The Effect of Anticoagulants and the Role of Thrombin on Neutrophil-Endothelial Cell Interactions in Septic Shock

Tsen, Anita; Kirschenbaum, Linda; LaRow, Catherine; Khan, Raymond; Kurtz, Susannah; Astiz, Mark E.

doi:10.1097/shk.0b013e318180ffe9

Cited by 11 publications

(4 citation statements)

References 37 publications

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“…In vitro experiment was performed in a coagulation factor-free medium, and the effect of argatroban could not be expected. Tsen et al [ 26 ] performed the in vitro experiment by using plasma and reported that both UFH and argatroban significantly decreased neutrophil adhesion and platelet-neutrophil aggregation. They concluded that UFH and argatroban decrease sepsis-induced neutrophil-endothelial cell interactions by inhibiting thrombin activity.…”

Section: Discussionmentioning

confidence: 99%

Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction

Iba

Hashiguchi

Nagaoka

et al. 2015

ICMx

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BackgroundThe beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported. However, the mechanisms underlying the therapeutic benefits of heparin in these conditions have not yet been clearly elucidated. The purpose of this study was to confirm the effect of heparin of neutralizing histone toxicity.MethodsRat models of histone H3-induced organ dysfunction were administered in a low or high dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or argatroban, and the therapeutic effects of each anticoagulant were examined. In another series, the survival of the histone H3-administered animals was evaluated. Furthermore, the effect of each of the aforementioned anticoagulants on cell death induced by histone H3 was examined in cultured vascular endothelial cells and leukocytes.ResultsAlthough UFH, LMWH, and argatroban significantly suppressed the histone-induced decrease of the WBC and platelet counts in the animal models of organ dysfunction, only UFH and LMWH attenuated hepatic and renal dysfunction. In addition, the mortality was significantly reduced only by high-dose UFH and LMWH. The in vitro study revealed that both vascular endothelial cell death and leukocyte cell death were significantly attenuated by UFH and LMWH but not by argatroban.ConclusionsThe histone-neutralizing effect of heparin may contribute to the beneficial effects of heparins observed in the animal study. The results of the in vitro study further confirmed the above contention and suggested that heparin binds to histones to attenuate the cytotoxic actions of the latter. Since heparin has been demonstrated to protect animals from the organ damage induced by histones and consequently reduce the mortality, administration of heparin could become a treatment of choice for patients suffering from severe sepsis.

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Section: Discussionmentioning

confidence: 99%

Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction

Iba

Hashiguchi

Nagaoka

et al. 2015

ICMx

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“…Additionally, thrombin, one of the key participants in the coagulation cascade, can also be involved in the control of neutrophil migration. Previously, Tsen et al showed that a range of thrombin-specific inhibitors significantly decreased the adhesion of neutrophils to endothelial cells and increased their rolling velocity [89], thereby diminishing the transmigration of neutrophils from blood vessels into inflamed sites. Thus, we supposed that the anti-inflammatory properties of compound 3d could be due to its inhibitory effect on the activity of MMP9, neutrophil elastase, and thrombin, which can lead to the dysregulation of optimal chemokine processing and the generation of that chemotactic gradient that guides neutrophils into an inflamed site, as well as the suppression of transendothelial neutrophil migration.…”

Section: Figurementioning

confidence: 99%

Novel 3′-Substituted-1′,2′,4′-Oxadiazole Derivatives of 18βH-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

Markov

Sen’kova

Popadyuk

et al. 2020

IJMS

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A series of novel 18βH-glycyrrhetinic acid (GA) derivatives containing 3′-(alkyl/phenyl/pyridin(-2″, -3″, and -4″)-yl)-1′,2′,4′-oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid’s carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates—O-acylated amidoxime 3a-h—display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1′,2′,4′-oxadiazole analogs 4f-h (median IC50 = 7.0 and 49.7 µM, respectively). Subsequent replacement of the 3-acetoxy group by the hydroxyl group of pyridin(-2″, 3″, and -4″)-yl-1′,2′,4′-oxadiazole-bearing GA derivatives produced compounds 5f-h, showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed analysis of the antitumor activity of hit derivative 5f revealed its marked proapoptotic activity and inhibitory effects on clonogenicity and motility of HeLa cervical carcinoma cells in vitro, and the metastatic growth of B16 melanoma in vivo. Additionally, the comprehensive in silico study revealed intermediate 3d, bearing the tert-butyl moiety in O-acylated amidoxime, as a potent anti-inflammatory candidate, which was able to effectively inhibit inflammatory response induced by IFNγ in macrophages in vitro and carrageenan in murine models in vivo, probably by primary interactions with active sites of MMP9, neutrophil elastase, and thrombin. Taken together, our findings provide a basis for a better understanding of the structure–activity relationship of 1′,2′,4′-oxadiazole-containing triterpenoids and reveal two hit molecules with pronounced antitumor (5f) and anti-inflammatory (3d) activities.

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“…APC treatment is still recommended for the therapy of severe sepsis and septic shock (3,4). Because of the central role of the coagulation cascade in sepsis, other anticoagulants were studied in clinical and experimental sepsis, including heparin, antithrombin (ATIII), tissue factor pathway inhibitor (TFPI), and hirudin (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Argatroban administration reduces leukocyte adhesion and improves capillary perfusion within the intestinal microcirculation in experimental sepsis

Fuchs

Ladwig²,

Pavlović³

et al. 2010

Thromb Haemost

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Co-activation of pro-coagulatory pathways in sepsis may result in disseminated intravascular coagulation and contributes to microvascular dysfunction. We investigated the effects of the direct thrombin inhibitor, argatroban (ARG), on the sepsis-induced impairment of the intestinal microcirculation (capillary perfusion, leukocyte adhesion) and the vascular contractility in rats. Forty male Lewis rats were randomly assigned to one of four groups: sham surgery (SHAM), experimental sepsis (colon ascendens stent peritonitis--CASP), CASP+ARG, and SHAM+ARG. At 16 hours after colon stent insertion (or sham surgery), 2 mg/kg argatroban or buffer were given intravenously, and 1 hour thereafter, intravital microscopy was performed. In addition, experiments to study the impact of ARG on vascular contractility were conducted in vitro . ARG administration in CASP rats significantly increased functional capillary density in mucosal (+128%) and muscular layers (longitudinal: +42%; circular: +64%) and decreased the number of firmly adhering leukocytes in the intestinal submucosa compared to untreated animals. In vitro findings indicated a vasodilating effect of ARG. ARG administration during experimental sepsis improved intestinal microcirculation by preserving functional capillary density, an indicator of microvascular perfusion, and by reducing leukocyte adherence to the endothelium in submucosal venules.

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The Effect of Anticoagulants and the Role of Thrombin on Neutrophil-Endothelial Cell Interactions in Septic Shock

Cited by 11 publications

References 37 publications

Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction

Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction

Novel 3′-Substituted-1′,2′,4′-Oxadiazole Derivatives of 18βH-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

Argatroban administration reduces leukocyte adhesion and improves capillary perfusion within the intestinal microcirculation in experimental sepsis

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