Heparin Interaction with the Primed Polymorphonuclear Leukocyte CD11b Induces Apoptosis and Prevents Cell Activation

Heparin is known to have anti-inflammatory effects, yet the mechanisms are not completely understood. In this study, we tested the hypothesis that heparin has a direct effect on activated polymorphonuclear leukocytes (PMNLs), changing their activation state, and can explain its anti-inflammatory effect. To test our hypothesis, we designed both in vitro and ex vivo studies to elucidate the mechanism by which heparin modulates PMNL functions and therefore the inflammatory response. We specifically tested the hypothesis that priming of PMNLs renders them more susceptible to heparin. Amplified levels of CD11b and increased rate of superoxide release manifested PMNL priming. Increase in cell priming resulted in a dose-dependent increase in heparin binding to PMNLs followed by augmented apoptosis. Blocking antibodies to CD11b inhibited heparin binding and abolished the apoptotic response. Moreover, heparin caused a significant dose-dependent decrease in the rate of superoxide release from PMNLs, which was blunted by blocking antibodies to CD11b. Altogether, this study shows that the interaction of heparin with the PMNL CD11b results in cell apoptosis and explains heparin’s anti-inflammatory effects

Elastase and Cathepsin G from Primed Leukocytes Cleave Vascular Endothelial Cadherin in Hemodialysis Patients

Aims. To test the hypothesis that primed PMNLs in blood of chronic kidney disease patients release the active form of elastase and cathepsin G causing degradation of vital proteins and promote tissue damage. Methods. RT-PCR, immunocytochemical staining, immunoblotting, and FACS analyses were used to study these enzymes in hemodialysis patients (HD) versus healthy normal controls (NC). Using PMNLs and endothelial cells cocultivation system we measure the effect of HD PMNLs on the endothelial VE-cadherin, an essential protein for maintaining endothelial integrity. Results. Levels of elastase and cathepsin G were reduced in PMNLs of HD patients, while mRNA enzymes levels were not different. Elevated levels of the active form of these enzymes were found in blood of HD patients compared to NC.HD plasma had higher levels of soluble VE-cadherin present in three molecular forms: whole 140 kDa molecule and two fragments of 100 and 40 kDa. Cocultivation studies showed that primed PMNLs cleave the endothelial cadherin, resulting in a 100 kDa fragment. Conclusions. Elastase and cathepsin G are elevated in the plasma of HD patients, originating from primed PMNLs. In these patients, chronic elevation of these enzymes contributes to cleavage of VE-cadherin and possible disruption of endothelial integrity

Heparin Interaction with the Primed Polymorphonuclear Leukocyte CD11b Induces Apoptosis and Prevents Cell Activation.

Heparin is known to have anti-inflammatory effects, yet the mechanisms are not completely understood. In this study, we tested the hypothesis that heparin has a direct effect on activated polymorphonuclear leukocytes (PMNLs), changing their activation state, and can explain its anti-inflammatory effect. To test our hypothesis, we designed both in vitro and ex vivo studies to elucidate the mechanism by which heparin modulates PMNL functions and therefore the inflammatory response. We specifically tested the hypothesis that priming of PMNLs renders them more susceptible to heparin. Amplified levels of CD11b and increased rate of superoxide release manifested PMNL priming. Increase in cell priming resulted in a dose-dependent increase in heparin binding to PMNLs followed by augmented apoptosis. Blocking antibodies to CD11b inhibited heparin binding and abolished the apoptotic response. Moreover, heparin caused a significant dose-dependent decrease in the rate of superoxide release from PMNLs, which was blunted by blocking antibodies to CD11b. Altogether, this study shows that the interaction of heparin with the PMNL CD11b results in cell apoptosis and explains heparin's anti-inflammatory effects

In vivo safety and pulmonary vein isolation performance of a new cryoballoon for the treatment of atrial fibrillation

Background: Cryoablation to achieve pulmonary vein (PV) isolation has become one of the standard approaches for atrial fibrillation (AF) ablation. The Arctic Front series cryoballoon and Achieve circular mapping catheter (Medtronic) inherently possess design defects that have been associated with unfavorite clinical outcomes. Lately, a new cryoablation system (Nordica Cryoablation System, Synaptic Medical) was developed with improved design of the cryoballoon and circular mapping catheter to address the inadequacies of current cryoablation technology. An animal study was conducted to test the efficacy and safety in performing PVI with the Nordica Cryoablation System. Methods: Pulmonary vein isolation with the Nordica Cryoablation System was performed on 12 PVs of six healthy canines. Acute PVI and peri-procedural complications were recorded. All animals underwent a repeat EP study at least 4 weeks after index procedures followed by pathological and histological assessments of the heart and collateral/downstream organs after planned euthanasia. Results: Acute PV isolation was achieved in all targeted PVs with 50% of PVs being isolated with a single cryoablation application. There were no major peri-procedural complications or device malfunction events. All PVs remained isolated after 29–30 days follow-up. Histological examination showed transmural cryo-lesions at treated sites with minimal inflammation, neovascularization, and neointima formation but no significant injury to adjacent tissue or embolization in downstream organs. Conclusion: Acute and durable PVI can be achieved by using the novel Nordica Cryoablation System. Ablation with this new cryoablation system is associated with transmural lesions at targeted myocardium but creates no injury to the collateral tissues or downstream organs.12 month embargo; published 03 June 2024This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]