Antithrombin III Prevents and Rapidly Reverses Leukocyte Recruitment in Ischemia/Reperfusion

Ostrovsky, Lena; Woodman, Richard C.; Payne, Derrice; Teoh, Diane; Kubes, Paul

doi:10.1161/01.cir.96.7.2302

Cited by 179 publications

(152 citation statements)

References 42 publications

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“…Although there was some attenuation of rolling, it was definitely not complete. This is consistent with our previous work showing a role for oxidant-independent mechanisms including thrombin (43). Although O 2 Ϫ can mobilize the stored pool of P-selectin to the endothelial cell surface, where it then mediates leukocyte rolling, this likely occurs via the formation of H 2 O 2 .…”

Section: Discussionsupporting

confidence: 92%

Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion

Bonder¹,

Knight²,

Hernández-Saavedra³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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After an ischemic episode, reperfusion causes profound oxidative stress in the vasculature of the afflicted tissue/organ. The dysregulated accumulation of reactive oxygen species (ROS), such as superoxide, has been closely linked to the production and release of proinflammatory mediators, a profound increase in adhesion molecule expression by the vascular endothelium, and infiltration of neutrophils during ischemia-reperfusion (I/R). Superoxide dismutase (SOD) has been shown to protect tissues and organs against I/R-induced injury; however, the drug had to be continuously perfused or kidneys had to be occluded to prevent clearance. We used intravital microscopy, a system that allowed us to visualize neutrophil-endothelial interactions within the mesenteric postcapillary venules of cats subjected to I/R and tested the hypothesis that I/R-induced neutrophil recruitment was inhibited by treatment with SOD2/3. SOD2/3 is a chimeric fusion gene product that contains the mature SOD2 as well as the COOH-terminal “tail” of SOD3 and, unlike the three naturally occurring SODs (SOD1, SOD2, and SOD3), which bear a net negative charge at pH 7.4, SOD2/3 is positively charged and physiologically stable. Our results suggest that not only does SOD2/3 have a much greater efficacy in vivo than the native human SOD2, but its administration prevents I/R-induced neutrophil-endothelial cell interactions and microvascular dysfunction. Moreover, our data support the hypothesis that reactive oxidants mediate I/R-induced injury and that the chimeric recombinant SOD2/3 has the potential to be a therapeutic agent against this debilitating illness.

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Section: Discussionsupporting

confidence: 92%

Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion

Bonder¹,

Knight²,

Hernández-Saavedra³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…[17][18][19] Briefly, umbilical cord veins were rinsed of formed blood products with warm phosphate-buffered saline (PBS), after which the vein was filled with collagenase (320 U/ml in PBS; Worthington Biochemical Corporation, Lakewood, NJ). After a 20-minute incubation period in warm PBS, the cords were gently massaged to ensure detachment of endothelial cells from the vessel wall.…”

Section: Huvec Isolationmentioning

confidence: 99%

“…A flow chamber assay was used as previously described 17 to study leukocyte recruitment from whole blood by cytokine-treated HUVECs (OSM, 1 to 10 ng/ml, or TNF-␣, 25 ng/ml, for 24 hours; thrombin, 0.5 U/ml for 10 minutes). Glass coverslips with confluent monolayers of HUVECs or HDMECs were mounted into a polycarbonate chamber with parallel plate geometry.…”

Section: Flow Chamber Assaymentioning

confidence: 99%

Exclusive Neutrophil Recruitment with Oncostatin M in a Human System

Kerfoot

Raharjo

et al. 2001

The American Journal of Pathology

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Oncostatin M (OSM), a member of the IL-6 family has been postulated to be a potent recruiter of leukocytes, however information regarding the molecular mechanism(s) underlying this event is extremely limited. Therefore, the aim of this study was to investigate the role of OSM-mediated leukocyte recruitment in a human system in vitro under flow conditions. A parallelplate flow chamber assay was used to examine leukocyte recruitment from whole blood by human umbilical vein endothelium treated for 24 hours with OSM. OSM in a dose-response manner revealed very significant leukocyte rolling and adhesion reaching optimal levels at a very low concentration of OSM (10 ng/ml). The OSM-induced leukocyte rolling and adhesion was comparable to levels seen with tumor necrosis factor. OSM was extremely selective for neutrophil recruitment (96%) with <3% lymphocyte recruitment. By contrast, tumor necrosis factor-␣ revealed no such selectivity, recruiting 70% neutrophils and at least 25% lymphocytes and detectable levels of eosinophils at 24 hours. The molecular mechanism underlying the leukocyte recruitment seemed to be entirely dependent on P-selectin as leukocyte recruitment could be completely blocked by the addition of a P-selectin-blocking antibody. An elevation in both Pselectin message and protein was observed with 24 hours of OSM stimulation of endothelium. By contrast, E-selectin and VCAM-1 were not detectable after OSM stimulation. Similar results were seen with passaged dermal microvascular endothelium that does not have a prestored pool of P-selectin. Based on these results, we conclude that OSM may be a very selective potent recruiter of neutrophils in more prolonged inflammatory conditions, an event exclusively dependent on P-selectin. Leukocytes are recruited to sites of inflammation through a well-defined series of interactions with activated endothelium. Cytokines induce endothelium to express various adhesion molecules that mediate this cascade of events.1-3 Initially, selectins on endothelium mediate transient interactions with their leukocyte ligands, resulting in leukocyte tethering and rolling along the vessel wall. Activation of leukocytes by chemoattractants leads to functional up-regulation of integrins, resulting in firm adhesion to their immunoglobulin superfamily ligands on endothelium and permitting extravasion into the surrounding tissue.

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“…Voigt et al 38 demonstrated that ATIII inhibits the binding of the virus to the endothelium. In a recent paper Ostrovsky et al 39 describe that the leukocyte-endothelium interaction was inhibited by ATIII in a feline mesenterial ischemia/reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

Dickneite¹,

Leithäuser²

1999

ATVB

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Abstract-The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 g ⅐ kg Ϫ1 ⅐ h Ϫ1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (nϭ10) or placebo (nϭ10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (Ϫ60 to Ϫ30 minutes) followed by a single IV bolus of 125 U/kg (tϭ0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4Ϯ9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (PϽ0.05). ATIII significantly prevented the increase in thromboxane (TXB 2 ) levels, which were 809Ϯ287 pg/mL in the placebo and 420Ϯ174 pg/mL in the verum group after 6 hours (PϽ0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (PϽ0.05, 2 test) a significant reduction of pulmonary hypertension (placebo, 42.0Ϯ11.1 mm Hg; ATIII, 23.6Ϯ7.5 mm Hg, PϽ0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock. Key Words: lipopolysaccharide Ⅲ disseminated intravascular coagulation Ⅲ pulmonary hypertension Ⅲ soluble fibrin monomers Ⅲ thromboxane S epsis as a severe complication of infection is characterized by systemic inflammation, activation of proteolytic cascades, coagulation abnormalities (DIC) and a gradually developing hypodynamic status with impaired organ perfusion, and finally death in a septic shock. Lung circulation in septic shock is characterized by hypertension and increased pulmonary resistance, resulting in low cardiac output, and, frequently, in lung failure. Mortality in septic shock is usually high, ie, in the range of 40% to 50%. 1 If associated with multi-organ dysfunction such as respiratory or renal failure, mortality might exceed 90%. 2 The initiating event for the development of sepsis is the activation of macrophages by lipopolysaccharide (LPS) liberated from Gram-negative bacteria via binding to its surface receptor CD14. 3 However, sepsis might be induced by other agents, such as Grampositive bacteria, fungi or viruses. The initial excessive secretion of cytokine mediators such as interleukin 1 (IL-1) and tumor necrosis factor (TNF-␣) is followed by the activation of biological cascades including the coagulation, the complement, the fibrinolytic and the...

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Antithrombin III Prevents and Rapidly Reverses Leukocyte Recruitment in Ischemia/Reperfusion

Cited by 179 publications

References 42 publications

Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion

Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion

Exclusive Neutrophil Recruitment with Oncostatin M in a Human System

Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

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