Inhibition of Tumor Necrosis Factor Induced Human Aortic Endothelial Cell Adhesion Molecule Gene Expression by an Alkoxybenzo[b]thiophene-2-carboxamide

1995 ◽  
Vol 214 (1) ◽  
pp. 6-10 ◽  
Author(s):  
J. Wolle ◽  
E. Ferguson ◽  
C. Keshava ◽  
L.J. Devall ◽  
D.H. Boschelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cell Adhesion Molecule ◽  
Human Aortic Endothelial Cell ◽  
Adhesion Molecule Gene ◽  
Necrosis Factor ◽  
Endothelial Cell Adhesion

scholarly journals T-Lymphocyte–Derived Tumor Necrosis Factor Exacerbates Anoxia-Reoxygenation–Induced Neutrophil–Endothelial Cell Adhesion

2000 ◽  
Vol 86 (2) ◽  
pp. 205-213 ◽  
Author(s):  
Satoshi Kokura ◽  
Robert E. Wolf ◽  
Toshikazu Yoshikawa ◽  
D. Neil Granger ◽  
Tak Yee Aw
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Tumor Necrosis Factor ◽  
T Lymphocyte ◽  
Tumor Necrosis ◽  
Necrosis Factor ◽  
Endothelial Cell Adhesion

Effect of Tumor Necrosis Factor-α Blockade on Mucosal Addressin Cell-adhesion Molecule-1 in Crohnʼs Disease

2013 ◽  
Vol 19 (2) ◽  
pp. 259-264 ◽  
Author(s):  
Paolo Biancheri ◽  
Antonio Di Sabatino ◽  
Laura Rovedatti ◽  
Paolo Giuffrida ◽  
Sandra A. Calarota ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tumor Necrosis Factor ◽  
Adhesion Molecule ◽  
Tumor Necrosis ◽  
Cell Adhesion Molecule ◽  
Tumor Necrosis Factor Α ◽  
Factor Α ◽  
Cell Adhesion Molecule 1 ◽  
Necrosis Factor

scholarly journals Defibrotide for the Treatment of Endotheliitis Complicating Sars-Cov-2 Infection: Rationale and Ongoing Studies As Part of the International Defacovid Study Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-8
Author(s):  
Jose M. Moraleda ◽  
Carmelo Carlo-Stella ◽  
David Garcia-Bernal ◽  
Ruben Jara Rubio ◽  
Enriqueta Andreu ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Tumor Necrosis Factor ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Necrosis ◽  
Cell Injury ◽  
Advisory Committees ◽  
Endothelial Cell Injury ◽  
Necrosis Factor

Coronavirus disease 2019 (COVID-19) is a heterogeneous clinical condition caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial stage of infection occurs at the time of respiratory viral invasion through angiotensin-converting enzyme 2 (ACE2) receptors in alveolar pneumocytes and macrophages. In the second stage of established pulmonary disease without and with hypoxia, viral multiplication and localized inflammation occurs. The third stage COVID-19 is the most severe, characterized by systemic hyperinflammation, acute respiratory distress syndrome (ARDS) and generalized microangiopathy, with significantly elevated biomarkers including IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, tumor necrosis factor-α, C-reactive protein, ferritin, D-dimer, von Willebrand factor (vWF) and thrombomodulin (TM). Evidence suggests that endothelial damage and activation play a key role in the pathobiology of the disease, and thus protecting endothelium and reversing endotheliitis may be a key therapeutic goal (Teuwen et al,Nat Rev Immunol2020). Defibrotide (DF), a complex mixture of poly-deoxyribonucleotides extracted from porcine mucosa, modulates expression of thrombogenic and inflammatory mediators produced in response to endothelial cell injury and/or leukocyte activation. DF increases tissue plasminogen activator (t-PA) and TM expression, thereby enhancing the enzymatic activity of plasmin to hydrolyze fibrin clot, while also decreasing vWF and plasminogen activator inhibitor-1 (PAI-1). Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) (Falanga A et al,Leukemia 2003). Anti-inflammatory properties via inhibition of p38 MAPK pathway have been demonstrated with DF, attenuating the release of inflammatory mediators including IL-6, thromboxane A2, leukotriene B4, tumor necrosis factor-alpha, and reactive oxygen species (Mitsiades et al,Clin Cancer Res2009). Additionally, DF inhibits both the expression and activity of heparanase, which in turn modulates heparan sulfate, a vital moiety for viral infection (Richardson et al,Blood Adv2018; Koganti et al,Cell Mol Life Sci2020). DF also modulates endothelial cell injury in murine models by down-regulating the expression of endothelial cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are critical to leukocyte adhesion and migration, and by increasing the endothelial cell release of anti-inflammatory cytokines, conferring survival benefit (Garcia-Bernal et al,J Cell Mol Med2020). DF is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) complicating stem cell transplantation and has demonstrated efficacy and safety in critically ill patients with multi-organ failure, underpinned by vasculopathy, endotheliitis, immune activation and hemorrhagic risk (Richardson et al,Blood2016). This multi-target and pleiotropic approach makes DF an attractive candidate for the treatment of advanced stage COVID 19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality (Figure 1). Various clinical studies in Spain, Italy, Ireland, the UK and USA are underway, with the larger randomized placebo-controlled prospective phase 2 study in Spain (clinicaltrials.gov: NCT04348383) leading in accrual with promising early results, demonstrating safety to date with potential efficacy, as reflected by favorable outcome in a subset of intubated patients as part of an ongoing multi-center trial. Other studies within the group have focused on safety and particularly the therapeutic role of DF in advanced disease, including those patients requiring extracorporeal membrane oxygenation (ECMO) and full dose systemic anticoagulation. These trials include common in-depth biological correlatives, assessing biomarkers including heparanase, inflammatory cytokines, immune cell sub-populations, vWF and soluble TM, as well as other novel markers and pharmacokinetics. In aggregate, these studies will hopefully help demonstrate the effects of DF on the proposed targets in COVID-19 and successfully correlate these effects with improved clinical outcome. Disclosures Moraleda: Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis, Sandoz, Takeda:Honoraria;Gilead:Honoraria, Other: Travel expenses.Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca:Honoraria;Boehringer Ingelheim and Sanofi:Consultancy;ADC Therapeutics and Rhizen Pharmaceuticals:Research Funding.Jara Rubio:Edwards Lifesciences, Getinge:Honoraria.Diaz-Ricart:Jazz Pharmaceuticals:Honoraria, Research Funding;German Jose Carreras Leukaemia Foundation:Research Funding.Carreras:Jazz Pharmaceuticals:Research Funding, Speakers Bureau;German Jose´ Carreras Leukaemia Foundation:Research Funding.Mo:Celgene/BMS:Membership on an entity's Board of Directors or advisory committees.Cooke:Jazz Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.Soiffer:Be the Match/ National Marrow Donor Program:Membership on an entity's Board of Directors or advisory committees;alexion:Consultancy;Celgene:Membership on an entity's Board of Directors or advisory committees;Juno:Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy;VOR Biopharma:Consultancy;Mana Therapeutics:Consultancy;Precision Bioscience:Consultancy;Cugene:Consultancy;Rheos Therapeutics:Consultancy;Gilead:Consultancy;Kiadis:Membership on an entity's Board of Directors or advisory committees.Baron:Genetech:Consultancy;Merck:Consultancy.Pagliuca:Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm:Research Funding. OffLabel Disclosure: Defibrotide used for the treatment of endotheliitis complicating SARS-Cov-2 infection

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