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Michael Kirschfink - One of the best experts on this subject based on the ideXlab platform.
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The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via Complement Inhibition
Thrombosis and Haemostasis, 2012Co-Authors: Ilya Vinnikov, Khurrum Shahzad, Fabian Bock, Satish Ranjan, Juliane Wolter, Muhammed Kashif, Angelika Bierhaus, Peter Nawroth, Michael KirschfinkAbstract:SummaryCoagulation and Complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and Complement activation, in part through discrete domains. TM’s lectin like domain dampens Complement activation, while its EGF-like domains independently enhance activation of the anticoagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating Complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeDmice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeDmice. Complement Inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeDmice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p <0.001). In vitroTM’s lectin-like domain cell-autonomously prevented glucose-induced Complement activation on endothelial cells and –notably –on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeDmice, was reduced following Complement Inhibition with enoxaparin. The current study identifies a novel mechanism regulating Complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced Complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.
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Therapeutic Complement Inhibition: new developments.
Seminars in thrombosis and hemostasis, 2010Co-Authors: Woodruff Emlen, Michael KirschfinkAbstract:Activation of the Complement system significantly contributes to the pathogenesis of various acute and chronic inflammatory diseases. Current strategies to inhibit Complement include the replacement or substitution of endogenous soluble Complement inhibitors (e.g., C1 inhibitor [C1 inh], recombinant soluble Complement receptor 1, TP10), the administration of antibodies to block key proteins of the cascade reaction (e.g., C5) or to neutralize the action of the Complement-derived anaphylatoxins, or blockade of Complement receptors (e.g., C5aR, CD88). The recent approvals of anti-C5 for the treatment of paroxysmal nocturnal hemoglobinuria as well as of C1 inh for the treatment of hereditary angioedema beyond European countries have provided a resurgence of interest in the potential of Complement therapeutics for the treatment of disease.
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Strategies of therapeutic Complement Inhibition.
Molecular immunology, 2006Co-Authors: Tom E Mollnes, Michael KirschfinkAbstract:The involvement of Complement in the pathogenesis of a great number of partly life threatening diseases defines the importance to develop inhibitors which specifically interfere with its deleterious action. Endogenous soluble Complement-inhibitors, antibodies or low molecular weight antagonists, either blocking key proteins of the cascade reaction or neutralizing the action of the Complement-derived anaphylatoxins have successfully been tested in various animal models over the past years. Promising results consequently led to first clinical trials. This review is focused on different approaches for the development of inhibitors, on their site of action in the cascade, on possible indications for Complement Inhibition based on experimental animal data, and on potential side effects of such treatment.
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In vivo microscopy reveals that Complement Inhibition by C1‐esterase inhibitor reduces ischemia/reperfusion injury in the liver
Transplant International, 2000Co-Authors: Thorsten G. Lehmann, Michael Kirschfink, M Heger, S Münch, E KlarAbstract:Complement plays a decisive role in postischemic tissue injury, a process responsible for severe damage after organ ischemia. Several pathophysiologic mechanisms initiated upon reperfusion are mediated by Complement inducing microcirculatory disturbances. Here, we demonstrate the effects of Complement Inhibition using C1-esterase inhibitor (C1-INH) on microcirculation after liver ischemia by invivo microscopy (IVM). In rats, the left liver lobe was clamped for 70 min. C1-INH was given 1 min prior to reperfusion. Controls received Ringer's solution. IVM was performed 30–100 min after reperfusion. Non-perfused acini decreased and sinusoidal perfusion increased substantially after treatment. Leukocyte adherence to sinusoidal and venular endothelium was markedly reduced by C1-INH. Transaminases were significantly decreased by C1-INH. Our data obtained by IVM suggest that Complement activation is an early key event of ischemia/reperfusion injury. These observations demonstrate for the first time that reperfusion related microcirculatory disorders can be minimized by C1-INH. This compound should be evaluated in clinical application.
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Therapeutic Complement Inhibition
Multiple Organ Failure, 2000Co-Authors: Katrin Jurianz, Michael KirschfinkAbstract:Excessive Complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases, including ischemia/reperfusion injury, sepsis, and multiple organ failure syndrome. Current strategies to interfere with the deleterious action of Complement include the application of endogenous soluble Complement inhibitors (C1 inhibitor, recombinant soluble Complement receptor 1-rsCR1), administration of antibodies, blocking key proteins of the cascade reaction (e.g., C5), neutralizing the action of the Complement-derived anaphylatoxin C5a, or interfering with Complement receptor 3 (CR3, CD18/11b)-mediated adhesion of inflammatory cells to the vascular endothelium. Incorporation of membrane-bound Complement regulators (DAF-CD55, MCP-CD46, CD59) has provided a major step forward in protecting xenografts from hyperacute rejection. Numerous animal studies and first clinical trials strongly suggest that Complement Inhibition is a suitable novel therapeutic approach to preventing inflammatory disorders.
Robert Rieben - One of the best experts on this subject based on the ideXlab platform.
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ischemia reperfusion injury effect of simultaneous Inhibition of plasma cascade systems versus specific Complement Inhibition
Biochemical Pharmacology, 2014Co-Authors: Claudia Duehrkop, Robert RiebenAbstract:Ischemia/reperfusion injury (IRI) may occur from ischemia due to thrombotic occlusion, trauma or surgical interventions, including transplantation, with subsequent reestablishment of circulation. Time-dependent molecular and structural changes result from the deprivation of blood and oxygen in the affected tissue during ischemia. Upon restoration of blood flow a multifaceted network of plasma cascades is activated, including the Complement-, coagulation-, kinin-, and fibrinolytic system, which plays a major role in the reperfusion-triggered inflammatory process. The plasma cascade systems are therefore promising therapeutic targets for attenuation of IRI. Earlier studies showed beneficial effects through Inhibition of the Complement system using specific Complement inhibitors. However, pivotal roles in IRI are also attributed to other cascades. This raises the question, whether drugs, such as C1 esterase inhibitor, which regulate more than one cascade at a time, have a higher therapeutic potential. The present review discusses different therapeutic approaches ranging from specific Complement Inhibition to simultaneous Inhibition of plasma cascade systems for reduction of IRI, gives an overview of the plasma cascade systems in IRI as well as highlights recent findings in this field.
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Ischemia/reperfusion injury: effect of simultaneous Inhibition of plasma cascade systems versus specific Complement Inhibition.
Biochemical pharmacology, 2013Co-Authors: Claudia Duehrkop, Robert RiebenAbstract:Ischemia/reperfusion injury (IRI) may occur from ischemia due to thrombotic occlusion, trauma or surgical interventions, including transplantation, with subsequent reestablishment of circulation. Time-dependent molecular and structural changes result from the deprivation of blood and oxygen in the affected tissue during ischemia. Upon restoration of blood flow a multifaceted network of plasma cascades is activated, including the Complement-, coagulation-, kinin-, and fibrinolytic system, which plays a major role in the reperfusion-triggered inflammatory process. The plasma cascade systems are therefore promising therapeutic targets for attenuation of IRI. Earlier studies showed beneficial effects through Inhibition of the Complement system using specific Complement inhibitors. However, pivotal roles in IRI are also attributed to other cascades. This raises the question, whether drugs, such as C1 esterase inhibitor, which regulate more than one cascade at a time, have a higher therapeutic potential. The present review discusses different therapeutic approaches ranging from specific Complement Inhibition to simultaneous Inhibition of plasma cascade systems for reduction of IRI, gives an overview of the plasma cascade systems in IRI as well as highlights recent findings in this field.
Shaf Keshavjee - One of the best experts on this subject based on the ideXlab platform.
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A randomized, placebo-controlled trial of Complement Inhibition in ischemia-reperfusion injury after lung transplantation in human beings
The Journal of thoracic and cardiovascular surgery, 2005Co-Authors: Shaf Keshavjee, Robert D. Davis, Martin R. Zamora, M. De Perrot, G.a. PattersonAbstract:Objective Complement activation has been shown to play a significant role in ischemia-reperfusion injury after lung transplantation. TP-10 (soluble Complement receptor 1 inhibitor) inhibits the activation of Complement by inactivating C3a and C5a convertases. This was a clinical trial of TP-10 to reduce ischemia-reperfusion injury in lung transplantation. Methods In a randomized, double-blinded, multicenter, placebo-controlled trial, 59 patients from four lung transplant programs received TP-10 (10 mg/kg, n=28) or placebo (n = 31) before reperfusion. This dose achieved 90% Complement Inhibition for 24 hours, and activity had returned toward normal by 72 hours. Results At 24 hours, 14 of 28 patients in the TP-10 group (50%) were extubated, whereas only 6 of 31 patients in the placebo group (19%) were ( P = .01). The total times on the ventilator and in the intensive care unit both tended to be shorter in the TP-10 group, but these differences did not achieve statistical significance. Among patients requiring cardiopulmonary bypass (n = 5 in placebo group and n=7 in TP-10 group), the mean duration of mechanical ventilation was reduced by 11 days in the TP-10 group (10.6 ± 5.0 days vs 21.5 ± 5.9 days in placebo group, P = .2). Operative deaths, incidences of infection and rejection, and length of hospital stay were not significantly different between the two groups. Conclusions Short-term Complement Inhibition with TP-10 led to early extubation in a significantly higher proportion of lung transplant recipients. The effect of TP-10 was greater among patients undergoing cardiopulmonary bypass, with a large reduction in ventilator days. Complement Inhibition thus significantly decreases the duration of mechanical ventilation and could be useful in improving the outcome of lung transplant recipients.
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Effect of Complement Inhibition with soluble Complement receptor 1 on pig allotransplant lung function.
Transplantation, 1998Co-Authors: Andrew Pierre, Henry C. Marsh, Alexandre M. Xavier, Mingyao Liu, Stephen D. Cassivi, Thomas F. Lindsay, Arthur S. Slutsky, Shaf KeshavjeeAbstract:Background. Lung dysfunction after transplantation continues to be a significant clinical problem. Soluble Complement receptor 1 (sCR1) is a potent inhibitor of Complement activation. We evaluated the inhibitory effect of sCR1 on Complement activation and reperfusion injury in pig lung allografts. Methods. In a randomized and blinded study, left lung transplantation was performed in 13 pigs. Donor lungs were flushed and then stored for 30 hr at 4°C. Control pigs (n57) received saline, and the treatment group (n56) received 15 mg/kg sCR1 1 hr before reperfusion. One hour after reperfusion, the right pulmonary artery was clamped for 10 min to assess the function of the transplanted lung. Pulmonary function was assessed again on day 3. Results. Complement Inhibition was 93% in the sCR1 group and returned to baseline (8% Inhibition) after 3 days. There was a trend toward a higher partial pressure of oxygen at 1 hr in the sCR1 group compared with the control group (mean 6 SE: 408642 mmHg vs. 288669 mmHg, P50.19). Alveolar ventilation was better in the sCR1 group than in the control group (P50.01) at 1 hr. Mixed venous saturation was significantly lower in the control group at both 1 hr (P50.02) and 3 days (P50.001). The wet/dry weight of the lung tissue was lower in the sCR1 group compared with the control group on day 3 (P
Ahvie Herskowitz - One of the best experts on this subject based on the ideXlab platform.
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Neutrophil adhesion and Complement Inhibition prolongs survival of cardiac xenografts in discordant species.
Transplantation, 1994Co-Authors: Kenton J. Zehr, Ahvie Herskowitz, P. C. Lee, Pankaj Kumar, A. M. Gillinov, William A. BaumgartnerAbstract:Hyperacute rejection results in rapid destruction of a discordant cardiac xenograft and is characterized by antibody deposition, Complement activation, and platelet aggregation. The importance of neutrophils is unclear. Complement Inhibition prolongs discordant cardiac xenograft survival. The purpose of this experiment was to determine the relative roles of Complement and neutrophils. Selective Inhibition of Complement and neutrophil adhesion was used in a guinea pig-to-Lewis rat cardiac heterotopic xenotransplant model
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Complement Inhibition With Soluble Complement Receptor Type 1 in Cardiopulmonary Bypass
The Annals of thoracic surgery, 1993Co-Authors: A. Marc Gillinov, William A. Baumgartner, Patrick A. Devaleria, Jerry A. Winkelstein, Ian C. Wilson, William E. Curtis, David R. Shaw, C.grace Yeh, Alfred R. Rudolph, Ahvie HerskowitzAbstract:Although Complement activation during cardiopulmonary bypass (CPB) is well documented, its pathogenic role in postperfusion organ injury is unproven. In this study, soluble human Complement receptor type 1 (sCR1), a potent inhibitor of Complement activation, was used to determine the contribution of Complement activation to pulmonary injury in a porcine model of CPB. In vitro experiments demonstrated that sCR1 inhibits both classic and alternative Complement pathways in the pig. Seven control piglets and 6 piglets treated with sCR1 (12 mg/kg intravenously) underwent 2 hours of hypothermic (28 degrees C) CPB followed by 2 hours of observation. In control piglets, total hemolytic Complement activity and functional activities of C3 and C5 declined to 61.3%, 67.8%, and 61.4% of prebypass values, respectively, after 2 hours of CPB. Plasma from animals treated with sCR1 had virtually no hemolytic activity (total hemolytic Complement activity < 5% of baseline), demonstrating effective Complement Inhibition. Similar degrees of neutropenia developed in the two groups during CPB, and there was no difference in post-CPB lung tissue myeloperoxidase level. Two hours after CPB, pulmonary vascular resistance increased 338% in control piglets but only 147% in piglets pretreated with sCR1 (p < 0.05); the alveolar-arterial gradient was not significantly different between controls (331 +/- 52 mm Hg) and piglets receiving sCR1 (290 +/- 85 mm Hg). Histologic examination revealed similar degrees of pulmonary edema in both groups. These data constitute direct evidence that Complement activation plays a pathogenic role in lung injury after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)
Thorsten G. Lehmann - One of the best experts on this subject based on the ideXlab platform.
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In vivo microscopy reveals that Complement Inhibition by C1‐esterase inhibitor reduces ischemia/reperfusion injury in the liver
Transplant International, 2000Co-Authors: Thorsten G. Lehmann, Michael Kirschfink, M Heger, S Münch, E KlarAbstract:Complement plays a decisive role in postischemic tissue injury, a process responsible for severe damage after organ ischemia. Several pathophysiologic mechanisms initiated upon reperfusion are mediated by Complement inducing microcirculatory disturbances. Here, we demonstrate the effects of Complement Inhibition using C1-esterase inhibitor (C1-INH) on microcirculation after liver ischemia by invivo microscopy (IVM). In rats, the left liver lobe was clamped for 70 min. C1-INH was given 1 min prior to reperfusion. Controls received Ringer's solution. IVM was performed 30–100 min after reperfusion. Non-perfused acini decreased and sinusoidal perfusion increased substantially after treatment. Leukocyte adherence to sinusoidal and venular endothelium was markedly reduced by C1-INH. Transaminases were significantly decreased by C1-INH. Our data obtained by IVM suggest that Complement activation is an early key event of ischemia/reperfusion injury. These observations demonstrate for the first time that reperfusion related microcirculatory disorders can be minimized by C1-INH. This compound should be evaluated in clinical application.
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Complement Inhibition by soluble Complement receptor type 1 improves microcirculation after rat liver transplantation.
Transplantation, 1998Co-Authors: Thorsten G. Lehmann, Michael Kirschfink, Thomas A. Koeppel, Martha-maria Gebhard, Christian Herfarth, Gerd Otto, Stefan PostAbstract:BACKGROUND Recent observations provide evidence that Complement is involved in the pathophysiology of ischemia/reperfusion injury. In this study, we assessed the impact of Complement Inhibition on hepatic microcirculation and graft function using a rat model of liver transplantation. METHODS Arterialized orthotopic liver transplantation was performed in Lewis rats after cold preservation (University of Wisconsin solution, 4 degrees C, 24 h). Eight animals received the physiological Complement regulator soluble Complement receptor type 1 (sCR1) intravenously 1 min before reperfusion. Controls received Ringer's solution (n=8). Microvascular perfusion, leukocyte adhesion, and Kupffer cell phagocytic activity were studied 30-100 min after reperfusion by in vivo microscopy. RESULTS Microvascular perfusion in hepatic sinusoids was improved in the sCR1 group (87+/-0.7% vs. 50+/-1%; P < 0.001). The number of adherent leukocytes was reduced in sinusoids (68.3+/-4.7 vs. 334.1+/-15.8 [adherent leukocytes per mm < or = liver surface]; P < 0.001) and in postsinusoidal venules after sCR1 treatment (306.6+/-21.8 vs. 931.6+/-55.9 [adherent leukocytes per mm < or = endothelial surface]; P < 0.001). Kupffer cell phagocytic activity was decreased in the sCR1 group compared to controls. Postischemic bile production reflecting hepatocellular function was increased by almost 200% (P = 0.004) after Complement Inhibition. Plasmatic liver enzyme activity was decreased significantly upon sCR1 treatment, indicating reduced parenchymal cell injury. CONCLUSIONS Our results provide further evidence that the Complement system plays a decisive role in hepatic ischemia/reperfusion injury. We conclude that Complement Inhibition by sCR1 represents an effective treatment to prevent reperfusion injury in liver transplantation.