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Vera Jankowski - One of the best experts on this subject based on the ideXlab platform.
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P1101A BIFUNCTIONAL ADSORBER PARTICLE FOR THE REMOVAL OF HYDROPHOBIC UREMIC TOXINS FROM WHOLE BLOOD OF RENAL FAILURE PATIENTS
Nephrology Dialysis Transplantation, 2020Co-Authors: Marieke Sternkopf, Thimoteus Speer, Claudia Göttsch, Vera Jankowski, Joachim Jankowski, Heidi NoelsAbstract:Abstract Background and Aims Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. Method We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. Results A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on Complement Component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. Conclusion In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.
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A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients
Toxins, 2019Co-Authors: Marieke Sternkopf, Thimoteus Speer, Sven Thoröe-boveleth, Tobias Beck, Kirsten Oleschko, Ansgar Erlenkötter, Ulrich Tschulena, Sonja Steppan, Claudia Goettsch, Vera JankowskiAbstract:Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on Complement Component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.
Marieke Sternkopf - One of the best experts on this subject based on the ideXlab platform.
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P1101A BIFUNCTIONAL ADSORBER PARTICLE FOR THE REMOVAL OF HYDROPHOBIC UREMIC TOXINS FROM WHOLE BLOOD OF RENAL FAILURE PATIENTS
Nephrology Dialysis Transplantation, 2020Co-Authors: Marieke Sternkopf, Thimoteus Speer, Claudia Göttsch, Vera Jankowski, Joachim Jankowski, Heidi NoelsAbstract:Abstract Background and Aims Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. Method We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. Results A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on Complement Component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. Conclusion In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.
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A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients
Toxins, 2019Co-Authors: Marieke Sternkopf, Thimoteus Speer, Sven Thoröe-boveleth, Tobias Beck, Kirsten Oleschko, Ansgar Erlenkötter, Ulrich Tschulena, Sonja Steppan, Claudia Goettsch, Vera JankowskiAbstract:Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on Complement Component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.
Trent M. Woodruff - One of the best experts on this subject based on the ideXlab platform.
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The Alternative Receptor for Complement Component 5a, C5aR2, Conveys Neuroprotection in Traumatic Spinal Cord Injury.
Journal of neurotrauma, 2017Co-Authors: Patrick J. Biggins, Trent M. Woodruff, Stephen M. Taylor, Faith H. Brennan, Marc J. RuitenbergAbstract:Abstract This study investigated the role of the alternative receptor for Complement activation fragment C5a, C5aR2, in secondary inflammatory pathology after contusive spinal cord injury (SCI) in mice. C5ar2–/– mice exhibited decreased intraparenchymal tumor necrosis factor alpha and interleukin-6 acutely post-injury, but these reductions did not translate into improved outcomes. We show that loss of C5aR2 leads to increased lesion volumes, reduced myelin sparing, and significantly worsened recovery from SCI in C5ar2–/– animals compared to wild-type (WT) controls. Loss of C5aR2 did not alter leukocyte mobilization from the bone marrow in response to SCI, and neutrophil recruitment/presence at the lesion site was also not different between genotypes. Acute treatment of SCI mice with the selective C5aR1 antagonist, PMX205, improved SCI outcomes, compared to vehicle controls, and, importantly, fully alleviated the worsened recovery of C5ar2–/– mice compared to their WT counterparts. Collectively, these find...
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Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2016Co-Authors: Amanda J. Fisher, Trent M. Woodruff, Elizabeth A. Mickler, Frank Duerson, Oscar W. Cummings, Marc Peters-golden, Homer L. Twigg, David S. Wilkes, Ragini VittalAbstract:Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Whereas we have previously reported elevated anaphylatoxins-Complement Component 3a (C3a) and Complement Component 5a (C5a)-in IPF, which interact with TGF-β and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors (C3aR and C5aR) in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of C3aR and C5aR in lung fibrosis by using bleomycin-injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition (Masson's trichrome, hydroxyproline, collagen type I α 1 chain, and collagen type I α 2 chain). Pharmacologic or RNA interference-specific interventions suppressed Complement activation (C3a and C5a) and soluble terminal Complement complex formation (C5b-9) locally and active TGF-β1 systemically. C3aR/C5aR antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of C5aR, local and systemic induction of soluble C5b-9, and amplified expression of C3aR/C5aR in lesions. The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local Complement activation and TGF-β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis.
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Complement in Pregnancy: A Delicate Balance
American journal of reproductive immunology (New York N.Y. : 1989), 2012Co-Authors: Kerina J. Denny, Trent M. Woodruff, Stephen M. Taylor, Leonie K. CallawayAbstract:The Complement system is a key Component of innate host defence that, under normal conditions, is responsible for the opsonization and destruction of potential pathogens. However, inappropriate or excessive activation of Complement can have a detrimental effect on the host and has been implicated in the pathophysiology of numerous disease states. Recently, there has been increasing evidence for a role of the Complement system and, in particular, the potent pro-inflammatory anaphylatoxin Complement Component 5a (C5a) in both normal and complicated pregnancy. The following review describes the results of in vitro, animal, and human clinical studies investigating the role of the Complement system in healthy pregnancy, recurrent miscarriage, preterm birth, and preeclampsia.
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Complement Component 5a (C5a).
The international journal of biochemistry & cell biology, 2009Co-Authors: Helga D. Manthey, Trent M. Woodruff, Stephen M. Taylor, Peter N. MonkAbstract:The 74 amino acid glycoprotein, Complement Component 5a (C5a), is a potent pro-inflammatory mediator cleaved enzymatically from its precursor, C5, upon activation of the Complement cascade. C5a is quickly metabolised by carboxypeptidases, forming the less potent C5adesArg. Acting via a classical G protein-coupled receptor, CD88, C5a and C5adesArg exert a number of effects essential to the innate immune response, while their actions at the more recently discovered non-G protein-coupled receptor, C5L2 (or GPR77), remain unclear. The widespread expression of C5a receptors throughout the body allows C5a to elicit a broad range of effects. Thus, C5a has been found to be a significant pathogenic driver in a number of immuno-inflammatory diseases, making C5a inhibition an attractive therapeutic strategy.
Marc J. Ruitenberg - One of the best experts on this subject based on the ideXlab platform.
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The Alternative Receptor for Complement Component 5a, C5aR2, Conveys Neuroprotection in Traumatic Spinal Cord Injury.
Journal of neurotrauma, 2017Co-Authors: Patrick J. Biggins, Trent M. Woodruff, Stephen M. Taylor, Faith H. Brennan, Marc J. RuitenbergAbstract:Abstract This study investigated the role of the alternative receptor for Complement activation fragment C5a, C5aR2, in secondary inflammatory pathology after contusive spinal cord injury (SCI) in mice. C5ar2–/– mice exhibited decreased intraparenchymal tumor necrosis factor alpha and interleukin-6 acutely post-injury, but these reductions did not translate into improved outcomes. We show that loss of C5aR2 leads to increased lesion volumes, reduced myelin sparing, and significantly worsened recovery from SCI in C5ar2–/– animals compared to wild-type (WT) controls. Loss of C5aR2 did not alter leukocyte mobilization from the bone marrow in response to SCI, and neutrophil recruitment/presence at the lesion site was also not different between genotypes. Acute treatment of SCI mice with the selective C5aR1 antagonist, PMX205, improved SCI outcomes, compared to vehicle controls, and, importantly, fully alleviated the worsened recovery of C5ar2–/– mice compared to their WT counterparts. Collectively, these find...
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Targeting acute inflammation to Complement spinal cord repair.
Neural regeneration research, 2015Co-Authors: Faith H. Brennan, Marc J. RuitenbergAbstract:Immune effector mechanisms play key roles in the progressive (secondary) neurodegenerative changes that follow spinal cord injury (SCI). In our recent paper (Brennan et al., 2015), we showed that the inflammatory response to SCI includes rapid and robust activation of the innate immune Complement system, with tissue levels of Complement Component 5a (C5a – an activation product generated by the proteolysis of Complement factor 5 (C5)) peaking 12 to 24 hours post-injury.
Stephen M. Taylor - One of the best experts on this subject based on the ideXlab platform.
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The Alternative Receptor for Complement Component 5a, C5aR2, Conveys Neuroprotection in Traumatic Spinal Cord Injury.
Journal of neurotrauma, 2017Co-Authors: Patrick J. Biggins, Trent M. Woodruff, Stephen M. Taylor, Faith H. Brennan, Marc J. RuitenbergAbstract:Abstract This study investigated the role of the alternative receptor for Complement activation fragment C5a, C5aR2, in secondary inflammatory pathology after contusive spinal cord injury (SCI) in mice. C5ar2–/– mice exhibited decreased intraparenchymal tumor necrosis factor alpha and interleukin-6 acutely post-injury, but these reductions did not translate into improved outcomes. We show that loss of C5aR2 leads to increased lesion volumes, reduced myelin sparing, and significantly worsened recovery from SCI in C5ar2–/– animals compared to wild-type (WT) controls. Loss of C5aR2 did not alter leukocyte mobilization from the bone marrow in response to SCI, and neutrophil recruitment/presence at the lesion site was also not different between genotypes. Acute treatment of SCI mice with the selective C5aR1 antagonist, PMX205, improved SCI outcomes, compared to vehicle controls, and, importantly, fully alleviated the worsened recovery of C5ar2–/– mice compared to their WT counterparts. Collectively, these find...
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Complement in Pregnancy: A Delicate Balance
American journal of reproductive immunology (New York N.Y. : 1989), 2012Co-Authors: Kerina J. Denny, Trent M. Woodruff, Stephen M. Taylor, Leonie K. CallawayAbstract:The Complement system is a key Component of innate host defence that, under normal conditions, is responsible for the opsonization and destruction of potential pathogens. However, inappropriate or excessive activation of Complement can have a detrimental effect on the host and has been implicated in the pathophysiology of numerous disease states. Recently, there has been increasing evidence for a role of the Complement system and, in particular, the potent pro-inflammatory anaphylatoxin Complement Component 5a (C5a) in both normal and complicated pregnancy. The following review describes the results of in vitro, animal, and human clinical studies investigating the role of the Complement system in healthy pregnancy, recurrent miscarriage, preterm birth, and preeclampsia.
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Complement Component 5a (C5a).
The international journal of biochemistry & cell biology, 2009Co-Authors: Helga D. Manthey, Trent M. Woodruff, Stephen M. Taylor, Peter N. MonkAbstract:The 74 amino acid glycoprotein, Complement Component 5a (C5a), is a potent pro-inflammatory mediator cleaved enzymatically from its precursor, C5, upon activation of the Complement cascade. C5a is quickly metabolised by carboxypeptidases, forming the less potent C5adesArg. Acting via a classical G protein-coupled receptor, CD88, C5a and C5adesArg exert a number of effects essential to the innate immune response, while their actions at the more recently discovered non-G protein-coupled receptor, C5L2 (or GPR77), remain unclear. The widespread expression of C5a receptors throughout the body allows C5a to elicit a broad range of effects. Thus, C5a has been found to be a significant pathogenic driver in a number of immuno-inflammatory diseases, making C5a inhibition an attractive therapeutic strategy.