The Experts below are selected from a list of 180 Experts worldwide ranked by ideXlab platform
Paul Simon - One of the best experts on this subject based on the ideXlab platform.
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The decellularized porcine heart valve matrix in tissue engineering
Thrombosis and Haemostasis, 2020Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Guenter Weigel, Jyotindra Sharma, Paul SimonAbstract:SummaryAn approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation. The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet Activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on Thrombocyte Activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630® followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-1 (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde. Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet Activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and Activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.
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Decellularization does not eliminate thrombogenicity and inflammatory stimulation in tissue-engineered porcine heart valves.
Journal of Heart Valve Disease, 2006Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Anneliese Nigisch, Barbara Dekan, G. Weigel, Paul SimonAbstract:In tissue engineering of heart valves using decellularized xenogenic valves, it has been suggested that cell elimination would result in a biologically inert matrix. The aim of this in-vitro investigation was to evaluate different decellularization methods in regard to the completeness of cell removal, inflammatory response, and Thrombocyte Activation. Decellularized porcine Synergraft valves were compared with porcine pulmonary conduits decellularized with Triton X-100, sodium deoxycholate, Igepal CA-630 and ribonuclease. Completeness of decellularization was evaluated with staining for nuclei and alpha-Gal epitope. Decellularized heart valves with and without seeding with endothelial cells (ECs) were incubated with human platelet-rich plasma and stained for CD41 and PAC-1 to evaluate Thrombocyte Activation. Samples were processed for laser scanning microscopy (LSM) and scanning electron microscopy (SEM). Migration of human monocytic cells towards extracted valve proteins was tested. In contrast to the Synergraft, complete cell removal and elimination of the alpha-gal epitope was achieved with the new decellularization method. Numerous adherent and activated platelets were found on the decellularized matrix. This was inhibited by seeding with ECs. Even in completely cell-free valve tissue extracellular matrix proteins attracted human monocytic cells as in early inflammation, depending on whether porcine or human tissue was used. Important differences were found in the decellularization efficacy of treatment methods. However, even complete elimination of cells and their remnants did not result in a biologically inert matrix. The decellularized porcine heart valve matrix has the potential to attract inflammatory cells and to induce platelet Activation. These findings suggest that it will be important to control the different inflammation-stimulating factors if porcine tissues are to be used successfully in tissue engineering.
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Tissue Engineering of heart valves—Immunologic and inflammatory challenges of the allograft scaffold
Progress in Pediatric Cardiology, 2006Co-Authors: Paul Simon, Marie-theres Kasimir, Erwin Rieder, Guenter WeigelAbstract:Abstract Tissue Engineering of heart valves is aimed to produce valve substitutes which are accepted by the recipient indistinguishable of his own valve, function physiologically from the day of the implantation, perform reliably during the early remodeling period and long term and importantly to have growth potential in children. However, many challenges have to be overcome to realize this goal. Some of these relate to design, defining the ideal scaffold for such a heart valve and the ideal cell source and method of repopulation of the scaffold with cells. The focus of this review is the challenges posed by the immunologic and inflammatory responses of the host against tissue engineered heart valves, specifically of decellularized xenogeneic and allogeneic tissues. Decellularization is being used as the method of choice to reduce or eliminate the cellular components of both xenogeneinc and allogeneic tissues. It has been documented that completeness of decellularization is important and the various protocols described in the literature differ importantly. In incompletely decellularized porcine tissue the xenoantigen Gal (alpha 1,3) Gal is detected which may be responsible for an immediate hyperacute rejection type host response. Thrombocyte Activation and inflammation are closely interrelated. Thrombocyte adherence and Activation in both human and porcine decellularized tissue was observed and was prevented by reseeding with endothelial cells. Decellularization was furthermore documented to reduce the early non-specific inflammatory response more in human tissues than in porcine tissues. The specific humoral host response against decellularized allografts has been documented clinically. We conclude that complete decellularization is suitable to reduce the specific host response against human tissue. The early inflammatory stimulus is also more effectively reduced in human tissue. Ex vivo repopulation of the scaffold appears necessary to avoid Thrombocyte Activation after implantation which may induce, perpetuate and increase early inflammation.
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The decellularized porcine heart valve matrix in tissue engineering Platelet adhesion and Activation
Thrombosis and Haemostasis, 2005Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Guenter Weigel, Jyotindra Sharma, Paul SimonAbstract:An approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation.The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet Activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on Thrombocyte Activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630 ® followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-1 (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde.Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet Activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and Activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.
Roland Prondzinsky - One of the best experts on this subject based on the ideXlab platform.
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Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia
Clinical Research in Cardiology, 2007Co-Authors: Samir M. Said, Judit Hahn, E Schleyer, Marc Müller, Georg Martin Fiedler, Michael Buerke, Roland ProndzinskyAbstract:Thrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby Thrombocyte aggregation. The inhibition of Thrombocyte Activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI). Thrombocytopenia is a known complication of glycoprotein (GP) IIb/IIIa inhibitors. Although, in general, GP IIb/IIIa inhibitor-induced thrombocytopenia is a harmless side effect which responds readily to Thrombocyte transfusion, it can occasionally be a very serious complication associated with serious bleeding. In addition patients developing thrombocytopenia have unfavorable outcome (e.g., death, myocardial infarction, bypass surgery or additional PCI) in comparison to patients without thrombocytopenia. Advanced age (> 65 years), low BMI and a low initial Thrombocyte count (
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Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia : Diagnosis and treatment
Clinical Research in Cardiology, 2006Co-Authors: Samir M. Said, Judit Hahn, E Schleyer, Marc Müller, Georg Martin Fiedler, Michael Buerke, Roland ProndzinskyAbstract:Thrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby Thrombocyte aggregation. The inhibition of Thrombocyte Activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI).
Marie-theres Kasimir - One of the best experts on this subject based on the ideXlab platform.
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The decellularized porcine heart valve matrix in tissue engineering
Thrombosis and Haemostasis, 2020Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Guenter Weigel, Jyotindra Sharma, Paul SimonAbstract:SummaryAn approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation. The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet Activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on Thrombocyte Activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630® followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-1 (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde. Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet Activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and Activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.
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Decellularization does not eliminate thrombogenicity and inflammatory stimulation in tissue-engineered porcine heart valves.
Journal of Heart Valve Disease, 2006Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Anneliese Nigisch, Barbara Dekan, G. Weigel, Paul SimonAbstract:In tissue engineering of heart valves using decellularized xenogenic valves, it has been suggested that cell elimination would result in a biologically inert matrix. The aim of this in-vitro investigation was to evaluate different decellularization methods in regard to the completeness of cell removal, inflammatory response, and Thrombocyte Activation. Decellularized porcine Synergraft valves were compared with porcine pulmonary conduits decellularized with Triton X-100, sodium deoxycholate, Igepal CA-630 and ribonuclease. Completeness of decellularization was evaluated with staining for nuclei and alpha-Gal epitope. Decellularized heart valves with and without seeding with endothelial cells (ECs) were incubated with human platelet-rich plasma and stained for CD41 and PAC-1 to evaluate Thrombocyte Activation. Samples were processed for laser scanning microscopy (LSM) and scanning electron microscopy (SEM). Migration of human monocytic cells towards extracted valve proteins was tested. In contrast to the Synergraft, complete cell removal and elimination of the alpha-gal epitope was achieved with the new decellularization method. Numerous adherent and activated platelets were found on the decellularized matrix. This was inhibited by seeding with ECs. Even in completely cell-free valve tissue extracellular matrix proteins attracted human monocytic cells as in early inflammation, depending on whether porcine or human tissue was used. Important differences were found in the decellularization efficacy of treatment methods. However, even complete elimination of cells and their remnants did not result in a biologically inert matrix. The decellularized porcine heart valve matrix has the potential to attract inflammatory cells and to induce platelet Activation. These findings suggest that it will be important to control the different inflammation-stimulating factors if porcine tissues are to be used successfully in tissue engineering.
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Tissue Engineering of heart valves—Immunologic and inflammatory challenges of the allograft scaffold
Progress in Pediatric Cardiology, 2006Co-Authors: Paul Simon, Marie-theres Kasimir, Erwin Rieder, Guenter WeigelAbstract:Abstract Tissue Engineering of heart valves is aimed to produce valve substitutes which are accepted by the recipient indistinguishable of his own valve, function physiologically from the day of the implantation, perform reliably during the early remodeling period and long term and importantly to have growth potential in children. However, many challenges have to be overcome to realize this goal. Some of these relate to design, defining the ideal scaffold for such a heart valve and the ideal cell source and method of repopulation of the scaffold with cells. The focus of this review is the challenges posed by the immunologic and inflammatory responses of the host against tissue engineered heart valves, specifically of decellularized xenogeneic and allogeneic tissues. Decellularization is being used as the method of choice to reduce or eliminate the cellular components of both xenogeneinc and allogeneic tissues. It has been documented that completeness of decellularization is important and the various protocols described in the literature differ importantly. In incompletely decellularized porcine tissue the xenoantigen Gal (alpha 1,3) Gal is detected which may be responsible for an immediate hyperacute rejection type host response. Thrombocyte Activation and inflammation are closely interrelated. Thrombocyte adherence and Activation in both human and porcine decellularized tissue was observed and was prevented by reseeding with endothelial cells. Decellularization was furthermore documented to reduce the early non-specific inflammatory response more in human tissues than in porcine tissues. The specific humoral host response against decellularized allografts has been documented clinically. We conclude that complete decellularization is suitable to reduce the specific host response against human tissue. The early inflammatory stimulus is also more effectively reduced in human tissue. Ex vivo repopulation of the scaffold appears necessary to avoid Thrombocyte Activation after implantation which may induce, perpetuate and increase early inflammation.
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The decellularized porcine heart valve matrix in tissue engineering Platelet adhesion and Activation
Thrombosis and Haemostasis, 2005Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Guenter Weigel, Jyotindra Sharma, Paul SimonAbstract:An approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation.The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet Activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on Thrombocyte Activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630 ® followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-1 (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde.Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet Activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and Activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.
Ernst Wolner - One of the best experts on this subject based on the ideXlab platform.
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The decellularized porcine heart valve matrix in tissue engineering
Thrombosis and Haemostasis, 2020Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Guenter Weigel, Jyotindra Sharma, Paul SimonAbstract:SummaryAn approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation. The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet Activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on Thrombocyte Activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630® followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-1 (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde. Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet Activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and Activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.
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Decellularization does not eliminate thrombogenicity and inflammatory stimulation in tissue-engineered porcine heart valves.
Journal of Heart Valve Disease, 2006Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Anneliese Nigisch, Barbara Dekan, G. Weigel, Paul SimonAbstract:In tissue engineering of heart valves using decellularized xenogenic valves, it has been suggested that cell elimination would result in a biologically inert matrix. The aim of this in-vitro investigation was to evaluate different decellularization methods in regard to the completeness of cell removal, inflammatory response, and Thrombocyte Activation. Decellularized porcine Synergraft valves were compared with porcine pulmonary conduits decellularized with Triton X-100, sodium deoxycholate, Igepal CA-630 and ribonuclease. Completeness of decellularization was evaluated with staining for nuclei and alpha-Gal epitope. Decellularized heart valves with and without seeding with endothelial cells (ECs) were incubated with human platelet-rich plasma and stained for CD41 and PAC-1 to evaluate Thrombocyte Activation. Samples were processed for laser scanning microscopy (LSM) and scanning electron microscopy (SEM). Migration of human monocytic cells towards extracted valve proteins was tested. In contrast to the Synergraft, complete cell removal and elimination of the alpha-gal epitope was achieved with the new decellularization method. Numerous adherent and activated platelets were found on the decellularized matrix. This was inhibited by seeding with ECs. Even in completely cell-free valve tissue extracellular matrix proteins attracted human monocytic cells as in early inflammation, depending on whether porcine or human tissue was used. Important differences were found in the decellularization efficacy of treatment methods. However, even complete elimination of cells and their remnants did not result in a biologically inert matrix. The decellularized porcine heart valve matrix has the potential to attract inflammatory cells and to induce platelet Activation. These findings suggest that it will be important to control the different inflammation-stimulating factors if porcine tissues are to be used successfully in tissue engineering.
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The decellularized porcine heart valve matrix in tissue engineering Platelet adhesion and Activation
Thrombosis and Haemostasis, 2005Co-Authors: Marie-theres Kasimir, Ernst Wolner, Erwin Rieder, Gernot Seebacher, Guenter Weigel, Jyotindra Sharma, Paul SimonAbstract:An approach in tissue engineering of heart valves is the use of decellularized xenogeneic matrices to avoid immune response after implantation.The decellularization process must preserve the structural components of the extracellular matrix to provide a biomechanically stable scaffold. However, it is known that in vascular lesions platelet adhesion to extracellular matrix components occurs and platelet Activation is induced. In the present study we examined the effects of a decellularized porcine heart valve matrix on Thrombocyte Activation and the influence of re-endothelialisation in vitro. Porcine pulmonary conduits were decellularized using Triton X-100, Na-deoxycholate and Igepal CA-630 ® followed by a ribonuclease digestion. Cryostat sections of decellularized heart valves with and without seeding with human umbilical vein endothelial cells (HUVEC) were incubated with platelet rich plasma. Samples were either stained with fluorescent antibodies for CD41 and PAC-1 (recognizing the activated fibrinogen receptor) or fixed with glutaraldehyde.Thereafter, the samples were processed for laser scanning microscopy (LSM) or scanning electron microscopy (SEM). Examination by LSM showed numerous platelets with co-localized staining for CD41 and PAC-1 on the nonseeded decellularized heart valve matrix whereas after seeding with endothelial cells no platelet Activation was detected. SEM revealed platelet adhesion and aggregate formation only on the surface of the non-seeded or partially denuded matrix specimens. We show in this study that the decellularized porcine matrix acts as a platelet-activating surface. Seeding with endothelial cells effectively abolishes the platelet adhesion and Activation and therefore is necessary to eliminate thrombogenicity in tissue engineered heart valves.
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MIE - Whole Blood Aggregometry: A PC-Based System for Clinical Routine Application
Medical Informatics Europe 1991, 1991Co-Authors: Wolfgang Schreiner, M. R. Müller, Wolfgang Premauer, Ernst WolnerAbstract:Thrombocyte disfunction adds an important risk factor, especially for patients in the intensive care after cardiovascular surgery. Unintended Thrombocyte Activation may cause thromboembolic complications, whereas insufficient aggregability leads to bleedings, regardless of normal coagulation parameters. Whole blood electrical aggregometry (1), designed to assess Thrombocyte function, is therefore a valuable diagnostic tool, capable of rapidly screening Thrombocyte (“platelet”) function (3).
Stefan H Oehlers - One of the best experts on this subject based on the ideXlab platform.
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Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, Tuong Nguyen, Jordan A Shavit, Warwick J Britton, David M Tobin, Johansen, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for infection-induced Thrombocyte Activation. We find that the reduction in mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that infection-induced platelet Activation compromises protective host immunity to mycobacterial infection. Our study illuminates platelet Activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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Thrombocyte inhibition restores protective immunity to mycobacterial infection
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, Matt D Johansen, Tuong Nguyen, Jordan A Shavit, Warwick J Britton, David M Tobin, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action. Here we utilise the zebrafish-Mycobacterium marinum model to show mycobacteria drive host haemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for infection-induced Thrombocyte Activation. We find that the reduction in mycobacterial burden is dependent on macrophages and granuloma formation providing the first in vivo experimental evidence that infection-induced platelet Activation compromises protective host immunity to mycobacterial infection. Our study illuminates platelet Activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
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inhibition of Thrombocyte Activation restores protective immunity to mycobacterial infection
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, Matt D Johansen, Tuong Nguyen, Jordan A Shavit, Warwick J Britton, David M Tobin, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action. Here we utilise the zebrafish-Mycobacterium marinum model to show mycobacteria drive host haemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for infection-induced Thrombocyte Activation. We find that the reduction in mycobacterial burden is dependent on macrophages and granuloma formation providing the first in vivo experimental evidence that infection-induced platelet Activation compromises protective host immunity to mycobacterial infection. Our study illuminates platelet Activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.