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Elena Y Senchenkova, Janice Russell, Alper Yildirim, D Neil Granger, Felicity N E Gavins
Hypertension is an established risk factor for subsequent cardiovascular diseases, with Ang II (angiotensin II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and IL-6 (interleukin-6) play an important role in adaptive immune responses, little is known about their role(s) in the thromboinflammatory responses associated with Ang II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1-/- ) and IL-6 deficient (IL-6-/- ) mice are afforded protection against Ang II-induced thrombosis...
February 11, 2019: Hypertension
Shaun P Jackson, Roxane Darbousset, Simone M Schoenwaelder
Thrombosis with associated inflammation (thromboinflammation) occurs commonly in a broad range of human disorders. It is well recognized clinically in the context of superficial thrombophlebitis (thrombosis and inflammation of superficial veins), however it is more dangerous when it develops in the microvasculature of injured tissues and organs. Microvascular thrombosis with associated inflammation is well recognized in the context of sepsis and ischemia-reperfusion injury, however it also occurs in organ transplant rejection, major trauma, severe burns, the antiphospholipid syndrome, preeclampsia, sickle cell disease and biomaterial-induced thromboinflammation...
January 14, 2019: Blood
Maximilian Mauler, Nadine Herr, Claudia Schoenichen, Thilo Witsch, Timoteo Marchini, Carmen Härdtner, Christoph Koentges, Korbinian Kienle, Veronique Ollivier, Maximilian Schell, Ludwig Dorner, Christopher Wippel, Daniela Stallmann, Claus Normann, Heiko Bugger, Paul Walther, Dennis Wolf, Ingo Ahrens, Tim Lämmermann, Benoît Ho-Tin-Noé, Klaus Ley, Christoph Bode, Ingo Hilgendorf, Daniel Duerschmied
BACKGROUND: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. METHODS: Infarct size, heart function and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacologic depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome...
October 25, 2018: Circulation
Eleni Frangou, Akrivi Chrysanthopoulou, Alexandros Mitsios, Konstantinos Kambas, Stella Arelaki, Iliana Angelidou, Athanasios Arampatzioglou, Hariklia Gakiopoulou, George K Bertsias, Panayotis Verginis, Konstantinos Ritis, Dimitrios T Boumpas
OBJECTIVES: The release of neutrophil extracellular traps (NETs) represents a novel neutrophil effector function in systemic lupus erythematosus (SLE) pathogenesis. However, the molecular mechanism underlying NET release and how NETs mediate end-organ injury in SLE remain elusive. METHODS: NET formation and NET-related proteins were assessed in the peripheral blood and biopsies from discoid lupus and proliferative nephritis, using immunofluorescence, immunoblotting, quantitative PCR and ELISA...
December 18, 2018: Annals of the Rheumatic Diseases
Susanne Karbach, Jérémy Lagrange, Philip Wenzel
Thromboinflammation and vascular dysfunction are inseparably combined with the innate and the adaptive immune response. While the role of this interplay has gained considerable attention in the arena of atherosclerosis/atherothrombosis and in deep vein thrombosis, its role in other forms of vascular disease and risk factors is currently emerging. In this brief review, we will focus on thromboinflammation with regard to cytokine signalling as well as on the novel role of a vascular coagulation-inflammatory circuit in arterial hypertension...
December 4, 2018: Hämostaseologie
Dimitrios C Mastellos, Edimara S Reis, Ali-Reza Biglarnia, Meryl Waldman, Richard J Quigg, Markus Huber-Lang, Marc A Seelen, Mohamed R Daha, John D Lambris
Owing to an increasing shortage of donor organs, the majority of patients with end-stage kidney disease remains reliant on extracorporeal hemodialysis (HD) in order to counter the lifelong complications of a failing kidney. While HD remains a life-saving option for these patients, mounting evidence suggests that it also fuels a vicious cycle of thromboinflammation that can increase the risk of cardiovascular disease. During HD, blood-borne innate immune systems become inappropriately activated on the biomaterial surface, instigating proinflammatory reactions that can alter endothelial and vascular homeostasis...
November 22, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Paola E J van der Meijden, Johan W M Heemskerk
Platelets - blood cells continuously produced from megakaryocytes mainly in the bone marrow - are implicated not only in haemostasis and arterial thrombosis, but also in other physiological and pathophysiological processes. This Review describes current evidence for the heterogeneity in platelet structure, age, and activation properties, with consequences for a diversity of platelet functions. Signalling processes of platelet populations involved in thrombus formation with ongoing coagulation are well understood...
November 14, 2018: Nature Reviews. Cardiology
Mirjam Dreikorn, Zeljko Milacic, Vladimir Pavlovic, Sven G Meuth, Christoph Kleinschnitz, Peter Kraft
Background: 'Thromboinflammation' describes a novel concept in stroke pathophysiology that has opened up the possibility of immunotherapeutic approaches which could become promising strategies for targeted stroke therapies in the future. Methods: We reviewed current evidence for agents approved for multiple sclerosis in preclinical and clinical stroke studies. A systematic review was performed in accordance with the PRISMA statement, searching MEDLINE, the Cochrane Central Register of Controlled Trials, and reference lists of articles published until 16 October 2017...
2018: Therapeutic Advances in Neurological Disorders
Jean-Philippe Desilles, Varouna Syvannarath, Lucas Di Meglio, Célina Ducroux, William Boisseau, Liliane Louedec, Martine Jandrot-Perrus, Jean-Baptiste Michel, Mikael Mazighi, Benoît Ho-Tin-Noé
BACKGROUND: Previous experimental studies have shown that downstream microvascular thromboinflammation is involved in brain damage from acute ischemic stroke. Using intravital microscopy, we investigated and characterized the sequence of downstream microvascular thromboinflammation in an ischemia/reperfusion acute ischemic stroke model. METHODS AND RESULTS: Rats underwent transient monofilament middle cerebral artery (MCA) occlusion. Cerebral microcirculation in the MCA territory was exposed through a craniotomy and analyzed using real-time intravital imaging coupled with laser Doppler interferometry...
March 1, 2018: Journal of the American Heart Association
Adam Z Blatt, Gurpanna Saggu, Claudio Cortes, Andrew P Herbert, David Kavanagh, Daniel Ricklin, John D Lambris, Viviana P Ferreira
Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndrome (aHUS), yet it is unknown whether increased PGA formation contributes to the thrombosis seen in patients with aHUS. Here, flow cytometry assays were used to evaluate the effects of aHUS-related mutations on FH regulation of PGA formation and characterize the mechanism...
2017: Frontiers in Immunology
Rong Jin, Adam Y Xiao, Rui Chen, D Neil Granger, Guohong Li
BACKGROUND AND PURPOSE: Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses...
December 2017: Stroke; a Journal of Cerebral Circulation
Devin W McBride, Spiros L Blackburn, Kumar T Peeyush, Kanako Matsumura, John H Zhang
Delayed cerebral ischemia (DCI) is a major determinant of patient outcome following aneurysmal subarachnoid hemorrhage. Although the exact mechanisms leading to DCI are not fully known, inflammation, cerebral vasospasm, and microthrombi may all function together to mediate the onset of DCI. Indeed, inflammation is tightly linked with activation of coagulation and microthrombi formation. Thromboinflammation is the intersection at which inflammation and thrombosis regulate one another in a feedforward manner, potentiating the formation of thrombi and pro-inflammatory signaling...
2017: Frontiers in Neurology
Anke C Fender, Bernhard H Rauch, Tobias Geisler, Karsten Schrör
Thrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions...
November 2017: Thrombosis and Haemostasis
Saskia N I von Ungern-Sternberg, Sebastian Vogel, Britta Walker-Allgaier, Sascha Geue, Andreas Maurer, Anna-Maria Wild, Patrick Münzer, Madhumita Chatterjee, David Heinzmann, Elisabeth Kremmer, Oliver Borst, Patricia Loughran, Alma Zernecke, Matthew D Neal, Timothy R Billiar, Meinrad Gawaz, Peter Seizer
Cyclophilin A (CyPA) is involved in the pathophysiology of several inflammatory and cardiovascular diseases. To our knowledge, there is no specific inhibitor targeting extracellular CyPA without affecting other extracellular cyclophilins or intracellular CyPA functions. In this study, we developed an antibody-based inhibitor of extracellular CyPA and analysed its effects in vitro and in vivo . To generate a specific antibody, mice and rats were immunized with a peptide containing the extracellular matrix metalloproteinase inducer binding site and various antibody clones were selected and purified...
November 2017: Thrombosis and Haemostasis
Akrivi Chrysanthopoulou, Konstantinos Kambas, Dimitrios Stakos, Ioannis Mitroulis, Alexandros Mitsios, Veroniki Vidali, Iliana Angelidou, Magdalena Bochenek, Stella Arelaki, Athanasios Arampatzioglou, Ioanna-Evdokia Galani, Panagiotis Skendros, Elias A Couladouros, Stavros Konstantinides, Evangelos Andreakos, Katrin Schäfer, Konstantinos Ritis
Neutrophils and neutrophil-released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN-λ1/IL-29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST-segment elevation myocardial infarction (STEMI), we show that IFN-λ1/IL-29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils...
September 2017: Journal of Pathology
Jing Li, Jaehyung Cho
PURPOSE OF REVIEW: Interactions between neutrophils and platelets contribute to the progression of thromboinflammatory disease. However, the regulatory mechanism governing these interactions is poorly understood. The present review focuses on the crucial role of Ser/Thr protein kinase B (AKT)β-NADPH oxidase 2 (NOX2) signaling in regulating neutrophil and platelet activation and their heterotypic interactions under thromboinflammatory conditions. RECENT FINDINGS: Growing evidence has shown that platelets, leukocytes, and blood coagulation need to be considered to treat thromboinflammatory disease in which inflammation and thrombosis occur concurrently...
September 2017: Current Opinion in Hematology
Felice Gragnano, Simona Sperlongano, Enrica Golia, Francesco Natale, Renatomaria Bianchi, Mario Crisci, Fabio Fimiani, Ivana Pariggiano, Vincenzo Diana, Andreina Carbone, Arturo Cesaro, Claudia Concilio, Giuseppe Limongelli, Mariagiovanna Russo, Paolo Calabrò
Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions...
2017: Mediators of Inflammation
Jean-Philippe Desilles, Varouna Syvannarath, Véronique Ollivier, Clément Journé, Sandrine Delbosc, Célina Ducroux, William Boisseau, Liliane Louedec, Lucas Di Meglio, Stéphane Loyau, Martine Jandrot-Perrus, Louis Potier, Jean-Baptiste Michel, Mikael Mazighi, Benoit Ho-Tin-Noé
BACKGROUND AND PURPOSE: Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. METHODS: Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging...
July 2017: Stroke; a Journal of Cerebral Circulation
Lina Paola D' Atri, Mirta Schattner
Besides their undiscussed role in hemostasis and thrombosis, platelets are also key effector cells capable of assisting and modulating inflammatory reactions and immune responses. Platelets play a sentinel role in immune surveillance by recognizing danger signals from pathogens and cell damage through the expression of toll-like receptors (TLRs) on its surface and internal compartments. Platelets express all 10 TLRs transcripts and its signalosome, including adaptor proteins and transcription factors. The activation of these receptors in platelets triggers hemostatic and inflammatory responses which participate in the host's response to bacterial and viral infections, linking thrombosis with infection and immunity...
June 1, 2017: Frontiers in Bioscience (Landmark Edition)
Katsue Suzuki-Inoue
No abstract text is available yet for this article.
April 6, 2017: Blood
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