Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats

Murakami, Kazunori; Okajima, Kenji; Uchiba, Mitsuhiro; Johno, Masayoshi; Nakagaki, Tomohiro; Okabe, Hiroaki; Takatsuki, Kiyoshi

doi:10.1182/blood.v87.2.642.bloodjournal872642

Cited by 240 publications

(99 citation statements)

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“…It inhibits the responses of monocytes to the mediators of inflammation through its specific receptor (16,18). Activated protein C and protein C inhibited endotoxin-induced and Escherichia coli-induced inflammatory changes in baboons and rats, respectively (35,50). These findings suggest that ART-123 is an anticoagulant with antiinflammatory effects.…”

Section: Other In Vivo Effectsmentioning

confidence: 90%

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ART‐123: Recombinant Human Soluble Thrombomodulin

Mohri

2000

Cardiovascular Drug Reviews

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ART-123 is a soluble form of recombinant human thrombomodulin comprising all extracellular domains of thrombomodulin. Bound to thrombin, ART-123 inhibits its procoagulant activity and promotes activation of protein C. ART-123 inhibits thrombin generation by the activation of protein C and the subsequent inactivation of factor Va in the presence of protein S. ART-123 attenuates the extension of the clot by inhibiting further thrombin generation on clots, while other anticoagulants inhibit the initiation of clot formation. A higher concentration of ART-123 is needed to affect clotting time and platelet aggregation than thrombin generation. Intravenous administration of ART-123 is effective in animal models of disseminated intravascular coagulation (DIC), AV-shunt, and other models with a wider safety margin than conventional anticoagulants. The plasma half-life of ART-123 is long, especially on subcutaneous injection. Clinical studies have been performed or are planned to evaluate the efficacy of ART-123 in DIC and deep venous thrombosis (DVT). In clinical trials against DIC ART-123 was well tolerated and showed a good dose-response effect. These findings suggested that ART-123 is a promising drug for thrombotic diseases.

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Section: Other In Vivo Effectsmentioning

confidence: 90%

“…Activated protein C has antiinflammatory activities suppressing TNF production and CD11b downregulation induced by lipopolysaccarides in monocytes (15,16). It is effective against thrombotic and coagulation disorders in animal models (17,19,35,50) and in humans in clinical studies (10,28).…”

Section: Introductionmentioning

confidence: 99%

ART‐123: Recombinant Human Soluble Thrombomodulin

Mohri

2000

Cardiovascular Drug Reviews

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“…Tumor necrosis factor production during human renal allograft rejection is inversely correlated with levels of plasma protein C antigen (Tsuchida et al, 1992). AFT prevents the lethal effects of E. coli infusion in baboons (Taylor et al, 1987), and APC attenuates LPS induced pulmonary vascular injury in rats, an effect mediated by the inhibition of activated leukocytes (Murakami et al, 1996). In tissue culture, APC appears to inhibit selective responses of human mononuclear macrophages to LPS, IFN-y, or phorbol ester (Grey et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Nonenzymatic anticoagulant activity of the mutant serine protease Ser360Ala‐activated protein C mediated by factor Va

et al. 1997

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The human plasma serine protease, activated protein C (APC), primarily exerts its anticoagulant function by proteolytic inactivation of the blood coagulation cofactors Va and VIIIa. A recombinant active site Ser 360 to Ala mutation of protein C was prepared, and the mutant protein was expressed in human 293 kidney cells and purified. The activation peptide of the mutant protein C zymogen was cleaved by a snake venom activator, Protac C, but the "activated" S360A APC did not have amidolytic activity. However, it did exhibit significant anticoagulant activity both in clotting assays and in a purified protein assay system that measured prothrombinase activity. The S360A APC was compared to plasma-derived and wild-type recombinant APC. The anticoagulant activity of the mutant, but not native APC, was resistant to diisopropyl fluorophosphate, whereas all APCs were inhibited by monoclonal antibodies against APC. In contrast to native APC, S360A APC was not inactivated by serine protease inhibitors in plasma and did not bind to the highly reactive mutant protease inhibitor M358R alpha 1 antitrypsin. Since plasma serpins provide the major mechanism for inactivating APC in vivo, this suggests that S360A APC would have a long half-life in vivo, with potential therapeutic advantages. S360A APC rapidly inhibited factor Va in a nonenzymatic manner since it apparently did not proteolyze factor Va. These data suggest that native APC may exhibit rapid nonenzymatic anticoagulant activity followed by enzymatic irreversible proteolysis of factor Va. The results of clotting assays and prothrombinase assays showed that S360A APC could not inhibit the variant Gln 506-FVa compared with normal Arg 506-FVa, suggesting that the active site of S360A APC binds to FVa at or near Arg 506.

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“…In addition to the anticoagulant functions, APC exhibits antiinflammatory properties. In rats or mice, infusion of APC reduced leukocyte sequestration in lung tissue in experimental respiratory distress syndrome (ARDS) [3] and in post-ischemic liver, renal, and cerebral tissues [4][5][6]. We previously studied protein C activation [2] and cardiac neutrophil sequestration and activation [7] in two, partially overlapping patient series undergoing open heart surgery.…”

Section: Introductionmentioning

confidence: 99%