:Lipopolysaccharides; D008074:Lipoproteins; D009281:Naphthalenes; D011422:Propionates; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C109749:dansyl-glutamyl-glycyl-arginyl-factor VIIa; C051928:lipoprotein-associated coagulation inhibitor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D015942:Factor VIIa